Updated May, 2016

Studies examining the role of a gluten and casein free diet in autism continue to be conflicting, with the general concensus that the diet may be very helpful in a subset of, but not all patients. International recognition of the role of the gut microbiome (intestinal bacteria) has increased significantly, with a vast number of supportive studies appearing from 2015 onward.

Neuroscience. 2016 Jun 2;324:131-9. doi: 10.1016/j.neuroscience.2016.03.013. Epub 2016 Mar 8.

The microbiota-gut-brain axis and its potential therapeutic role in autism spectrum disorder.

Li Q1, Zhou JM2.

Department of Central Laboratory, Shanghai Children's Hospital, Shanghai Jiaotong University, Shanghai, China.

Department of Central Laboratory, Shanghai Children's Hospital, Shanghai Jiaotong University, Shanghai, China. Electronic address: junmei_zhou@139.com.

Abstract

Autism spectrum disorder (ASD) is a series of neurodevelopmental disorders that are characterized by deficits in both social and cognitive functions. Although the exact etiology and pathology of ASD remain unclear, a disorder of the microbiota-gut-brain axis is emerging as a prominent factor in the generation of autistic behaviors. Clinical studies have shown that gastrointestinal symptoms and compositional changes in the gut microbiota frequently accompany cerebral disorders in patients with ASD. A disturbance in the gut microbiota, which is usually induced by a bacterial infection or chronic antibiotic exposure, has been implicated as a potential contributor to ASD. The bidirectional microbiota-gut-brain axis acts mainly through neuroendocrine, neuroimmune, and autonomic nervous mechanisms. Application of modulators of the microbiota-gut-brain axis, such as probiotics, helminthes and certain special diets, may be a promising strategy for the treatment of ASD. This review mainly discusses the salient observations of the disruptions of the microbiota-gut-brain axis in the pathogenesis of ASD and reveals its potential therapeutic role in autistic deficits.

Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

PMID: 26964681 [PubMed - in process]

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Nutrition.  2016 Apr;32(4):474-7. doi: 10.1016/j.nut.2015.10.019. Epub 2015 Dec 2.

Abnormal fatty acids in Canadian children with  autism.

Jory J1.  1Guelph, Ontario N1G 2X6, Canada. Electronic address: jjory@uoguelph.ca.

Abstract

OBJECTIVE:

Fatty acids are critical for pediatric neurodevelopment and are abnormal in  autism, although prior studies have demonstrated conflicting results and methodological differences. To our knowledge, there are no published data on fatty acid in Canadian children with  autism. The aim of this study was to investigate red blood cell and serum fatty acid status to identify whether abnormalities exist in Canadian children with  autism, and to enhance future cross-study comparison.

METHODS:

Eleven Canadian children with  autism  (3 girls, 8 boys; age 3.05  ±  0.79  y) and 15 controls (9 girls, 6 boys; age 3.87  ±  1.06  y) met inclusion criteria, which included prior Diagnostic and Statistical Manual diagnosis of  autism  spectrum  disorder, no recent medication or supplements, no specialty diets, and no recent illness.

RESULTS:

The children with  autism  demonstrated lower red blood cell docosahexaenoic acid (P  <  0.0003), eicosapentaenoic acid (P  <  0.03), arachidonic acid (P  <  0.002), and ω-3/ω-6 ratios (P  <  0.001). They also demonstrated lower serum docosahexaenoic acid (P  <  0.02), arachidonic acid (P  <  0.05), and linoleic acid (P  <  0.02) levels.

CONCLUSIONS:

Fatty acids in both serum and red blood cells were abnormal in this small group of Canadian children with  autism  than in controls, underlining a need for larger age- and sex-matched investigations in this community. A potential role for fatty acid abnormalities within the complex epigenetic etiology of  autism  is proposed in relation to emerging understanding of relationships between cobalamin metabolism, gut microbiota, and propionic acid production.

Copyright © 2016 Elsevier Inc. All rights reserved.

PMID:  26746679  [PubMed - in process]

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Mycopathologia.  2016 Feb;181(1-2):1-7. doi: 10.1007/s11046-015-9949-3. Epub 2015 Oct 6.

Microbiota-Gut-Brain Axis: Yeast Species Isolated from Stool Samples of Children with Suspected or DiagnosedAutism  Spectrum Disorders and In Vitro Susceptibility Against Nystatin and Fluconazole.

Kantarcioglu AS1,2,  Kiraz N3,  Aydin A4.

1  Department of Medical Microbiology, Istanbul University, Istanbul, Turkey. mycologist1@yahoo.com.
2  Deep Mycosis Laboratory, Department of Microbiology and Clinical Microbiology, Cerrahpaşa Medical Faculty, Istanbul University, 34098, Cerrahpaşa, Istanbul, Turkey. mycologist1@yahoo.com.
3  Department of Medical Microbiology, Istanbul University, Istanbul, Turkey.
4  Department of Pediatrics Metabolic Diseases, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey.

Abstract

Autism  spectrum  disorder  (ASD) is a general term for a group of complex neurodevelopmental disorders of brain development that limits a person's ability to function normally. Etiology has not been clearly defined up to date. However, gut  microbiota  and the bidirectional communication between the gastrointestinal tract and brain, the so-called  microbiota-gut-brain axis, are hypothesized, which may be involved in the etiology of several mental disorders. Recent reports suggest that Candida, particularly Candida albicans, growth in intestines may cause lower absorption of carbohydrates and minerals and higher toxin levels which are thought to contribute  autistic  behaviors. The aim of this study was to identify the 3-year deposited yeasts isolated from stool samples of children with diagnosed or suspected ASD and to determine in vitro activity of nystatin and fluconazole against these isolates using Clinical Laboratory Standards Institute M27-A3 guidelines. A 17-year retrospective assessment was also done using our laboratory records. Among the species identified [in autistic subjects], intrinsically fluconazole-resistant Candida krusei (19.8 %) and Candida glabrata (14.8 %) with elevated MICs were remarkable. Overall, C. albicans (57.4 %) was the most commonly isolated species in 17 years. The species identification and/or antifungal susceptibility tests have to be performed using the strain isolated from stool sample, to select the appropriate antifungal agent, if antimycotic therapy is needed.

PMID:  26442855

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Biomed Res Int.  2016;2016:9485412. doi: 10.1155/2016/9485412. Epub 2016 Mar 30.

Urinary 3-(3-Hydroxyphenyl)-3-hydroxypropionic Acid, 3-Hydroxyphenylacetic Acid, and 3-Hydroxyhippuric Acid Are Elevated in Children with  Autism  Spectrum Disorders.

Xiong X1,  Liu D1,  Wang Y1,  Zeng T1,  Peng Y1.

Maternal and Child Health Care Hospital of Hunan Province, Changsha 410008, China.

Abstract

Autism  spectrum disorders (ASDs) are a group of mental illnesses highly correlated with gut  microbiota. Recent studies have shown that some abnormal aromatic metabolites in  autism  patients are presumably derived from overgrown Clostridium species in gut, which may be used for diagnostic purposes. In this paper, a GC/MS based metabolomic approach was utilized to seek similar biomarkers by analyzing the urinary information in 62 ASDs patients compared with 62 non-ASDs controls in China, aged 1.5-7. Three compounds identified as 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), 3-hydroxyphenylacetic acid (3HPA), and 3-hydroxyhippuric acid (3HHA) were found in higher concentrations inautistic  children than in the controls (p < 0.001). After oral vancomycin treatment, urinary excretion of HPHPA (p < 0.001), 3HPA (p < 0.005), and 3HHA (p < 0.001) decreased markedly, which indicated that these compounds may also be from gut Clostridium species. The sensitivity and specificity of HPHPA, 3HPA, and 3HHA were evaluated by receiver-operating characteristic (ROC) analysis. The specificity of each compound for ASDs was very high (>96%). After two-regression analysis, the optimal area under the curve (AUC, 0.962), sensitivity (90.3%), and specificity (98.4%) were obtained by ROC curve of Prediction probability based on the three metabolites. These findings demonstrate that the measurements of the three compounds are strong predictors of ASDs and support the potential clinical utility for identifying a subgroup of ASDs subjects.

PMID:  27123458  [PubMed - in process]  PMCID:  PMC4829699  Free PMC Article

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World J Gastroenterol. 2016 Jan 7;22(1):361-8. doi: 10.3748/wjg.v22.i1.361.

Gut microbiota in autism and mood disorders.

Mangiola F1, Ianiro G1, Franceschi F1, Fagiuoli S1, Gasbarrini G1, Gasbarrini A1.
1Francesca Mangiola, Gianluca Ianiro, Francesco Franceschi, Antonio Gasbarrini, Catholic University, School of Medicine, 00168 Rome, Italy.

Abstract

The hypothesis of an important role of gut microbiota in the maintenance of physiological state into the gastrointestinal (GI) system is supported by several studies that have shown a qualitative and quantitative alteration of the intestinal flora in a number of gastrointestinal and extra-gastrointestinal diseases. In the last few years, the importance of gut microbiota impairment in the etiopathogenesis of pathology such as autism, dementia and mood disorder, has been raised. The evidence of the inflammatory state alteration, highlighted in disorders such as schizophrenia, major depressive disorder and bipolar disorder, strongly recalls the microbiota alteration, highly suggesting an important role of the alteration of GI system also in neuropsychiatric disorders. Up to now, available evidences display that the impairment of gut microbiota plays a key role in the development of autism and mood disorders. The application of therapeutic modulators of gut microbiota to autism and mood disorders has been experienced only in experimental settings to date, with few but promising results. A deeper assessment of the role of gut microbiota in the development of autism spectrum disorder (ASD), as well as the advancement of the therapeutic armamentarium for the modulation of gut microbiota is warranted for a better management of ASD and mood disorders.

PMID: 26755882 [PubMed - in process] PMCID: PMC4698498 Free PMC Article

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Nutr Metab (Lond). 2015 Dec 9;12:54. doi: 10.1186/s12986-015-0050-1. eCollection 2015.

Epigenetic effects of casein-derived opioid peptides in SH-SY5Y human neuroblastoma cells.

Trivedi MS1, Hodgson NW2, Walker SJ3, Trooskens G4, Nair V1, Deth RC1.

1Department of Pharmaceutical Sciences, Nova Southeastern University, Rm # 3103, HPD building, Fort Lauderdale, FL USA.

2Department of Molecular and Cellular Biology, Harvard Medical School, Boston, MA USA.

3Wake Forest Institute for Regenerative Medicine, Wake Forest University Health Sciences, Winston Salem, NC USA.

4Department of Mathematical Modelling, Statistics and Bioinformatics, University of Ghent, Ghent, Belgium.

Abstract

BACKGROUND:

Casein-free, gluten-free diets have been reported to mitigate some of the inflammatory gastrointestinal and behavioral traits associated with autism, but the mechanism for this palliative effect has not been elucidated. We recently showed that the opioid peptide beta-casomorphin-7, derived from bovine (bBCM7) milk, decreases cysteine uptake, lowers levels of the antioxidant glutathione (GSH) and decreases the methyl donor S-adenosylmethionine (SAM) in both Caco-2 human GI epithelial cells and SH-SY5Y human neuroblastoma cells. While human breast milk can also release a similar peptide (hBCM-7), the bBCM7 and hBCM-7 vary greatly in potency; as the bBCM-7 is highly potent and similar to morphine in it's effects. Since SAM is required for DNA methylation, we wanted to further investigate the epigenetic effects of these food-derived opioid peptides. In the current study the main objective was to characterize functional pathways and key genes responding to DNA methylation effects of  food-derived opioid peptides.

METHODS:

SH-SY5Y neuroblastoma cells were treated with 1  μM hBCM7 and bBCM7 and RNA and DNA were isolated after 4  h with or without treatment. Transcriptional changes were assessed using a microarray approach and CpG methylation status was analyzed at 450,000 CpG sites. Functional implications from both endpoints were evaluated via Ingenuity Pathway Analysis 4.0 and KEGG pathway analysis was performed to identify biological interactions between transcripts that were significantly altered at DNA methylation or transcriptional levels (p  .05, FDR <0.1).

RESULTS:

Here we show that hBCM7 and bBCM7, as well as morphine, cause epigenetic changes affecting gene pathways related to gastrointestinal disease and inflammation. These epigenetic consequences exhibited the same potency order as opiate inhibition of cysteine uptake insofar as hBCM7 was less potent than bBCM7, which was less potent than morphine.

CONCLUSION:

Our findings indicate that epigenetic effects of milk-derived opiate peptides may contribute to GI dysfunction and inflammation in sensitive individuals. While the current study was performed using SH-SY5Y neuronal cellular models, similar actions on other cells types might combine to cause symptoms of intolerance. These actions may provide a potential contributing mechanism for the beneficial effects of a casein-free diet in alleviating gastrointestinal symptoms in neurological conditions including autism and other conditions. Lastly, our study also contributes to the evolving awareness of a "gut-brain connection".

PMID: 26664459 [PubMed] PMCID: PMC4673759 Free PMC Article

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Nutrients.

2015 Jul 8;7(7):5532-9. doi: 10.3390/nu7075235.

Gluten Psychosis: Confirmation of a New Clinical Entity.

Lionetti E1, Leonardi S2, Franzonello C3, Mancardi M4, Ruggieri M5, Catassi C6,7.

1  Department of Pediatrics, University of Catania, Via S. Sofia 78, 95124 Catania, Italy. elenalionetti@inwind.it.

2 Department of Pediatrics, University of Catania, Via S. Sofia 78, 95124 Catania, Italy. leonardi@unict.itDepartment of Pediatrics,

3 University of Catania, Via S. Sofia 78, 95124 Catania, Italy. franzo.chiara@gmail.com.

4  Pediatric Neuro-Psychiatric Unit, G. Gaslini Institute, Via Gerolamo Gaslini 5, 16147 Genova, Italy. margheritamancardi@ospedale-gaslini.ge.it.

5  Department of Pediatrics, University of Catania, Via S. Sofia 78, 95124 Catania, Italy. m.ruggieri@unict.it.

6  Department of Pediatrics, Marche Polytechnic University, Ancona, Via Corridoni, 11, 60123 Ancona, Italy. c.catassi@univpm.it.

7  The Division of Paediatric Gastroenterology and Nutrition and Center for Celiac Research, MassGeneral Hospital for Children, 55 Fruit Street, Boston, MA 02114, USA. c.catassi@univpm.it.

Abstract

Non-celiac gluten sensitivity (NCGS) is a syndrome diagnosed in patients with symptoms that respond to removal of gluten from the diet, after celiac disease and wheat allergy have been excluded. NCGS has been related to neuro-psychiatric disorders, such as autism, schizophrenia and depression. A singular report of NCGS presenting with hallucinations has been described in an adult patient. We report a pediatric case of a psychotic disorder clearly related to NCGS and investigate the causes by a review of literature. The pathogenesis of neuro-psychiatric manifestations of NCGS is unclear. It has been hypothesized that: (a) a "leaky gut" allows some gluten peptides to cross the intestinal membrane and the blood brain barrier, affecting the endogenous opiate system and neurotransmission; or (b) gluten peptides may set up an innate immune response in the brain similar to that described in the gut mucosa, causing exposure from neuronal cells of a transglutaminase primarily expressed in the brain. The present case-report confirms that psychosis may be a manifestation of NCGS, and may also involve children; the diagnosis is difficult with many cases remaining undiagnosed. Well-designed prospective studies are needed to establish the real role of gluten as a triggering factor in neuro-psychiatric disorders.

PMID: 26184290 [PubMed - indexed for MEDLINE] PMCID: PMC4517012   Free PMC Article

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Brain Behav Immun. 2015 Feb;44:148-58. doi: 10.1016/j.bbi.2014.09.009. Epub 2014 Sep 20.

IgG dynamics of dietary antigens point to cerebrospinal fluid barrier or flow dysfunction in first-episode schizophrenia.

Severance EG1, Gressitt KL2, Alaedini A3, Rohleder C4, Enning F5, Bumb JM4, Müller JK4, Schwarz E4, Yolken RH2, Leweke FM4.

Stanley Division of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Blalock 1105, Baltimore, MD 21287-4933, USA. Electronic address: eseverance@jhmi.edu.

Stanley Division of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Blalock 1105, Baltimore, MD 21287-4933, USA.

Department of Medicine, Columbia University Medical Center, 1130 Saint Nicholas Ave., ICRC 901B, New York, NY 10032, USA.

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Department of Psychosomatics and Psychotherapeutic Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Abstract

Schizophrenia is a complex brain disorder that may be accompanied by idiopathic inflammation. Classic central nervous system (CNS) inflammatory disorders such as viral encephalitis or multiple sclerosis can be characterized by incongruent serum and cerebrospinal fluid (CSF) IgG due in part to localized intrathecal synthesis of antibodies. The dietary antigens, wheat gluten and bovine milk casein, can induce a humoral immune response in susceptible individuals with schizophrenia, but the correlation between the food-derived serological and intrathecal IgG response is not known. Here, we measured IgG to wheat gluten and bovine milk casein in matched serum and CSF samples from 105 individuals with first-episode schizophrenia (n=75 antipsychotic-naïve), and 61 controls. We found striking correlations in the levels of IgG response to dietary proteins between serum and CSF of schizophrenia patients, but not controls (schizophrenia, R(2)=0.34-0.55, p⩽0.0001; controls R(2)=0.05-0.06, p>0.33). A gauge of blood-CSF barrier permeability and CSF flow rate, the CSF-to-serum albumin ratio, was significantly elevated in cases compared to controls (p⩽0.001-0.003). Indicators of intrathecal IgG production, the CSF IgG index and the specific Antibody Index, were not significantly altered in schizophrenia compared to controls. Thus, the selective diffusion of bovine milk casein and wheat gluten antibodies between serum and CSF in schizophrenia may be the function of a low-level anatomical barrier dysfunction or altered CSF flow rate, which may be transient in nature.

Copyright © 2014 Elsevier Inc. All rights reserved.

PMID: 25241021 [PubMed - indexed for MEDLINE] PMCID: PMC4275312 Free PMC Article

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Med Hypotheses.  2015 Apr;84(4):395-401. doi: 10.1016/j.mehy.2015.01.027. Epub 2015 Jan 28.

An agent-based modeling framework for evaluating hypotheses on risks for developing  autism: effects of the gut microbial environment.

Weston B1,  Fogal B1,  Cook D1,  Dhurjati P2.

University of Delaware, Department of Chemical and Biomolecular Engineering, 150 Academy Street, Newark, DE 19716, USA. Electronic address: dhurjati@udel.edu.

Abstract

The number of cases diagnosed with  Autism  Spectrum Disorders is rising at an alarming rate with the Centers for Disease Control estimating the 2014 incidence rate as 1 in 68. Recently, it has been hypothesized that gut bacteria may contribute to the development of  autism. Specifically, the relative balances between the inflammatory microbes clostridia and desulfovibrio and the anti-inflammatory microbe bifidobacteria may become destabilized prior to  autism  development. The imbalance leads to a leaky gut, characterized by a more porous epithelial membrane resulting in microbial toxin release into the blood, which may contribute to brain inflammation and  autism  development. To test how changes in population dynamics of the gut  microbiome  may lead to the imbalanced microbial populations associated with  autism  patients, we constructed a novel agent-based model of clostridia, desulfovibrio, and bifidobacteria population interactions in the gut. The model demonstrates how changing physiological conditions in the gut can affect the population dynamics of the  microbiome. Simulations using our agent-based model indicate that despite large perturbations to initial levels of bacteria, the populations robustly achieve a single steady-state given similar gut conditions. These simulation results suggests that disturbance such as a prebiotic or antibiotic treatment may only transiently affect the gut  microbiome. However, sustained prebiotic treatments may correct low population counts of bifidobacteria. Furthermore, our simulations suggest that clostridia growth rate is a key determinant of risk of  autism  development. Treatment of high-risk infants with supra-physiological levels of lysozymes may suppress clostridia growth rate, resulting in a steep decrease in the clostridia population and therefore reduced risk of  autism  development.

Copyright © 2015 Elsevier Ltd. All rights reserved. PMID:  25670416  [PubMed - indexed for MEDLINE]

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Gut Microbes. 2015;6(3):207-13. doi: 10.1080/19490976.2015.1035855.

Autism spectrum disorders and intestinal microbiota.

De Angelis M1, Francavilla R, Piccolo M, De Giacomo A, Gobbetti M.

Author information

1. 1Department of Soil; Plant and Food Sciences; University of Bari Aldo Moro ; Bari , Italy.
   

Abstract

Through extensive microbial-mammalian co-metabolism, the intestinal microbiota have evolved to exert a marked influence on health and disease via gut-brain-microbiota interactions. In this addendum, we summarize the findings of our recent study on the fecal microbiota and metabolomes of children with pervasive developmental disorder-not otherwise specified (PDD-NOS) or autism (AD) compared with healthy children (HC). Children with PDD-NOS or AD have altered fecal microbiota and metabolomes (including neurotransmitter molecules). We hypothesize that the degree of microbial alteration correlates with the severity of the disease since fecal microbiota and metabolomes alterations were higher in children with PDD-NOS and, especially, AD compared to HC. Our study indicates that the levels of free amino acids (FAA) and volatile organic compounds (VOC) differ in AD subjects compared to children with PDD-NOS, who are more similar to HC. Finally, we propose a new perspective on the implications for the interaction between intestinal microbiota and AD.

PMID: 25835343 [PubMed - indexed for MEDLINE] PMCID: PMC4616908 

Free PMC Article

Microb Ecol Health Dis. 2015 May 7;26:27458. doi: 10.3402/mehd.v26.27458. eCollection 2015.

Gastrointestinal dysfunction in autism spectrum disorder: the role of the mitochondria and the entericmicrobiome.

Frye RE1,2, Rose S1,3, Slattery J1,3, MacFabe DF4.

1. 1.Autism Research Program, Arkansas Children's Hospital Research Institute, Little Rock, AR, USA.
   

2. 2.Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA; REFrye@uams.edu.
   

3. 3.Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
   

4. 4.Kilee Patchell-Evans Autism Research Group, Division of Developmental Disabilities, Departments of Psychology and Psychiatry, University of Western Ontario, London, ON, Canada.
   

Abstract

Autism spectrum disorder (ASD) affects a significant number of individuals worldwide with the prevalence continuing to grow. It is becoming clear that a large subgroup of individuals with ASD demonstrate abnormalities in mitochondrial function as well as gastrointestinal (GI) symptoms. Interestingly, GI disturbances are common in individuals with mitochondrial disorders and have been reported to be highly prevalent in individuals with co-occurring ASD and mitochondrial disease. The majority of individuals with ASD and mitochondrial disorders do not manifest a primary genetic mutation, raising the possibility that their mitochondrial disorder is acquired or, at least, results from a combination of genetic susceptibility interacting with a wide range of environmental triggers. Mitochondria are very sensitive to both endogenous and exogenous environmental stressors such as toxicants, iatrogenic medications, immune activation, and metabolic disturbances. Many of these same environmental stressors have been associated with ASD, suggesting that the mitochondria could be the biological link between environmental stressors and neurometabolic abnormalities associated with ASD. This paper reviews the possible links between GI abnormalities, mitochondria, and ASD. First, we review the link between GI symptoms and abnormalities in mitochondrial function. Second, we review the evidence supporting the notion that environmental stressors linked to ASD can also adversely affect both mitochondria and GI function. Third, we review the evidence that enteric bacteria that are overrepresented in children with ASD, particularly Clostridia spp., produce short-chain fatty acid metabolites that are potentially toxic to the mitochondria. We provide an example of this gut-brain connection by highlighting the propionic acid rodent model of ASD and the clinical evidence that supports this animal model. Lastly, we discuss the potential therapeutic approaches that could be helpful for GI symptoms in ASD and mitochondrial disorders. To this end, this review aims to help better understand the underlying pathophysiology associated with ASD that may be related to concurrent mitochondrial and GI dysfunction.

PMID: 25956238 [PUBMED] PMCID: PMC4425813 

Free PMC Article

J Nutr Biochem. 2014 Oct;25(10):1011-8. doi: 10.1016/j.jnutbio.2014.05.004. Epub 2014 Jun 6.

Food-derived opioid peptides inhibit cysteine uptake with redox and epigenetic consequences.

Trivedi MS1, Shah JS1, Al-Mughairy S1, Hodgson NW1, Simms B1, Trooskens GA2, Van Criekinge W2, Deth RC3.

Author information

1. 11Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA.
   

2. 22Department of Mathematical Modelling, Statistics and Bioinformatics, Faculty of Bioscience Engineering, Ghent University, Ghent 9000, Belgium.
   

3. 33Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA. Electronic address: r.deth@neu.edu.
   

Abstract

Dietary interventions like gluten-free and casein-free diets have been reported to improve intestinal, autoimmune and neurological symptoms in patients with a variety of conditions; however, the underlying mechanism of benefit for such diets remains unclear. Epigenetic programming, including CpG methylation and histone modifications, occurring during early postnatal development can influence the risk of disease in later life, and such programming may be modulated by nutritional factors such as milk and wheat, especially during the transition from a solely milk-based diet to one that includes other forms of nutrition. The hydrolytic digestion of casein (a major milk protein) and gliadin (a wheat-derived protein) releases peptides with opioid activity, and in the present study, we demonstrate that these food-derived proline-rich opioid peptides modulate cysteine uptake in cultured human neuronal and gastrointestinal (GI) epithelial cells via activation of opioid receptors. Decreases in cysteine uptake were associated with changes in the intracellular antioxidant glutathione and the methyl donor S-adenosylmethionine. Bovine and human casein-derived opioid peptides increased genome-wide DNA methylation in the transcription start site region with a potency order similar to their inhibition of cysteine uptake. Altered expression of genes involved in redox and methylation homeostasis was also observed. These results illustrate the potential of milk- and wheat-derived peptides to exert antioxidant and epigenetic changes that may be particularly important during the postnatal transition from placental to GI nutrition. Differences between peptides derived from human and bovine milk may contribute to developmental differences between breastfed and formula-fed infants. Restricted antioxidant capacity, caused by wheat- and milk-derived opioid peptides, may predispose susceptible individuals to inflammation and systemic oxidation, partly explaining the benefits of gluten-free or casein-free diets.

Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

PMID: 25018147 [PubMed - indexed for MEDLINE] PMCID: PMC4157943 Free PMC Article

Nutr Res Rev. 2014 Dec;27(2):199-214. doi: 10.1017/S0954422414000110. Epub 2014 Jul 8.

Autism and nutrition: the role of the gut-brain axis.

van De Sande MM1, van Buul VJ1, Brouns FJ1.

Author information

1. 1Maastricht University, Nutrition, Toxicology and Metabolism Research Institute (NUTRIM), Faculty of Health, Medicine and Life Sciences (FHML), Department of Human Biology,PO Box 616,6200MD,Maastricht,The Netherlands.
   

Abstract

Autism spectrum disorder (ASD) is characterised by deficits in the ability to socialise, communicate and use imagination, and displays of stereotypical behaviour. It is widely accepted that ASD involves a disorder in brain development. However, the real causes of the neurodevelopmental disorders associated with ASD are not clear. In this respect, it has been found that a majority of children with ASD display gastrointestinal symptoms, and an increased intestinal permeability. Moreover, large differences in microbiotic composition between ASD patients and controls have been reported. Therefore, nutrition-related factors have been hypothesised to play a causal role in the aetiology of ASD and its symptoms. Through a review of the literature, it was found that abnormalities in carbohydrate digestion and absorption could explain some of the gastrointestinal problems observed in a subset of ASD patients, although their role in the neurological and behavioural problems remains uncertain. In addition, the relationship between an improved gut health and a reduction of symptoms in some patients was evaluated. Recent trials involving gluten-free diets, casein-free diets, and pre- and probiotic, and multivitamin supplementation show contradictive but promising results. It can be concluded that nutrition and other environmental influences might trigger an unstable base of genetic predisposition, which may lead to the development of autism, at least in a subset of ASD patients. Clear directions for further research to improve diagnosis and treatment for the different subsets of the disorder are provided.

Clinical features suggesting autism spectrum disorder as a manifestation of non-celiac gluten sensitivity

L. Alonso Canal to , , , Isasi C. Zaragoza b , I. Colmenero White c , MJ Martínez Gómezd , J. Arcas Martínez and

to Service Pediatric Gastroenterology, Hospital Rey Juan Carlos, Mostoles, Madrid, Spain

b Department of Rheumatology, Hospital Puerta de Hierro, Majadahonda, Madrid, Spain

c Department of Pathology, University Children 's Hospital Child Jesus, Madrid, Spain

d Service Pediatric Gastroenterology and Nutrition, Children 's Hospital Universitario Niño Jesús, Madrid, Spain

and Department of Pediatric Neurology, Children 's Hospital La Paz, Madrid, Spain

Received December 2, 2013, Accepted February 17, 2014

[TRANSLATED FROM SPANISH:]

Editor:

The ASDs are a group of neurodevelopmental disorders characterized by qualitative alterations, more or less serious, in domains such as reciprocal social interaction, communication and language, and the symbolic and imaginative activity, and the presence of a restricted interests and repetitive and stereotyped behaviors repertoire 1 . Asperger syndrome is a subtype of such disorders but less serious (high level of functioning) 1 . Its prevalence appears to be increasing.

The celiac gluten sensitivity not (SGNC) is defined within the diseases related to gluten, a clinical picture compatible with celiac disease (CD) and response to gluten - free diet, in theabsence of diagnostic criteria of EC. That is, anti-tissue transglutaminase negative antibodies without villous atrophy in the duodenal biopsy 2 . The SGNC is well described in adults, but their presence in children is an emerging and controversial issue, having already reportedcases in March .

Autism spectrum symptoms associated with celiac disease and has been described in connection with SGNC 4-6 . In these patients it has seen an increase in intestinal permeability (and gliadin IgG levels native) that could imply an alteration in the endogenous opioid system and in neurotransmission 6.7 . The usefulness of dietary gluten and casein in these patients has been the subject of study and debate 6.7 . Today it is argued that there is insufficient scientific evidence to support 8 .

We report the case of a child of 4 years. By unconfirmed diagnosis of intolerance to cow's milk protein, was restricted diet milk from breastfeeding. He was diagnosed from 2 years of conduct disorder with features suggestive of autism spectrum disorder. He had withdrawn behavior, prone to isolation and refusal to play in a group. Alternating episodes of "intense tantrums" with other passivity and inability showed when expressing their emotions.Sometimes he manifested obsessive behaviors. also he had clumsiness with frequent falls and limb weakness. He also had severe fatigue, weight development retardation, diarrhea alternating with periods of constipation and bloating. The analytical objectified iron deficiency.Celiac disease was suspected and ruled by the repeated negativity of anti-transglutaminase antibodies. Her mother had been diagnosed with SGNC by clinical symptoms of fibromyalgia, chronic fatigue and irritable bowel, with negative serology EC, intraepithelial lymphocytosis without villous atrophy on duodenal biopsy and presence of DQ8 in the HLA typing. Mother symptoms resolved with gluten-free diet without dairy.

The picture of the child was strongly suggestive of celiac disease and its malabsorptive habit (Fig. 1 ). However, experts consulted had been reluctant to get duodenal biopsies due to the negativity of serology. Finally, HLA typing was performed which showed the presence of HLA DQ8 and duodenal biopsies showed intraepithelial lymphocytosis that apical redistribution without villus atrophy obtained. The child began keeping gluten - free diet restriction favorably dairy clear evolution to neurological and gastroenterological resolution picture, with recurrence of their symptoms repeatedly after eating gluten. Clinical improvement was maintained after 2 years of follow - up. The Figure 2 shows the appearance of the patient after 2 years of diet.

The SGNC is a newly recognized entity and also controversial because of the absence of definitive diagnostic criteria and specific serologic marker. The presence in these patients of intraepithelial lymphocytosis without villous atrophy in the duodenal biopsy is nonspecific, but relevant because it is part of the spectrum of gluten enteropathy in September . The demarcation between the EC and the SGNC is often unclear. Probably no overlap between the two, and has even proposed the term celiac disease Marsh type 1 by a working group of the Spanish Society of Gastroenterology in October . The neurological manifestations described in the EC and SGNC syndrome include attention deficit disorder and hyperactivity, autism spectrum symptoms and schizophrenia in June .

This case illustrates that non-celiac gluten sensitivity can occur in children and associated severe neurologic manifestations. To our news is the first pediatric case described in Spain. It is important that gastroenterologists and pediatric neurologists are aware of this possibility.

Nutr Neurosci. 2014 Sep;17(5):207-13. doi: 10.1179/1476830513Y.0000000082. Epub 2013 Nov 26.

Data mining the ScanBrit study of a gluten- and casein-free dietary intervention for children with autismspectrum disorders: behavioural and psychometric measures of dietary response.

Pedersen L, Parlar S, Kvist K, Whiteley P, Shattock P.

Abstract

We previously reported results based on the examination of a gluten- and casein-free diet as an intervention for children diagnosed with an autism spectrum disorder as part of the ScanBrit collaboration. Analysis based on grouped results indicated several significant differences between dietary and non-dietary participants across various core and peripheral areas of functioning. Results also indicated some disparity in individual responses to dietary modification potentially indicative of responder and non-responder differences. Further examination of the behavioural and psychometric data garnered from participants was undertaken, with a view to determining potential factors pertinent to response to dietary intervention. Participants with clinically significant scores indicative of inattention and hyperactivity behaviours and who had a significant positive changes to said scores were defined as responders to the dietary intervention. Analyses indicated several factors to be potentially pertinent to a positive response to dietary intervention in terms of symptom presentation. Chronological age was found to be the strongest predictor of response, where those participants aged between 7 and 9 years seemed to derive most benefit from dietary intervention. Further analysis based on the criteria for original study inclusion on the presence of the urine compound, trans-indolyl-3-acryloylglycine may also merit further investigation. These preliminary observations on potential best responder characteristics to a gluten- and casein-free diet for children with autism require independent replication.

PMID: 24075141 [PubMed - indexed for MEDLINE]

PLoS One. 2013 Jun 18;8(6):e66155. Print 2013.

Markers of Celiac Disease and Gluten Sensitivity in Children with Autism.

Lau NM1, Green PH, Taylor AK, Hellberg D, Ajamian M, Tan CZ, Kosofsky BE, Higgins JJ, Rajadhyaksha AM, Alaedini A.

Author information

1. 1Department of Medicine, Columbia University, New York, New York, United States of America ; Celiac Disease Center, Columbia University, New York, New York, United States of America.
   

Abstract

OBJECTIVE:

Gastrointestinal symptoms are a common feature in children with autism, drawing attention to a potential association with celiac disease or gluten sensitivity. However, studies to date regarding the immune response to gluten in autism and its association with celiac disease have been inconsistent. The aim of this study was to assess immune reactivity to gluten in pediatric patients diagnosed with autism according to strict criteria and to evaluate the potential link between autism and celiac disease.

METHODS:

Study participants included children (with or without gastrointestinal symptoms) diagnosed with autism according to both the AutismDiagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview, Revised (ADI-R) (n = 37), their unaffected siblings (n = 27), and age-matched healthy controls (n = 76). Serum specimens were tested for antibodies to native gliadin, deamidated gliadin, and transglutaminase 2 (TG2). Affected children were genotyped for celiac disease associated HLA-DQ2 and -DQ8 alleles.

RESULTS:

Children with autism had significantly higher levels of IgG antibody to gliadin compared with unrelated healthy controls (p<0.01). The IgG levels were also higher compared to the unaffected siblings, but did not reach statistical significance. The IgG anti-gliadin antibody response was significantly greater in the autistic children with gastrointestinal symptoms in comparison to those without them (p<0.01). There was no difference in IgA response to gliadin across groups. The levels of celiac disease-specific serologic markers, i.e., antibodies to deamidated gliadin and TG2, did not differ between patients and controls. An association between increased anti-gliadin antibody and presence of HLA-DQ2 and/or -DQ8 was not observed.

CONCLUSIONS:

A subset of children with autism displays increased immune reactivity to gluten, the mechanism of which appears to be distinct from that in celiac disease. The increased anti-gliadin antibody response and its association with GI symptoms points to a potential mechanism involving immunologic and/or intestinal permeability abnormalities in affected children.

PMID: 23823064 [PubMed - as supplied by publisher] PMCID: PMC3688832 Free PMC Article

J Child Neurol. 2013 Aug;28(8):975-82. doi: 10.1177/0883073813488668. Epub 2013 May 10.

Autism and dietary therapy: case report and review of the literature.

Herbert MR1, Buckley JA.

Author information

1. 1Pediatric Neurology and TRANSCEND Research, Massachusetts General Hospital, Boston, MA 02129, USA. marthaherbertmd@gmail.com
   

Abstract

We report the history of a child with autism and epilepsy who, after limited response to other interventions following her regression into autism, was placed on a gluten-free, casein-free diet, after which she showed marked improvement in autistic and medical symptoms. Subsequently, following pubertal onset of seizures and after failing to achieve full seizure control pharmacologically she was advanced to a ketogenic diet that was customized to continue the gluten-free, casein-free regimen. On this diet, while still continuing on anticonvulsants, she showed significant improvement in seizure activity. This gluten-free casein-free ketogenic diet used medium-chain triglycerides rather than butter and cream as its primary source of fat. Medium-chain triglycerides are known to be highly ketogenic, and this allowed the use of a lower ratio (1.5:1) leaving more calories available for consumption of vegetables with their associated health benefits. Secondary benefits included resolution of morbid obesity and improvement of cognitive and behavioral features. Over the course of several years following her initial diagnosis, the child's Childhood Autism Rating Scale score decreased from 49 to 17, representing a change from severe autism to nonautistic, and her intelligence quotient increased 70 points. The initial electroencephalogram after seizure onset showed lengthy 3 Hz spike-wave activity; 14 months after the initiation of the diet the child was essentially seizure free and the electroencephalogram showed only occasional 1-1.5 second spike-wave activity without clinical accompaniments.

PMID: 23666039 [PubMed - indexed for MEDLINE]

Whiteley P, Shattock P, Knivsberg AM, Seim A, Reichelt KL, Todd L, Carr K, Hooper M. Gluten- and casein-free dietary intervention for autism spectrum conditions.

Front Hum Neurosci. 2012;6:344. doi: 10.3389/fnhum.2012.00344. Epub 2013 Jan 4.

ESPA Research, The Robert Luff Laboratory, Unit 133i Business and Innovation Centre Sunderland, UK.

Abstract

Dietary intervention as a tool for maintaining and improving physical health and wellbeing is a widely researched and discussed topic. Speculation thatdiet may similarly affect mental health and wellbeing particularly in cases of psychiatric and behavioral symptomatology opens up various avenues for potentially improving quality of life. We examine evidence suggestive that a gluten-free (GF), casein-free (CF), or gluten- and casein-free diet (GFCF) can ameliorate core and peripheral symptoms and improve developmental outcome in some cases of autism spectrum conditions. Although not wholly affirmative, the majority of published studies indicate statistically significant positive changes to symptom presentation following dietary intervention. In particular, changes to areas of communication, attention, and hyperactivity are detailed, despite the presence of various methodological shortcomings. Specific characteristics of best- and non-responders to intervention have not been fully elucidated; neither has the precise mode of action for any universal effect outside of known individual cases of food-related co-morbidity. With the publication of controlled medium- and long-term group studies of a gluten- and casein-free diet alongside more consolidated biological findings potentially linked to intervention, the appearance of a possible diet-related autism phenotype seems to be emerging supportive of a positive dietary effect in some cases. Further debate on whether such dietary intervention should form part of best practice guidelines for autism spectrum conditions (ASCs) and onward representative of an autismdietary-sensitive enteropathy is warranted.

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Chan AS, Sze SL, Han YM, Cheung MC. A chan dietary intervention enhances executive functions and anterior cingulate activity in autism spectrum disorders: a randomized controlled trial.

Evid Based Complement Alternat Med. 2012;2012:262136. doi: 10.1155/2012/262136. Epub 2012 May 14.

Source

Neuropsychology Laboratory, Department of Psychology, The Chinese University of Hong Kong, Shatin, NT, Hong Kong.

Abstract

Executive dysfunctions have been found to be related to repetitive/disinhibited behaviors and social deficits in autism spectrum disorders (ASDs). This study aims to investigate the potential effect of a Shaolin-medicine-based dietary modification on improving executive functions and behavioral symptoms of ASD and exploring the possible underlying neurophysiological mechanisms. Twenty-four children with ASD were randomly assigned into the experimental (receiving dietary modification for one month) and the control (no modification) groups. Each child was assessed on his/her executive functions, behavioral problems based on parental ratings, and event-related electroencephalography (EEG) activity during a response-monitoring task before and after the one month. The experimental group demonstrated significantly improved mental flexibility and inhibitory control after the diet modification, which continued to have a large effect size within the low-functioning subgroup. Such improvements coincided with positive evaluations by their parents on social communication abilities and flexible inhibitory control of daily behaviors and significantly enhanced event-related EEG activity at the rostral and subgenual anterior cingulate cortex. In contrast, the control group did not show any significant improvements. These positive outcomes of a one-month dietary modification on children with ASD have implicated its potential clinical applicability for patients with executive function deficits.

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Gorrindo P, Williams KC, Lee EB, Walker LS, McGrew SG, Levitt P. Gastrointestinal dysfunction in autism: parental report, clinical evaluation, and associated factors.

Autism Res. 2012 Apr;5(2):101-8. doi: 10.1002/aur.237.

Source

Medical-Scientist Training Program, Vanderbilt University, Nashville, TN, USA. phillip.gorrindo@vanderbilt.edu

Abstract

The objectives of this study were to characterize gastrointestinal dysfunction (GID) in autism spectrum disorder (ASD), to examine parental reports of GID relative to evaluations by pediatric gastroenterologists, and to explore factors associated with GID in ASD. One hundred twenty-one children were recruited into three groups: co-occurring ASD and GID, ASD without GID, and GID without ASD. A pediatric gastroenterologist evaluated both GID groups. Parents in all three groups completed questionnaires about their child's behavior and GI symptoms, and a dietary journal. Functional constipation was the most common type of GID in children with ASD (85.0%). Parental report of any GID was highly concordant with a clinical diagnosis of any GID (92.1%). Presence of GID in children with ASD was not associated with distinct dietary habits or medication status. Odds of constipation were associated with younger age, increased social impairment, and lack of expressive language (adjusted odds ratio in nonverbal children: 11.98, 95% confidence interval 2.54-56.57). This study validates parental concerns for GID in children with ASD, as parents were sensitive to the existence, although not necessarily the nature, of GID. The strong association between constipation and language impairment highlights the need for vigilance by health-care providers to detect and treat GID in children with ASD. Medications and diet, commonly thought to contribute to GID in ASD, were not associated with GID status. These findings are consistent with a hypothesis that GID in ASD represents pleiotropic expression of genetic risk factors.

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Kałużna-Czaplińska J, Socha E, Rynkowski J. B vitamin supplementation reduces excretion of urinary dicarboxylic acids in autistic children.

Nutr Res. 2011 Jul;31(7):497-502. doi: 10.1016/j.nutres.2011.06.002.

Source

Department of Chemistry, Institute of General and Ecological Chemistry, Technical University of Lodz, Zeromskiego 116, 90-924 Lodz, Poland. kaluzna@p.lodz.pl

Abstract

Urinary dicarboxylic acids are an important source of information about metabolism and potential problems especially connected with energy production, intestinal dysbiosis, and nutritional individuality in autistic children. A diet rich in vitamins and macroelements is a new idea of intervention in autism. The objective of the present study was to test the hypothesis that vitamin B2, vitamin B6, and magnesium supplementation is effective in reducing the level of dicarboxylic acids in the urine of autistic children. We examined the levels of succinic, adipic, and suberic acids in the urine ofautistic children before and after vitamin supplementation. Thirty children with autism received magnesium (daily dose, 200 mg), vitamin B6 (pyridoxine; daily dose, 500 mg), and vitamin B2 (riboflavin; daily dose, 20 mg). The treatment was provided for a period of 3 months. Organic acids were determined using gas chromatography/mass spectrometry. Before supplementation, the levels of succinic, adipic, and suberic acids in the urine of autistic children were 41.47 ± 50.40 μmol/mmol creatinine, 15.61 ± 15.31 μmol/mmol creatinine, 8.02 ± 6.08 μmol/mmol creatinine; and after supplementation, the levels were 9.90 ± 8.26 μmol/mmol creatinine, 2.92 ± 2.41 μmol/mmol creatinine, and 2.57 ± 3.53 μmol/mmol creatinine, respectively. The results suggest that the supplementation reduces the level of dicarboxylic acid in the urine of autistic children.

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Adams JB, Audhya T, McDonough-Means S, Rubin RA, Quig D, Geis E, Gehn E, Loresto M, Mitchell J, Atwood S, Barnhouse S, Lee W. Nutritional and metabolic status of children with autism vs. neurotypical children, and the association with autism severity. Nutr Metab (Lond). 2011 Jun 8;8(1):34.

Arizona State University, Tempe, AZ, USA. jim.adams@asu.edu.

Abstract:

BACKGROUND: The relationship between relative metabolic disturbances and developmental disorders is an emerging research focus. This study compares the nutritional and metabolic status of children with autism with that of neurotypical children and investigates the possible association of autism severity with biomarkers.

METHOD: Participants were children ages 5-16 years in Arizona with Autistic Spectrum Disorder (n = 55) compared with non-sibling, neurotypical controls (n = 44) of similar age, gender and geographical distribution. Neither group had taken any vitamin/mineral supplements in the two months prior to sample collection. Autism severity was assessed using the Pervasive Development Disorder Behavior Inventory (PDD-BI), Autism Treatment Evaluation Checklist (ATEC), and Severity of Autism Scale (SAS). Study measurements included: vitamins, biomarkers of vitamin status, minerals, plasma amino acids, plasma glutathione, and biomarkers of oxidative stress, methylation, sulfation and energy production.

RESULTS: Biomarkers of children with autism compared to those of controls using a t-test or Wilcoxon test found the following statistically significant differences (p < 0.001): Low levels of biotin, plasma glutathione, RBC SAM, plasma uridine, plasma ATP, RBC NADH, RBC NADPH, plasma sulfate (free and total), and plasma tryptophan; also high levels of oxidative stress markers and plasma glutamate. Levels of biomarkers for the neurotypical controls were in good agreement with accessed published reference ranges. In the Autism group, mean levels of vitamins, minerals, and most amino acids commonly measured in clinical care were within published reference ranges.A stepwise, multiple linear regression analysis demonstrated significant associations between several groups of biomarkers with all three autism severity scales, including vitamins (adjusted R2 of 0.25-0.57), minerals (adj. R2 of 0.22-0.38), and plasma amino acids (adj. R2 of 0.22-0.39).

CONCLUSION: The autism group had many statistically significant differences in their nutritional and metabolic status, including biomarkers indicative of vitamin insufficiency, increased oxidative stress, reduced capacity for energy transport, sulfation and detoxification. Several of the biomarker groups were significantly associated with variations in the severity of autism. These nutritional and metabolic differences are generally in agreement with other published results and are likely amenable to nutritional supplementation. Research investigating treatment and its relationship to the co-morbidities and etiology of autism is warranted.

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Kałużna-Czaplińska J, Michalska M, Rynkowski J. Vitamin supplementation reduces the level of homocysteine in the urine of autistic children. Nutr Res. 2011 Apr;31(4):318-21.

SourceInstitute of General and Ecological Chemistry, Technical University of Lodz, 90-924 Lodz, Poland. jkaluzna@p.lodz.pl

Abstract

Significant differences in homocysteine levels in the urine of autistic children are observed. We hypothesized that vitamin supplementation might reduce the level of urinary homocysteine. To rationalize such a hypothesis, analyses were performed using the gas chromatography/mass spectrometry method. The homocysteine level in the urine of autistic children was measured twice: (1) before vitamin supplementation (group C, 30 autistic children) and (2) after supplementation, with either folic acid and vitamins B(6) and B(12) (group A1, 24 autistic children) or vitamins B(6) and B(12) alone (group A2, 6 autistic children). The homocysteine level in the urine of autistic children before vitamin supplementation was 2.41 ± 1.10 mmol/mol creatinine (mean ± SD difference). After treatment, the homocysteine level was reduced to 1.13 ± 0.44 and 1.33 ± 0.39 mmol/mol creatinine for A1 and A2 groups, respectively. The intake of vitamins B(6) and B(12), together with folic acid, was found to be more effective in lowering the levels of urinary homocysteine than the intake of vitamins B(6) and B(12) alone. Our findings may lead to the recommendation of including vitamins B(6) and B(12) together with folic acid supplementation in the diets of children with autism.

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de Magistris L, Familiari V, Pascotto A, Sapone A, Frolli A, Iardino P, Carteni M, De Rosa M, Francavilla R, Riegler G, Militerni R, Bravaccio C. Alterations of the Intestinal Barrier in Patients With Autism Spectrum Disorders and in Their First-degree Relatives. J Pediatr Gastroenterol Nutr. 2010 Oct;51(4):418-24.

*Department Magrassi-Lanzara, Gastroenterology, Italy daggerDepartment of Psychiatry, Neuropsychiatry, Dermatovenereology, Italy double daggerDepartment of Experimental Medicine, Italy section signDepartment of Laboratory Medicine, Second University of Naples, Italy ||Department of Paediatrics, Federico II University of Naples, Italy paragraph signClinica Pediatrica "B Trambusti," University of Bari, Italy #Fondazione Istituto Antoniano, Naples, Italy.

Abstract

OBJECTIVES: Intestinal permeability (IPT) was investigated in patients with autism as well as in their first-degree relatives to investigate leaky gut hypothesis. Faecal calprotectin (FC) was also measured in patients with autism, either with or without gastrointestinal symptoms, and in their first-degree relatives.

PATIENTS AND METHODS: IPT results, assessed by means of the lactulose/mannitol test, were compared with adult and child controls and with FC values.

RESULTS: A high percentage of abnormal IPT values were found among patients with autism (36.7%) and their relatives (21.2%) compared with normal subjects (4.8%). Patients with autism on a reported gluten-casein-free diet had significantly lower IPT values compared with those who were on an unrestricted diet and controls. Gastrointestinal symptoms were present in 46.7% of children with autism: constipation (45.5%), diarrhoea (34.1%), and others (alternating diarrhoea/constipation, abdominal pain, etc: 15.9%). FC was elevated in 24.4% of patients with autism and in 11.6% of their relatives; it was not, however, correlated with abnormal IPT values.

CONCLUSIONS: The results obtained support the leaky gut hypothesis and indicate that measuring IPT could help to identify a subgroup of patients with autism who could benefit from a gluten-free diet. The IPT alterations found in first-degree relatives suggest the presence of an intestinal (tight-junction linked) hereditary factor in the families of subjects with autism.

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Yap IK, Angley M, Veselkov KA, Holmes E, Lindon JC, Nicholson JK. Urinary Metabolic Phenotyping Differentiates Children with Autism from Their Unaffected Siblings and Age-Matched Controls. J Proteome Res. 2010 May 13. [Epub ahead of print]

Biomolecular Medicine, Division of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, South Kensington Campus, London SW7 2AZ, United Kingdom, and Sansom Institute, Division of Health Sciences, University of South Australia.

Abstract

Autism is an early onset developmental disorder with a severe life-long impact on behavior and social functioning that has associated metabolic abnormalities. The urinary metabolic phenotypes of individuals (age range=3-9 years old) diagnosed with autism using the DSM-IV-TR criteria (n = 39; male = 35; female = 4), together with their nonautistic siblings (n = 28; male = 14; female = 14) and age-matched healthy volunteers (n = 34, male = 17; female = 17) have been characterized for the first time using (1)H NMR spectroscopy and pattern recognition methods. Novel findings associated with alterations in nicotinic acid metabolism within autistic individuals showing increased urinary excretion of N-methyl-2-pyridone-5-carboxamide, N-methyl nicotinic acid, and N-methyl nicotinamide indicate a perturbation in the tryptophan-nicotinic acid metabolic pathway. Multivariate statistical analysis indicated urinary patterns of the free amino acids, glutamate and taurine were significantly different between groups with the autistic children showing higher levels of urinary taurine and a lower level of urinary glutamate, indicating perturbation in sulfur and amino acid metabolism in these children. Additionally, metabolic phenotype (metabotype) differences were observed between autistic and control children, which were associated with perturbations in the relative patterns of urinary mammalian-microbial cometabolites including dimethylamine, hippurate, and phenyacetylglutamine. These biochemical changes are consistent with some of the known abnormalities of gut microbiota found in autistic individuals and the associated gastrointestinal dysfunction and may be of value in monitoring the success of therapeutic interventions.

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Whitely P, et al. The ScanBrit randomised, controlled, single-blind study of a gluten- and casein-free dietary intervention for children with autism spectrum disorders. Nutr Neurosci. 2010 Apr;13(2):87-100.

Abstract

There is increasing interest in the use of gluten- and casein-free diets for children with autism spectrum disorders (ASDs). We report results from a two-stage, 24-month, randomised, controlled trial incorporating an adaptive 'catch-up' design and interim analysis. Stage 1 of the trial saw 72 Danish children (aged 4 years to 10 years 11 months) assigned to diet (A) or non-diet (B) groups by stratified randomisation. Autism Diagnostic Observation Schedule (ADOS) and the Gilliam Autism Rating Scale (GARS) were used to assess core autism behaviours, Vineland Adaptive Behaviour Scales (VABS) to ascertain developmental level, and Attention-Deficit Hyperactivity Disorder - IV scale (ADHD-IV) to determine inattention and hyperactivity. Participants were tested at baseline, 8, and 12 months. Based on per protocol repeated measures analysis, data for 26 diet children and 29 controls were available at 12 months. At this point, there was a significant improvement to mean diet group scores (time*treatment interaction) on sub-domains of ADOS, GARS and ADHD-IV measures. Surpassing of predefined statistical thresholds as evidence of improvement in group A at 12 months sanctioned the re-assignment of group B participants to active dietary treatment. Stage 2 data for 18 group A and 17 group B participants were available at 24 months. Multiple scenario analysis based on inter- and intra-group comparisons showed some evidence of sustained clinical group improvements although possibly indicative of a plateau effect for intervention. Our results suggest that dietary intervention may positively affect developmental outcome for some children diagnosed with ASD. In the absence of a placebo condition to the current investigation, we are, however, unable to disqualify potential effects derived from intervention outside of dietary changes. Further studies are required to ascertain potential best- and non-responders to intervention. The study was registered with ClincialTrials.gov, number NCT00614198.

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Genuis SJ, Bouchard TP. Celiac disease presenting as autism. J Child Neurol. 2010 Jan;25(1):114-9.

University of Alberta, Alberta, Canada. sgenuis@ualberta.ca

Abstract

Gluten-restricted diets have become increasingly popular among parents seeking treatment for children diagnosed with autism. Some of the reported response to celiac diets in children with autism may be related to amelioration of nutritional deficiency resulting from undiagnosed gluten sensitivity and consequent malabsorption. A case is presented of a 5-year-old boy diagnosed with severe autism at a specialty clinic for autistic spectrum disorders. After initial investigation suggested underlying celiac disease and varied nutrient deficiencies, a gluten-free diet was instituted along with dietary and supplemental measures to secure nutritional sufficiency. The patient's gastrointestinal symptoms rapidly resolved, and signs and symptoms suggestive of autism progressively abated. This case is an example of a common malabsorption syndrome associated with central nervous system dysfunction and suggests that in some contexts, nutritional deficiency may be a determinant of developmental delay. It is recommended that all children with neurodevelopmental problems be assessed for nutritional deficiency and malabsorption syndromes.

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Buie T, et al. Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus report. Pediatrics. 2010 Jan;125 Suppl 1:S1-18.

Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA. tbuie@partners.org

Abstract

Autism spectrum disorders (ASDs) are common and clinically heterogeneous neurodevelopmental disorders. Gastrointestinal disorders and associated symptoms are commonly reported in individuals with ASDs, but key issues such as the prevalence and best treatment of these conditions are incompletely understood. A central difficulty in recognizing and characterizing gastrointestinal dysfunction with ASDs is the communication difficulties experienced by many affected individuals. A multidisciplinary panel reviewed the medical literature with the aim of generating evidence-based recommendations for diagnostic evaluation and management of gastrointestinal problems in this patient population. The panel concluded that evidence-based recommendations are not yet available. The consensus expert opinion of the panel was that individuals with ASDs deserve the same thoroughness and standard of care in the diagnostic workup and treatment of gastrointestinal concerns as should occur for patients without ASDs. Care providers should be aware that problem behavior in patients with ASDs may be the primary or sole symptom of the underlying medical condition, including some gastrointestinal disorders. For these patients, integration of behavioral and medical care may be most beneficial. Priorities for future research are identified to advance our understanding and management of gastrointestinal disorders in persons with ASDs.

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Chen B, Girgis S, El-Matary W. Childhood autism and eosinophilic colitis. Digestion. 2010;81(2):127-9. Epub 2010 Jan 9.

Division of Pediatric Gastroenterology, Hepatology and Nutrition, Stollery Children's Hospital, Edmonton, Alta, Canada.

Abstract

BACKGROUND/AIMS: The significance of the association between many gastrointestinal pathologies and autism is yet to be discovered. The aim of this report is to highlight an association between autism and microscopic eosinophilic colitis in 2 children. The possible mechanisms that may connect these two conditions are discussed. METHODS AND RESULTS: A rare association between autism and microscopic eosinophilic colitis in 2 children is reported through retrospective chart review. Common causes of secondary eosinophilic colitis were excluded. CONCLUSION: This report suggests the possibility of either impaired intestinal barrier function or an aberrant immune system that predisposes autistic children to sensitization to environmental antigens. Large controlled studies are needed to examine this hypothesis.

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Hsu CL, Lin CY, Chen CL, Wang CM, Wong MK. The effects of a gluten and casein-free diet in children with autism: a case report. Chang Gung Med J. 2009 Jul-Aug;32(4):459-65.

Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, Taipei, Chang Gung University College of Medicine, Taoyuan, Taiwan.

Abstract

A boy with autism, growth and developmental retardation was brought to our clinic. He was diagnosed with CHARGE syndrome. Subsequently, various therapies were introduced when he was 5 months old yet the developmental delays persisted. Gastrointestinal problems such as frequent post-prandial vomiting and severe constipation were noted as well. At the age of 42 months, the boy was subjected to a gluten and casein-free diet. Soybean milk and rice were substituted for cow's milk, bread and noodles. After 2.5 months, interpersonal relations including eye to eye contact and verbal communication improved. At 5.5 months the boy was capable of playing and sharing toys with his sibling and other children, behavior noted to be closer to that of an unaffected child. In addition, the decreased frequency of postprandial vomiting led to a significant increment in body weight, body height (from below the third percentile to the tenth percentile) and vitality after 11 months on the diet. In view of the lack of consensus on the benefits of dietary intervention in patients with autism, we are suggesting an adjuvant therapy that is simple, safe and economical. In addition, the therapy may be more feasible in Taiwan as opposed to western countries because of cultural factors such as dietary preference and product availability.

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Wasilewska J, Jarocka-Cyrta E, Kaczmarski M. [Gastrointestinal abnormalities in children with autism] [Article in Polish]. Pol Merkur Lekarski. 2009 Jul;27(157):40-3.

Abstract

The autistic spectrum disorder (ASD) is a neurodevelopmental disorder characterized by socially aloof behavior and impairment of language and social interaction. This paper is a review of literature on gastrointestinal problems in children with ASD. Gastrointestinal symptoms are described in 9-54% of autistic children, among which most common are: constipation, diarrhea and abdominal distension. The gastro-intestinal abnormalities reported in autism include: inflammation (esophagitis, gastritis, duodenitis, enterocolitis) with or without autoimmunity, lymphoid nodular hyperplasia, increased intestinal permeability, low activities of disaccharidase enzymes, impairment of detoxification (e.g. defective sulfation of ingested phenolic amines), dysbiosis with bacterial overgrowth, food intolerance or exorphin intoxication (by opioid derived from casein and gluten). A beneficial effect of dietary intervention on behavior and cognition of some autistic children indicates a functional relationship between the alimentary tract and the central nervous system. There are no epidemiologic data concerning the incidence or prevalence of gastrointestinal problems within the population of children with ASD in comparison to the population of non-ASD children.

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Smith RA, Farnworth H, Wright B, Allgar V. Are there more bowel symptoms in children with autism compared to normal children and children with other developmental and neurological disorders?: A case control study. Autism. 2009 Jul;13(4):343-55.

York Hospital, UK. robert.a.smith@york.nhs.uk

Abstract

There is considerable controversy as to whether there is an association between bowel disorders and autism. Using a bowel symptom questionnaire we compared 51 children with autism spectrum disorder with control groups of 35 children from special school and 112 from mainstream school. There was a significant difference in the reporting of certain bowel symptoms (constipation, diarrhoea, flatulence) and food faddiness between the autism group and the mainstream school control group. There was no significant difference between the autism group and children in the special schools except for faddiness, which is an autism specific symptom and not a bowel symptom. This study confirms previously reported findings of an increase in bowel symptoms in children with autism. It would appear, however, that this is not specifically associated with autism as bowel symptoms were reported in similar frequency to a comparison group of children with other developmental and neurological disorders.

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Lockner DW, Crowe TK, Skipper BJ. Dietary intake and parents' perception of mealtime behaviors in preschool-age children with autism spectrum disorder and in typically developing children. J Am Diet Assoc. 2008 Aug;108(8):1360-3.

Nutrition Program, College of Education, University of New Mexico, Albuquerque, NM 87131, USA. dlockner@unm.edu

Abstract

Parents of children with autism spectrum disorder (ASD) frequently report that their children have selective eating behaviors and refuse many foods, which could result in inadequate nutrient intake. This preliminary cross-sectional descriptive study investigated dietary intake and parents' reported perception of food behaviors of 20 3- to 5-year-old children with ASD. Twenty typically developing children matched for sex, age, and ethnicity were also studied as a case-control comparison. Nutrient intake determined from 3-day food records was adjusted for day-to-day variation to determine the estimate of usual intake distribution for the two groups. This distribution was compared with the Estimated Average Requirement or Adequate Intake recommendations. The reported food behaviors and use of vitamin or mineral supplements were compared for matched pairs using the exact McNemar test. Nutrient intake was similar for both groups of children, with the majority of children consuming more than the recommended amounts for most nutrients. Nutrients least likely to be consumed in recommended amounts were vitamin A, vitamin E, fiber, and calcium. Children with ASD were more likely to consume vitamin/mineral supplements than typically developing children. Compared with parents of typically developing children, parents of children with ASD were more likely to report that their children were picky eaters and resisted trying new foods, and they were less likely to describe their children as healthy eaters or that they eat a variety of foods. Despite the similar and generally adequate nutrient intake for the 40 children in this study, parents of children with ASD had more negative perceptions of their children's dietary behaviors.

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Levy SE, Souders MC, Ittenbach RF, Giarelli E, Mulberg AE, Pinto-Martin JA. Relationship of dietary intake to gastrointestinal symptoms in children with autistic spectrum disorders. Biol Psychiatry. 2007 Feb 15;61(4):492-7. Epub 2007 Jan 3.

Division of Child Development and Rehabilitation, Children's Seashore House of the Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. levys@email.chop.edu

Abstract

BACKGROUND: Gastrointestinal (GI) symptoms and abnormalities in stool consistency are frequently reported by parents of children with autism spectrum disorders (ASD). The purpose of this study was to 1) describe dietary intake of a cohort of children with ASD compared with normative data and 2) determine whether GI symptoms and stool consistency are related to dietary intake. METHODS: Data from diet diaries of children (3-8 years) with ASD (n = 62) were analyzed by a registered pediatric dietician to compare to RDA standards for total calories, protein, carbohydrate, and fat. Dietary intake was correlated with descriptors of stool consistency using cumulative logistic regression methods. RESULTS: Intake of calories, carbohydrates, and fat were in the average range; protein intake was increased (211% of RDA). Reported frequency of GI abnormalities, including abnormal stool consistency (e.g., bulky or loose), was increased (54%). No statistically significant relationships between stool consistency and dietary intake were observed. CONCLUSIONS: In this sample, there was a high rate of reported gastrointestinal symptoms, despite lack of medical causes. Intake was adequate for calories and carbohydrates and increased for protein. The children did not exhibit excessive carbohydrate intake. There was no association of nutrient intake to changes in stool consistency.

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Valicenti-McDermott M, McVicar K, Rapin I, Wershil BK, Cohen H, Shinnar S. “Frequency of gastrointestinal symptoms in children with autism spectrum disorders and association with family history of autoimmune disease.” J Dev Behav Pediatr. 2006 Apr;27(2 Suppl):S128-36.

Children's Evaluation and Rehabilitation Center, Bronx, New York 10461, USA. rvalicenti@hotmail.com

Abstract

This is a cross-sectional study that compares lifetime prevalence of gastrointestinal (GI) symptoms in children with autistic spectrum disorders (ASDs) and children with typical development and with other developmental disabilities (DDs) and examines the association of GI symptoms with a family history of autoimmune disease. A structured interview was performed in 50 children with ASD and 2 control groups matched for age, sex, and ethnicity-50 with typical development and 50 with other DDs. Seventy-four percent were boys with a mean age of 7.6 years (SD, +/-3.6). A history of GI symptoms was elicited in 70% of children with ASD compared with 28% of children with typical development (p <.001) and 42% of children with DD (p =.03). Abnormal stool pattern was more common in children with ASD (18%) than controls (typical development: 4%, p =.039; DD: 2%, p =.021). Food selectivity was also higher in children with ASD (60%) compared with those with typical development (22%, p =.001) and DD (36%, p =.023). Family history of autoimmune disease was reported in 38% of the ASD group and 34% of controls and was not associated with a differential rate of GI symptoms. In the multivariate analysis, autism (adjusted odds ratio (OR), 3.8; 95% confidence interval (CI), 1.7-11.2) and food selectivity (adjusted OR, 4.1; 95% CI, 1.8-9.1) were associated with GI symptoms. Children with ASD have a higher rate of GI symptoms than children with either typical development or other DDs. In this study, there was no association between a family history of autoimmune disease and GI symptoms in children with ASD.

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Kushak R, Winter H, Farber N, Buie T, “Gastrointestinal symptoms and intestinal disaccharidase activities in children with autism,” Journal of Pediatric Gastroenterology and Nutrition, Vol. 41, No.4, October 2005.

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Jyonouchi H, Geng L, Ruby A, Reddy C, Zimmerman-Bier B. “Evaluation of an association between gastrointestinal symptoms and cytokine production against common dietary proteins in children with autism spectrum disorders.” J Pediatr. 2005 May;146(5):605-10.

OBJECTIVE: To evaluate an association between cytokine production with common dietary proteins as a marker of non-allergic food hypersensitivity (NFH) and gastrointestinal (GI) symptoms in young children with autism spectrum disorders (ASD). STUDY DESIGN: Peripheral blood mononuclear cells (PBMCs) were obtained from 109 ASD children with or without GI symptoms (GI [+] ASD, N = 75 and GI (-) ASD, N = 34], from children with NFH (N = 15), and control subjects (N = 19). Diarrhea and constipation were the major GI symptoms. We measured production of type 1 T-helper cells (Th1), type 2 T-helper cells (Th2), and regulatory cytokines by PBMCs stimulated with whole cow's milk protein (CMP), its major components (casein, beta-lactoglobulin, and alpha-lactoalbumin), gliadin, and soy. RESULTS: PBMCs obtained from GI (+) ASD children produced more tumor necrosis factor-alpha (TNF-alpha)/interleukin-12 (IL-12) than those obtained from control subjects with CMP, beta-lactoglobulin, and alpha-lactoalbumin, irrespective of objective GI symptoms. They also produced more TNF-alpha with gliadin, which was more frequently observed in the group with loose stools. PBMCs obtained from GI (-) ASD children produced more TNF-alpha/IL-12 with CMP than those from control subjects, but not with beta-lactoglobulin, alpha-lactoalbumin, or gliadin. Cytokine production with casein and soy were unremarkable. CONCLUSION: A high prevalence of elevated TNF-alpha/IL-12 production by GI (+) ASD PBMCs with CMP and its major components indicates a role of non-allergic food hypersensitivity in GI symptoms observed in children with ASD.

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Jyonouchi H, Geng L, Ruby A, Zimmerman-Bier B.  Dysregulated innate immune responses in young children with autism spectrum disorders: their relationship to gastrointestinal symptoms and dietary intervention. Neuropsychobiology. 2005;51(2):77-85.

Department of Pediatrics, New Jersey Medical School, UMDNJ, Newark, NJ 07101-1709, USA. jyanouha@umdnj.edu

OBJECTIVE: Our previous study indicated an association between cellular immune reactivity to common dietary proteins (DPs) and excessive proinflammatory cytokine production with endotoxin (lipopolysaccharide, LPS), a major stimulant of innate immunity in the gut mucosa, in a subset of autism spectrum disorder (ASD) children. However, it is unclear whether such abnormal LPS responses are intrinsic in these ASD children or the results of chronic gastrointestinal (GI) inflammation secondary to immune reactivity to DPs. This study further explored possible dysregulated production of proinflammatory and counter-regulatory cytokines with LPS in ASD children and its relationship to GI symptoms and the effects of dietary intervention measures. METHODS: This study includes ASD children (median age 4.8 years) on the unrestricted (n = 100) or elimination (n = 77) diet appropriate with their immune reactivity. Controls include children with non-allergic food hypersensitivity (NFH; median age 2.9 years) on the unrestricted (n = 14) or elimination (n = 16) diet, and typically developing children (median age 4.5 years, n = 13). The innate immune responses were assessed by measuring production of proinflammatory (TNF-alpha, IL-1beta, IL-6, and IL-12) and counter-regulatory (IL-1ra, IL-10, and sTNFRII) cytokines by peripheral blood mononuclear cells (PBMCs) with LPS. The results were also compared to T-cell responses with common DPs and control T-cell mitogens assessed by measuring T-cell cytokine production. RESULTS: ASD and NFH PBMCs produced higher levels of TNF-alpha with LPS than controls regardless of dietary interventions. However, only in PBMCs from ASD children with positive gastrointestinal (GI(+)) symptoms, did we find a positive association between TNF-alpha levels produced with LPS and those with cow's milk protein (CMP) and its major components regardless of dietary interventions. In the unrestricted diet group, GI(+) ASD PBMCs produced higher IL-12 than controls and less IL-10 than GI(-) ASD PBMCs with LPS. GI(+) ASD but not GI(-) ASD or NFH PBMCs produced less counter-regulatory cytokines with LPS in the unrestricted diet group than in the elimination diet group. There was no significant difference among the study groups with regard to cytokine production in responses to T-cell mitogens and other recall antigens. Conclusion: Our results revealed that there are findings limited to GI(+) ASD PBMCs in both the unrestricted and elimination diet groups. Thus our findings indicate intrinsic defects of innate immune responses in GI(+) ASD children but not in NFH or GI(-) ASD children, suggesting a possible link between GI and behavioral symptoms mediated by innate immune abnormalities.

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Balzola F, Barbon V, Repici A, Rizzetto M, Clauser D, Gandione M, Sapino A. Panenteric IBD-like disease in a patient with regressive autism shown for the first time by the wireless capsule enteroscopy: another piece in the jigsaw of this gut-brain syndrome? Am J Gastroenterol. 2005 Apr;100(4):979-81.

[No Abstract Available.]

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Millward C, Ferriter M, Calver S, Connell-Jones G. Gluten- and casein-free diets for autistic spectrum disorder. Cochrane Database Syst Rev. 2004;(2):CD003498.

BACKGROUND: It has been suggested that peptides from gluten and casein may have a role in the origins of autism and that the physiology and psychology of autism might be explained by excessive opioid activity linked to these peptides. Research has reported abnormal levels of peptides in the urine and cerebrospinal fluid of persons with autism. If this is the case, diets free of gluten and /or casein should reduce the symptoms associated with autism. OBJECTIVES: To determine the efficacy of gluten- and/or casein- free diets as an intervention to improve behaviour, cognitive and social functioning in individuals with autism. SEARCH STRATEGY: Electronic searching of abstracts from the Cochrane Library (Issue 3, 2003), PsycINFO (1971- May 2003), EMBASE (1974- May 2003), CINAHL (1982- May 2003), MEDLINE (1986- May 2003), ERIC (1965-2003), LILACS (to 2003) and the specialist register of the Cochrane Complementary Medicine Field (January 2004). Review bibliographies were also examined to identify potential trials. SELECTION CRITERIA: All randomised controlled trials involving programmes which eliminated gluten, casein or both gluten and casein from the diets of individuals diagnosed with autistic spectrum disorder. DATA COLLECTION AND ANALYSIS: Abstracts of studies identified in searches of electronic databases were read and assessed to determine whether they might meet the inclusion criteria. The authors independently selected the relevant studies from the reports identified in this way. As only one trial fitted the inclusion criteria, no meta-analysis is currently possible and data are presented in narrative form. MAIN RESULTS: The one trial included reported results on four outcomes. Unsurprisingly in such a small-scale study, the results for three of these outcomes (cognitive skills, linguistic ability and motor ability) had wide confidence intervals that spanned the line of nil effect. However, the fourth outcome, reduction in autistic traits, reported a significant beneficial treatment effect for the combined gluten- and casein- free diet. REVIEWERS' CONCLUSIONS: This is an important area of investigation and large scale, good quality randomised controlled trials are needed.

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Kokkonen J, Haapalahti M, Tikkanen S, Karttunen R, Savilahti E. Gastrointestinal complaints and diagnosis in children: a population-based study. Acta Paediatr. 2004 Jul;93(7):880-6.

Department of Paediatrics, Oulu University Hospital, Oulu, Finland. jorma.kokkonen@ppshp.fi

AIM: To find out the extent to which children at 10-11 y of age suffer from various gastrointestinal complaints and how often a food-induced or other diagnostic disorder might be assessed behind them, we carried out a population-based survey of 404 children in a rural Finnish town. METHODS: A questionnaire filled in retrospectively by their parents was used to describe the frequency of various abdominal symptoms during the previous 2 y and to select the symptomatic subjects for closer clinical examination. In the clinical investigation of the children, an elimination challenge with milk protein and lactose intolerance tests, as well as endoscopic examinations in selected cases and blood tests, were performed. RESULTS: In all, 110 (27%) subjects reported some gastrointestinal (GI) complaints during the last 2 y; 64 (16%) meeting the Apley criteria for recurrent abdominal pain. A specific organic or functional disorder was found in 26 subjects (6%), two having no GI symptoms. Milk protein intolerance was the most common specific disorder diagnosed in nine subjects (2.2%), followed by lactose intolerance in eight (2%), coeliac disease in five (1.2%) and Helicobacter pylori infection in three (0.7%). An endoscopic examination performed on 17 subjects (4.2%) and a colonoscopy on three revealed significant findings in 11; lymphonodular changes being most common, occurring in five subjects. Subjects with milk protein-induced disorders showed significantly lower IgA-class antibodies to milk and its fractions than the non-symptomatic controls. Chronic diseases, short breastfeeding, GI problems and food intolerance during the first year of life were observed as significant risk factors in determining whether a subject belonged to the group experiencing any GI complaints. CONCLUSION: We conclude that in one in five of those with any, even mild, GI complaints we were able to assess a specific organic disease; milk-induced disorders being most common. A milk protein and/or lactose load test, completed in some cases with an endoscopic examination, would help in assessing a proper individual diagnosis.

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Vojdani A, O'Bryan T, Green JA, Mccandless J, Woeller KN, Vojdani E, Nourian AA, Cooper EL. Immune response to dietary proteins, gliadin and cerebellar peptides in children with autism. Nutr Neurosci. 2004 Jun;7(3):151-61.

Section of Neuroimmunology, Immunosciences Lab., Inc., 8693 Wilshire Blvd., Ste. 200, Beverly Hills, California 90211, USA. drari@msn.com

The mechanisms behind autoimmune reaction to nervous system antigens in autism are not understood. We assessed the reactivity of sera from 50 autism patients and 50 healthy controls to specific peptides from gliadin and the cerebellum. A significant percentage of autism patients showed elevations in antibodies against gliadin and cerebellar peptides simultaneously. For examining cross-reaction between dietary proteins and cerebellar antigens, antibodies were prepared in rabbits, and binding of rabbit anti-gliadin, anti-cerebellar peptides, anti-MBP, anti-milk, anti-egg, anti-soy and anti-corn to either gliadin- or cerebellar-antigen-coated wells was measured. In comparison to anti-gliadin peptide binding to gliadin peptide at 100%, the reaction of anti-cerebellar peptide to gliadin peptide was 22%, whereas the binding of anti-myelin basic protein (MBP), anti-milk, anti-egg and anti-soy to gliadin was less than 10%. Further examination of rabbit anti-gliadin (EQVPLVQQ) and anti-cerebellar (EDVPLLED) 8 amino acid (AA) peptides with human serum albumin (HSA) and an unrelated peptide showed no binding, but the reaction of these antibodies with both the cerebellar and gliadin peptides was greater than 60%. This cross-reaction was further confirmed by DOT-immunoblot and inhibition studies. We conclude that a subgroup of patients with autism produce antibodies against Purkinje cells and gliadin peptides, which may be responsible for some of the neurological symptoms in autism.

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Vojdani A, Bazargan M, Vojdani E, Samadi J, Nourian AA, Eghbalieh N, Cooper EL. Heat shock protein and gliadin peptide promote development of peptidase antibodies in children with autism and patients with autoimmune disease. Clin Diagn Lab Immunol. 2004 May;11(3):515-24.

Section of Neuroimmunology, Immunosciences Lab., Inc., 8693 Wilshire Blvd., Suite 200, Beverly Hills, CA 90211, USA. immunsci@ix.netcom.com

Searching for a mechanism underlying autoimmunity in autism, we postulated that gliadin peptides, heat shock protein 60 (HSP-60), and streptokinase (SK) bind to different peptidases resulting in autoantibody production against these components. We assessed this hypothesis in patients with autism and in those with mixed connective tissue diseases. Associated with antigliadin and anti-HSP antibodies, children with autism and patients with autoimmune disease developed anti-dipeptidylpeptidase I (DPP I), anti-dipeptidylpeptidase IV (DPP IV [or CD26]) and anti-aminopeptidase N (CD13) autoantibodies. A significant percentage of autoimmune and autistic sera were associated with elevated immunoglobulin G (IgG), IgM, or IgA antibodies against three peptidases, gliadin, and HSP-60. These antibodies are specific, since immune absorption demonstrated that only specific antigens (e.g., DPP IV absorption of anti-DPP IV), significantly reduced IgG, IgM, and IgA antibody levels. For direct demonstration of SK, HSP-60, and gliadin peptide binding to DPP IV, microtiter wells coated with DPP IV were reacted with SK, HSP-60, and gliadin. They were then reacted with anti-DPP IV or anti-SK, anti-HSP, and antigliadin antibodies. Adding SK, HSP-60, and gliadin peptides to DPP IV resulted in 27 to 43% inhibition of the DPP IV-anti-DPP IV reaction, but DPP IV-positive peptides caused 18 to 20% enhancement of antigen-antibody reactions. We propose that (i) superantigens (e.g., SK and HSP-60) and dietary proteins (e.g., gliadin peptides) in individuals with predisposing HLA molecules bind to aminopeptidases and (ii) they induce autoantibodies to peptides and tissue antigens. Dysfunctional membrane peptidases and autoantibody production may result in neuroimmune dysregulation and autoimmunity.

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Jyonouchi H, Geng L, Ruby A, Reddy C, Zimmerman-Bier B. Evaluation of an association between gastrointestinal symptoms and cytokine production against common dietary proteins in children with autism spectrum disorders. J Pediatr. 2005 May;146(5):605-10.

Objective To evaluate an association between cytokine production with common dietary proteins as a marker of non-allergic food hypersensitivity (NFH) and gastrointestinal (GI) symptoms in young children with autism spectrum disorders (ASD). Study design Peripheral blood mononuclear cells (PBMCs) were obtained from 109 ASD children with or without GI symptoms (GI [+] ASD, N = 75 and GI (-) ASD, N = 34], from children with NFH (N = 15), and control subjects (N = 19). Diarrhea and constipation were the major GI symptoms. We measured production of type 1 T-helper cells (Th1), type 2 T-helper cells (Th2), and regulatory cytokines by PBMCs stimulated with whole cow's milk protein (CMP), its major components (casein, beta-lactoglobulin, and alpha-lactoalbumin), gliadin, and soy. Results PBMCs obtained from GI (+) ASD children produced more tumor necrosis factor-alpha (TNF-alpha)/interleukin-12 (IL-12) than those obtained from control subjects with CMP, beta-lactoglobulin, and alpha-lactoalbumin, irrespective of objective GI symptoms. They also produced more TNF-alpha with gliadin, which was more frequently observed in the group with loose stools. PBMCs obtained from GI (-) ASD children produced more TNF-alpha/IL-12 with CMP than those from control subjects, but not with beta-lactoglobulin, alpha-lactoalbumin, or gliadin. Cytokine production with casein and soy were unremarkable. Conclusion A high prevalence of elevated TNF-alpha/IL-12 production by GI (+) ASD PBMCs with CMP and its major components indicates a role of NFH in GI symptoms observed in children with ASD.

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Turunen S, Karttunen TJ, Kokkonen J. “Lymphoid nodular hyperplasia and cow's milk hypersensitivity in children with chronic constipation.” J Pediatr. 2004 Nov;145(5):606-11.

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Ashwood P, Anthony A, Torrente F, Wakefield AJ. Spontaneous mucosal lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms: mucosal immune activation and reduced counter regulatory interleukin-10. J Clin Immunol. 2004 Nov;24(6):664-73.

Centre for Paediatric Gastroenterology, Royal Free and University College Medical School, London, United Kingdom. pashwood@ucdavis.edu

A lymphocytic enterocolitis has been reported in a cohort of children with autistic spectrum disorder (ASD) and gastrointestinal (GI) symptoms. This study tested the hypothesis that dysregulated intestinal mucosal immunity with enhanced pro-inflammatory cytokine production is present in these ASD children. Comparison was made with developmentally normal children with, and without, mucosal inflammation. Duodenal and colonic biopsies were obtained from 21 ASD children, and 65 developmentally normal paediatric controls, of which 38 had signs of histological inflammation. Detection of CD3+ lymphocyte staining for spontaneous intracellular TNFalpha, IL-2, IL-4, IFNgamma, and IL-10, was performed by multicolor flow cytometry. Duodenal and colonic mucosal CD3+ lymphocyte counts were elevated in ASD children compared with noninflamed controls (p<0.03). In the duodenum, the proportion of lamina propria (LP) and epithelial CD3(+)TNFalpha+ cells in ASD children was significantly greater compared with noninflamed controls (p<0.002) but not coeliac disease controls. In addition, LP and epithelial CD3(+)IL-2+ and CD3(+)IFNgamma+, and epithelial CD3(+)IL-4+ cells were more numerous in ASD children than in noninflamed controls (p<0.04). In contrast, CD3(+)IL-10+ cells were fewer in ASD children than in noninflamed controls (p<0.05). In the colon, LP CD3(+)TNFalpha+ and CD3(+)IFNgamma+ were more frequent in ASD children than in noninflamed controls (p<0.01). In contrast with Crohn's disease and non-Crohn's colitis, LP and epithelial CD3(+)IL-10+ cells were fewer in ASD children than in nondisease controls (p<0.01). There was a significantly greater proportion of CD3(+)TNFalpha+ cells in colonic mucosa in those ASD children who had no dietary exclusion compared with those on a gluten and/or casein free diet (p<0.05). There is a consistent profile of CD3+ lymphocyte cytokines in the small and large intestinal mucosa of these ASD children, involving increased pro-inflammatory and decreased regulatory activities. The data provide further evidence of a diffuse mucosal immunopathology in some ASD children and the potential for benefit of dietary and immunomodulatory therapies.

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Atkinson W, Sheldon TA, Shaath N, Whorwell PJ. Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial. Gut. 2004 Oct;53(10):1459-64.

Department of Medicine, University Hospital of South Manchester , Manchester M20 2LR , UK .

BACKGROUND: Patients with irritable bowel syndrome (IBS) often feel they have some form of dietary intolerance and frequently try exclusion diets. Tests attempting to predict food sensitivity in IBS have been disappointing but none has utilised IgG antibodies. AIMS: To assess the therapeutic potential of dietary elimination based on the presence of IgG antibodies to food. PATIENTS: A total of 150 outpatients with IBS were randomised to receive, for three months, either a diet excluding all foods to which they had raised IgG antibodies (enzyme linked immunosorbant assay test) or a sham diet excluding the same number of foods but not those to which they had antibodies. METHODS: Primary outcome measures were change in IBS symptom severity and global rating scores. Non-colonic symptomatology, quality of life, and anxiety/depression were secondary outcomes. Intention to treat analysis was undertaken using a generalised linear model. RESULTS: After 12 weeks, the true diet resulted in a 10% greater reduction in symptom score than the sham diet (mean difference 39 (95% confidence intervals (CI) 5-72); p = 0.024) with this value increasing to 26% in fully compliant patients (difference 98 (95% CI 52-144); p<0.001). Global rating also significantly improved in the true diet group as a whole (p = 0.048, NNT = 9) and even more in compliant patients (p = 0.006, NNT = 2.5). All other outcomes showed trends favouring the true diet. Relaxing the diet led to a 24% greater deterioration in symptoms in those on the true diet (difference 52 (95% CI 18-88); p = 0.003). CONCLUSION: Food elimination based on IgG antibodies may be effective in reducing IBS symptoms and is worthy of further biomedical research.

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Torrente F, Anthony A, Heuschkel RB, Thomson MA, Ashwood P, Murch SH. Focal-enhanced gastritis in regressive autism with features distinct from Crohn's and Helicobacter pylori gastritis. Am J Gastroenterol. 2004 Apr;99(4):598-605.

The Centre for Paediatric Gastroenterology, Department of Histopathology, Royal Free & University College Medical School, London.

BACKGROUND: Immunohistochemistry allowed recent recognition of a distinct focal gastritis in Crohn's disease. Following reports of lymphocytic colitis and small bowel enteropathy in children with regressive autism, we aimed to see whether similar changes were seen in the stomach. We thus studied gastric antral biopsies in 25 affected children, in comparison to 10 with Crohn's disease, 10 with Helicobacter pylori infection, and 10 histologically normal controls. All autistic, Crohn's, and normal patients were H. pylori negative. METHODS: Snap-frozen antral biopsies were stained for CD3, CD4, CD8, gammadelta T cells, HLA-DR, IgG, heparan sulphate proteoglycan, IgM, IgA, and C1q. Cell proliferation was assessed with Ki67. RESULTS: Distinct patterns of gastritis were seen in the disease states: diffuse, predominantly CD4+ infiltration in H. pylori, and focal-enhanced gastritis in Crohn's disease and autism, the latter distinguished by striking dominance of CD8+ cells, together with increased intraepithelial lymphocytes in surface, foveolar and glandular epithelium. Proliferation of foveolar epithelium was similarly increased in autism, Crohn's disease and H. pylori compared to controls. A striking finding, seen only in 20/25 autistic children, was colocalized deposition of IgG and C1q on the subepithelial basement membrane and the surface epithelium. CONCLUSIONS: These findings demonstrate a focal CD8-dominated gastritis in autistic children, with novel features. The lesion is distinct from the recently recognized focal gastritis of Crohn's disease, which is not CD8-dominated. As in the small intestine, there is epithelial deposition of IgG.

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Van Heest R, Jones S, Giacomantonio M. Rectal prolapse in autistic children. J Pediatr Surg. 2004 Apr;39(4):643-4.

Department of General Surgery, IWK Health Centre, Dalhousie University, Halifax, Nova Scotia, Canada.

Rectal prolapse in children is not uncommon, but surgery is rarely indicated. In mentally challenged adults and children, rectal prolapse occurs more frequently than in the general population and often requires surgical intervention in the second to third decade of life. The authors describe 3 children with autism and mental retardation who presented with rectal prolapse at an earlier age than would be anticipated with mental retardation alone. All 3 children required surgical intervention.

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Jyonounchi, H. Mechanisms of non-IgE mediated adverse reaction to common Dietary Proteins (DPs) in children with Autism Spectrum Disorders (ASD). February 2004, Supplement • Volume 113 • Number 2

Rationale We have reported elevated IFN-/TNF- production by peripheral blood mononuclear cells (PBMCs) against cow's milk protein (CMP), soy, and gliadin in a substantial number of ASD children (Neuropsychobiology 46:76, 2002). IFN-/TNF- production is partly regulated by IL-10 (negatively) and IL-12 (positively).

Methods We examined IFN-, IL-5, TNF-, IL-10 and IL-12 production by PBMCs against common DPs in 68 ASD children on a regular diet (Median age 5.4 yr): >50% of them had gastrointestinal symptoms. Controls include 11 children with DP intolerance (DPI) (Median age 2.5 yr), and 10 normal children (Median age 3.3 y).

Results ASD and DPI PBMCs produced larger amounts of IFN- and TNF-; against CMP and gliadin than controls (p<0.01). IL-12 production against CMP was higher in ASD PBMCs (p<0.01). IL-10 production by ASD, DPI, and control PBMCs were equivalent, resulting in higher TNF/IL-10 ratio with CMP/gliadin in ASD and DPI PBMCs (p<0.01). IL-12/IL-10 ratios with CMP/gliadin were also higher in ASD PBMCs (p<0.01), but not in DPI cells. In 11/11 DPI children, TNF-/IL-10 ratios with CMP and/or gliadin were >0.5 with excellent responses to the appropriate elimination diet. TNF-/IL-10 ratios >0.5 with CMP and gliadin were found in 41/68 and 32/68 ASD children, respectively. In these children, the elimination diet based on immune reactivity helped resolve GI symptoms and attenuate autistic behaviors by parental report.

Conclusions Disregulated production of inflammatory and counter-regulatory cytokines may be associated with non-IgE mediated adverse reaction to common DPs in some ASD children, indicating therapeutic significance of dietary interventions in these children.

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Ashwood P, Anthony A, Pellicer AA, Torrente F, Walker-Smith JA, Wakefield AJ. Intestinal lymphocyte populations in children with regressive autism: evidence for extensive mucosal immunopathology. J Clin Immunol. 2003 Nov;23(6):504-17.

The Inflammatory Bowel Disease Study Group, and Centre for Paediatric Gastroenterology, Royal Free and University College, Medical School, London, United Kingdom. pashwood@ucdavis.edu

Inflammatory intestinal pathology has been reported in children with regressive autism (affected children). Detailed analysis of intestinal biopsies in these children indicates a novel lymphocytic enterocolitis with autoimmune features; however, links with cognitive function remain unclear. To characterize further, the nature and extent of this disease we examined the mucosal infiltrate using flow cytometry. Duodenal, ileal, and colonic biopsies were obtained from 52 affected children, 25 histologically normal, and 54 histologically inflamed, developmentally normal controls. Epithelial and lamina propria lymphocyte populations were isolated and examined by multicolor flow cytometry. Adjacent biopsies were assessed by semiquantitative histopathology. At all sites, CD3(+) and CD3(+)CD8(+) IEL as well as CD3(+) LPL were significantly increased in affected children compared with developmentally normal noninflamed control groups (p<0.01) reaching levels similar to inflamed controls. In addition, two populations--CD3(+)CD4(+) IEL and LP CD19(+) B cells--were significantly increased in affected children compared with both noninflamed and inflamed control groups including IBD, at all sites examined (p<0.01). Histologically there was a prominent mucosal eosinophil infiltrate in affected children that was significantly lower in those on a gluten- and casein-free diet, although lymphocyte populations were not influenced by diet.The data provide further evidence of a pan-enteric mucosal immunopathology in children with regressive autism that is apparently distinct from other inflammatory bowel diseases.

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Bull G, Shattock P, Whiteley P, Anderson R, Groundwater PW, Lough JW, Lees G. Indolyl-3-acryloylglycine (IAG) is a putative diagnostic urinary marker for autism spectrum disorders. Med Sci Monit. 2003 Oct;9(10):CR422-5.

Abstract:

Sunderland General Hospital, Sunderland, UK.

BACKGROUND: Autism is a heterogeneous pervasive developmental disorder with a poorly defined aetiology and pathophysiology. There are indications that the incidence of the disease is rising but still no definitive diagnostic biochemical markers have been isolated. Here we have addressed the hypothesis that urinary levels of trans -indolyl-3-acryloylglycine (IAG) are abnormal in patients diagnosed with autism spectrum disorders (ASD) compared to age-matched controls. MATERIAL/METHODS: Urine samples were collected on an opportunistic basis and analysed for IAG concentration (normalised against creatinine content to account for changes in urinary volume) using reversed phase HPLC with UV detection. RESULTS: Statistical analysis (Mann-Whitney tests) showed highly significant increases (p=0.0002) in the levels of urinary IAG in the ASD group (median 942 microV per mmol/L of creatinine [interquartile range 521-1729], n=22) compared to asymptomatic controls (331 [163-456], n=18). Detailed retrospective analysis showed that gender (boys 625 microV per mmol/L of creatinine [294-1133], n=29; girls 460 [282-1193], n=11: P=0.79) and age (control donor median 10 years [8-14], n=15; ASD median 9 years [7-11] n=22: P=0.54) were not significantly correlated with IAG levels in this non-blinded volunteer study. CONCLUSIONS: Our results strongly suggest that urinary titres of IAG may constitute an objective diagnostic indicator for ASD. Mechanisms for the involvement of IAG in ASD are discussed together with future strategies to address its specificity.

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Afzal N, Murch S, Thirrupathy K, Berger L, Fagbemi A, Heuschkel R. Constipation with acquired megarectum in children with autism. Pediatrics. 2003 Oct;112(4):939-42.

Centre for Pediatric Gastroenterology, Royal Free Hospital, Hampstead, London, United Kingdom.

OBJECTIVE: Recent evidence suggests that autistic children may have significant gastrointestinal symptoms. Although constipation occurs in 2% to 5% of healthy children, its clinical diagnosis is often difficult in children with behavioral disorders. We thus aimed to assess the prevalence of fecal loading in autistic children with gastrointestinal symptoms and to identify possible predictors of constipation. METHODS: We studied abdominal radiographs of 103 autistic children (87 boys) who were referred for gastroenterological assessment, in comparison with 29 control radiographs from children who were referred to the emergency department, most with abdominal pain. Radiographs were scored independently, in blinded manner, by 4 pediatric gastroenterologists and a radiologist. The severity of constipation was determined using a validated index. Details of stool habit, abdominal pain, dietary history, and laxative use were obtained from case notes. RESULTS: The incidence of constipation in the control subjects with abdominal pain was higher than reported for normal children. Despite this, moderate or severe constipation was more frequent in the autistic group than in the control subjects (36% vs 10%). Analysis of rectosigmoid loading showed more striking differences (54.4% of autistic children had moderate/severe loading or acquired megarectum compared with 24.1% of control subjects). Multivariate regression analysis showed consumption of milk to be the strongest predictor of constipation in the autistic group, whereas stool frequency, gluten consumption, soiling, and abdominal pain were not predictive of constipation. CONCLUSIONS: Constipation is a frequent finding in children with gastrointestinal symptoms and autism, particularly in the rectosigmoid colon, often with acquired megarectum. The absence of any correlation between the clinical history and the degree of fecal impaction in autistic children confirms the importance of an abdominal radiograph in the assessment of their degree of constipation. 

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Welch MG, Keune JD, Welch-Horan TB, Anwar N, Anwar M, Ruggiero DA. Secretin activates visceral brain regions in the rat including areas abnormal in autism. Cell Mol Neurobiol. 2003 Oct;23(4-5):817-37.

Abstract:

Department of Psychiatry, Columbia University College of Physicians and Surgeons, NYSPI, 1051 Riverside Drive, New York, New York 10032, USA. mgw13@columbia.edu

1. The aim of this study was to determine whether central networks are involved in the presumptive behavioral and autonomic regulatory actions of secretin, a gut hormone that has been reported to have ameliorative effects in autistic children. 2. Central neural responses monitored by regional c-fos gene expression were examined in response to intracerebroventricular secretin injection in awake, freely-moving Sprague-Dawley rats. Tissue sections were incubated in an antibody to the c-fos gene product, Fos, and processed immunohistochemically. 3. Qualitative differences in Fos immunoreactivity in stress adaptation and visceral representation areas of the brain were observed between secretin- and vehicle-infused age-matched pairs (n = 4 pairs). Secretin-activated regions include the area postrema, dorsal motor nucleus, medial region of the nucleus of the solitary tract and its relay station in the lateral tegmentum, locus ceruleus, ventral periaqueductal gray, periventricular thalamic nucleus, paraventricular hypothalamus magnocellularis, medial and central amygdala, lateral septal complex as well as ependymal and subependymal nuclei lining the third ventricle. Specific areas of the cerebral cortex were heavily labeled in secretin-treated rats, as compared to controls: the medial bank of the anterior prefrontal cortex, orbitofrontal cortex, the piriform cortex. and the anterior olfactory nucleus. Secretin attenuated Fos immunoreactivity in the dorsal periaqueductal gray, intralaminar thalamus, medial parvicellular compartment of the hypothalamus, supraoptic nucleus of the hypothalamus, lateral amygdala, motor cortex, and the somatosensory and association areas of the parietal cortex. 4. Secretin alters the activity of structures involved in behavioral conditioning of stress adaptation and visceral reflex reactions. This study predicts a possible cellular mechanism, activation of third ventricular ependymal and subependymal cells, as well as central regulatory actions of secretin. The physiological effects of secretin on behavioral, endocrine, autonomic and sensory neuronal activation patterns, together, contribute to central c-fos activation. Secretin alters the activity of structures involved in behavioral conditioning of stress adaptation and visceral reflex reactions. This study predicts a possible cellular mechanism, activation of third ventricular ependymal and subependymal cells, and central regulatory actions of secretin. The physiological effects of secretin on behavioral, endocrine, autonomic and sensory neuronal activation patterns, together, contribute to central c-fos activation. These findings mandate further investigation of secretin as a brain/gut stress regulatory hormone.

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Latcham F, Merino F, Lang A, Garvey J, Thomson MA, Walker-Smith JA, Davies SE, Phillips AD, Murch SH: A consistent pattern of minor immunodeficiency and subtle enteropathy in children with multiple food allergy. J Pediatr. 2003 Jul;143(1):39-47.

Centre for Paediatric Gastroenterology and Department of Dietetics and Histopathology, Royal Free and University College School of Medicine, London, United Kingdom.

OBJECTIVE: Although immunoglobulin (Ig)E-mediated allergies are readily identifiable, non-IgE-mediated allergies present more diagnostic difficulty. We performed a formal retrospective analysis to determine whether there is a recognizable clinical pattern in children. METHODS: We studied 121 children (mean age, 17.3 months) with multiple food allergies who were recruited on the basis of adequate immunological assessment by using case notes and parental questionnaire. RESULTS: Group 1 (n=44) had rapid reactions to dietary antigens, of whom 41 also showed delayed reactions. Group 2 (n=77) had delayed reactions only. Mean IgE was increased in group 1 but both groups otherwise shared a pattern of increased IgG1, decreased IgG2/4, and low-normal IgA. Lymphocyte subsets were skewed, with an increased percentage of CD4 and CD19 and decreased CD8 and natural killer cells. Gastroesophageal reflux, esophagitis, subtle enteropathy, and constipation were frequent in both groups. Of 55 exclusively breast-fed infants, 44 sensitized before weaning. Twenty-one of the mothers suffered from autoimmunity. CONCLUSIONS: There appears to be a recognizable pattern of immune deviation and minor enteropathy in children with multiple food allergy, irrespective of the speed of reactions. Disturbed gut motility is particularly common, as is a maternal history of autoimmunity.

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White JF.: Intestinal pathophysiology in autism. Exp Biol Med (Maywood). 2003 Jun;228(6):639-49.

Department of Physiology, Emory University, Atlanta, Georgia 30322, USA. jfwhite@physio.emory.edu

Autism is a life-long developmental disorder affecting as many as 1 in 500 children. The causes for this profound disorder are largely unknown. Recent research has uncovered pathology in the gastrointestinal tract of autistic children. The pathology, reported to extend from the esophagus to the colon, is described here along with other studies pointing to a connection between diet and the severity of symptoms expressed in autism. The evidence that there is impaired intestinal permeability in autism is reviewed, and various theories are discussed by which a leaky gut could develop. Lastly, some possible ways in which impaired gastrointestinal function might influence brain function are discussed.

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Molloy CA, Manning-Courtney P.: Prevalence of chronic gastrointestinal symptoms in children with autism and autistic spectrum disorders. Autism. 2003 Jun;7(2):165-71.

Abstract:

Center for Epidemiology and Biostatistics, Cincinnati Children's Hospital Medical Center, OH 45229-3039, USA. Cynthia.molloy@chmcc.org

The purpose of this study was to estimate the prevalence of chronic gastrointestinal symptoms in a general population of children with autism or autistic spectrum disorder (ASD). The study site was a clinic specializing in ASD in a large pediatric medical center serving a 10 county area in the midwestern USA. In a sample of 137 children, age 24-96 months, classified as having autism or ASD by the Autism Diagnostic Observation Schedule-Generic, 24 percent had a history of at least one chronic gastrointestinal symptom. The most common symptom was diarrhea, which occurred in 17 percent. There was no association between chronic gastrointestinal symptoms and a history of developmental regression. The potential phenotypic association between autism and gastrointestinal symptoms is discussed.

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Reichelt KL, Knivsberg AM. Can the pathophysiology of autism be explained by the nature of the discovered urine peptides? Nutr Neurosci. 2003 Feb;6(1):19-28.

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Buie T, Winter H, Kushak, R. Preliminary findings in gastrointestinal investigation of autistic patients. 2002. 

Summary:

Harvard University and Mass General Hospital, http://www.ladders.org/autism.php

111 patients evaluated, ages 14 Months to 20 Years, all with GI symptoms of pain or diarrhea. Endoscopic findings: Esophagitis in 23 (20%), Gastritis in 14 (12%); 4 had Helicobacter pylori; Duodenitis in 11 (10%); 2 had Celiac Sprue; Eosinophilic Inflammation in 5 (5%). 10 out of 90 tested (11%) had unusually low enzyme activity: 2 with total pancreatic insufficiency and 5 with multiple enzyme defects. Lactase deficiency was found in 55% of ASD children tested, and combined deficiency of disacchraridase enzymes was found in 15%. Enzyme assays correlate well with hydrogen breath tests. Colitis was found in 11 of 89 patients (12%), none with features of Ulcerative Colitis or Crohn's. Histologic (biopsy reviewed) lymphoid nodular hyperplasia was found in 15 of 89 patients (16%). Eosinophilic inflammation was found in 13 of 89 patients (14%); cause or significance is unclear. Conclusions: more than 50% of autistic children appear to have GI symptoms, food allergies, and maldigestion or malabsorption issues. We need large, evidence-based studies need to be done in order to fully understand the gut-brain association in autism.  

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Krigsman, A, et al: Preliminary data presented at congressional hearing. 2002 Jun.  

Summary:  

New York University School of  Medicine: www.med.nyu.edu   

We examined 43 patients with autism, in whom we demonstrated enterocolitis in 65% and terminal ileal LNH in 90%. As of November, 2002, our total patient population now stands at 82, and the percentages of enterocolitis and LNH are essentially unchanged. Additional studies will follow.

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Whiteley P, Shattock P: Biochemical aspects in autism spectrum disorders: updating the opioid-excess theory and presenting new opportunities for biomedical intervention. Expert Opin Ther Targets. 2002 Apr;6(2):175-83.  

Abstract:  

Autism Research Unit, School of Sciences (Health), University of Sunderland, Sunderland, SR2 7EE, UK. aru@sunderland.ac.uk  

Autism is a lifelong condition usually described as affecting social, cognitive and imaginative abilities. For many years, parents and some professionals have observed that in concordance with the behavioural and psychological symptoms of the condition, there are a number of physiological and biochemical correlates which may also be of relevance to the syndrome. One area of interest that encompasses many of these observations is the opioid-excess theory of autism. The main premise of this theory is that autism is the result of a metabolic disorder. Peptides with opioid activity derived from dietary sources, in particular foods that contain gluten and casein, pass through an abnormally permeable intestinal membrane and enter the central nervous system (CNS) to exert an effect on neurotransmission, as well as producing other physiologically-based symptoms. Numerous parents and professionals worldwide have found that removal of these exogenously derived compounds through exclusion diets can produce some amelioration in autistic and related behaviours. There is a surprisingly long history of research accompanying these ideas. The aim of this paper is to review the accompanying evidence in support of this theory and present new directions of intervention as a result of it.

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Vojdani A, Campbell AW, Anyanwu E, Kashanian A, Bock K, Vojdani E: Antibodies to neuron-specific antigens in children with autism: possible cross-reaction with encephalitogenic proteins from milk, Chlamydia pneumoniae and Streptococcus group A. J Neuroimmunol 2002 Aug;129(1-2):168-77.

Abstract:

Section of Neuroimmunology, Immunosciences Laboratory, Inc., 8693 Wilshire Boulevard, Suite 200, Beverly Hills, CA 90211, USA. immunsci@ix.netcom.com

We measured autoantibodies against nine different neuron-specific antigens and three cross-reactive peptides in the sera of autistic subjects and healthy controls by means of enzyme-linked immunosorbent assay (ELISA) testing. The antigens were myelin basic protein (MBP), myelin-associated glycoprotein (MAG), ganglioside (GM1), sulfatide (SULF), chondroitin sulfate (CONSO4), myelin oligodendrocyte glycoprotein (MOG), alpha,beta-crystallin (alpha,beta-CRYS), neurofilament proteins (NAFP), tubulin and three cross-reactive peptides, Chlamydia pneumoniae (CPP), streptococcal M protein (STM6P) and milk butyrophilin (BTN). Autistic children showed the highest levels of IgG, IgM and IgA antibodies against all neurologic antigens as well as the three cross-reactive peptides. These antibodies are specific because immune absorption demonstrated that only neuron-specific antigens or their cross-reactive epitopes could significantly reduce antibody levels. These antibodies may have been synthesized as a result of an alteration in the blood-brain barrier. This barrier promotes access of preexisting T-cells and central nervous system antigens to immunocompetent cells, which may start a vicious cycle. These results suggest a mechanism by which bacterial infections and milk antigens may modulate autoimmune responses in autism.

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Knivsberg AM, Reichelt KL, Hoien T, Nodland M: A randomised, controlled study of dietary intervention in autistic syndromes. Nutr Neurosci 2002 Sep;5(4):251-61.

Center for Reading Research, Stavanger University College, Norway. ann-mari.knivsberg@slf.his.no

Abstract:

Impaired social interaction, communication and imaginative skills characterize autistic syndromes. In these syndromes urinary peptide abnormalities, derived from gluten, gliadin, and casein, are reported. They reflect processes with opioid effect. The aim of this single blind study was to evaluate effect of gluten and casein-free diet for children with autistic syndromes and urinary peptide abnormalities. A randomly selected diet and control group with 10 children in each group participated. Observations and tests were done before and after a period of 1 year. The development for the group of children on diet was significantly better than for the controls.

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Kidd PM.: Autism, an extreme challenge to integrative medicine. Part: 1: The knowledge base. Altern Med Rev. 2002 Aug;7(4):292-316.

Kidd PM.: Autism, an extreme challenge to integrative medicine. Part 2: medical management. Altern Med Rev. 2002 Dec;7(6):472-99.

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Hadjivassiliou M, Grunewald RA, Davies-Jones GA. Gluten sensitivity as a neurological illness. J Neurol Neurosurg Psychiatry. 2002 May;72(5):560-3. [No abstract available]

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Finegold SM, Molitoris D, Song Y, Liu C, Vaisanen ML, Bolte E, McTeague M, Sandler R, Wexler H, Marlowe EM, Collins MD, Lawson PA, Summanen P, Baysallar M, Tomzynski TJ, Read E, Johnson E, Rolfe R, Nasir P, Shah H, Haake DA, Manning P, Kaul A. Gastrointestinal microflora studies in late-onset autism. Clin Infect Dis. 2002 Sep 1;35(Suppl 1):S6-S16.

Infectious Diseases Section, Veterans Affairs Medical Center, West Los Angeles, CA, USA. sidfinegol@aol.com

Some cases of late-onset (regressive) autism may involve abnormal flora because oral vancomycin, which is poorly absorbed, may lead to significant improvement in these children. Fecal flora of children with regressive autism was compared with that of control children, and clostridial counts were higher. The number of clostridial species found in the stools of children with autism was greater than in the stools of control children. Children with autism had 9 species of Clostridium not found in controls, whereas controls yielded only 3 species not found in children with autism. In all, there were 25 different clostridial species found. In gastric and duodenal specimens, the most striking finding was total absence of non-spore-forming anaerobes and microaerophilic bacteria from control children and significant numbers of such bacteria from children with autism. These studies demonstrate significant alterations in the upper and lower intestinal flora of children with late-onset autism and may provide insights into the nature of this disorder.

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Wakefield AJ, Puleston JM, Montgomery SM, Anthony A, O'Leary JJ, Murch SH. Review article: the concept of entero-colonic encephalopathy, autism and opioid receptor ligands. Aliment Pharmacol Ther 2002 Apr;16(4):663-74.

Abstract:

Inflammatory Bowel Disease Study Group, Centre for Gastroenterology, Department of Medicine, Royal Free and University College Medical School, London, UK. wakers@aol.com

There is growing awareness that primary gastrointestinal pathology may play an important role in the inception and clinical expression of some childhood developmental disorders, including autism. In addition to frequent gastrointestinal symptoms, children with autism often manifest complex biochemical and immunological abnormalities. The gut-brain axis is central to certain encephalopathies of extra-cranial origin, hepatic encephalopathy being the best characterized. Commonalities in the clinical characteristics of hepatic encephalopathy and a form of autism associated with developmental regression in an apparently previously normal child, accompanied by immune-mediated gastrointestinal pathology, have led to the proposal that there may be analogous mechanisms of toxic encephalopathy in patients with liver failure and some children with autism. Aberrations in opioid biochemistry are common to these two conditions, and there is evidence that opioid peptides may mediate certain aspects of the respective syndromes. The generation of plausible and testable hypotheses in this area may help to identify new treatment options in encephalopathies of extra-cranial origin. Therapeutic targets for this autistic phenotype may include: modification of diet and entero-colonic microbial milieu in order to reduce toxin substrates, improve nutritional status and modify mucosal immunity; anti-inflammatory/immunomodulatory therapy; and specific treatment of dysmotility, focusing, for example, on the pharmacology of local opioid activity in the gut.

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Uhlmann V, Martin CM, Sheils O, Pilkington L, Silva I, Killalea A, Murch SB, Walker-Smith J, Thomson M, Wakefield AJ, O'Leary JJ. Potential viral pathogenic mechanism for new variant inflammatory bowel disease. Mol Pathol 2002 Apr;55(2):84-90

Abstract:

Department of Pathology, Coombe Women's Hospital, Dublin 8, Ireland .

AIMS: A new form of inflammatory bowel disease (ileocolonic lymphonodular hyperplasia) has been described in a cohort of children with developmental disorder. This study investigates the presence of persistent measles virus in the intestinal tissue of these patients (new variant inflammatory bowel disease) and a series of controls by molecular analysis. METHODS: Formalin fixed, paraffin wax embedded and fresh frozen biopsies from the terminal ileum were examined from affected children and histological normal controls. The measles virus Fusion (F) and Haemagglutinin (H) genes were detected by TaqMan reverse transcription polymerase chain reaction (RT-PCR) and the Nucleocapsid (N) gene by RT in situ PCR. Localisation of the mRNA signal was performed using a specific follicular dendritic cell antibody. RESULTS: Seventy five of 91 patients with a histologically confirmed diagnosis of ileal lymphonodular hyperplasia and enterocolitis were positive for measles virus in their intestinal tissue compared with five of 70 control patients. Measles virus was identified within the follicular dendritic cells and some lymphocytes in foci of reactive follicular hyperplasia. The copy number of measles virus ranged from one to 300,00 copies/ng total RNA. CONCLUSIONS: The data confirm an association between the presence of measles virus and gut pathology in children with developmental disorder.

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Torrente F, Ashwood P, Day R, Machado N, Furlano RI, Anthony A, Davies SE, Wakefield AJ, Thomson MA, Walker-Smith JA, Murch SH. Small intestinal enteropathy with epithelial IgG and complement deposition in children with regressive autism. Mol Psychiatry 2002;7(4):375-82, 334

Abstract:

Centre for Paediatric Gastroenterology, Royal Free & University College Medical School , London , UK .

We have reported lymphocytic colitis in children with regressive autism, with epithelial damage prominent. We now compare duodenal biopsies in 25 children with regressive autism to 11 with coeliac disease, five with cerebral palsy and mental retardation and 18 histologically normal controls. Immunohistochemistry was performed for lymphocyte and epithelial lineage and functional markers. We determined the density of intraepithelial and lamina propria lymphocyte populations, and studied mucosal immunoglobulin and complement C1q localisation. Standard histopathology showed increased enterocyte and Paneth cell numbers in the autistic children. Immunohistochemistry demonstrated increased lymphocyte infiltration in both epithelium and lamina propria with upregulated crypt cell proliferation, compared to normal and cerebral palsy controls. Intraepithelial lymphocytes and lamina propria plasma cells were lower than in coeliac disease, but lamina propria T cell populations were higher and crypt proliferation similar. Most strikingly, IgG deposition was seen on the basolateral epithelial surface in 23/25 autistic children, co-localising with complement C1q. This was not seen in the other conditions. These findings demonstrate a novel form of enteropathy in autistic children, in which increases in mucosal lymphocyte density and crypt cell proliferation occur with epithelial IgG deposition. The features are suggestive of an autoimmune lesion.  

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Hadjivassiliou M, Boscolo S, Davies-Jones GA, Grunewald RA, Not T, Sanders DS, Simpson JE, Tongiorgi E, Williamson CA, Woodroofe NM: The humoral response in the pathogenesis of gluten ataxia. Neurology 2002 Apr 23;58(8):1221-6.

Abstract:

Department of Clinical Neurology, The Royal Hallamshire Hospital, Sheffield, UK. m.hadjivassiliou@sheffield.ac.uk

OBJECTIVE: To characterize humoral response to cerebellum in patients with gluten ataxia. BACKGROUND: Gluten ataxia is a common neurologic manifestation of gluten sensitivity. METHODS: The authors assessed the reactivity of sera from patients with gluten ataxia (13), newly diagnosed patients with celiac disease without neurologic dysfunction (24), patients with other causes of cerebellar degeneration (11), and healthy control subjects (17) using indirect immunocytochemistry on human cerebellar and rat CNS tissue. Cross-reactivity of a commercial IgG antigliadin antibody with human cerebellar tissue also was studied. RESULTS: Sera from 12 of 13 patients with gluten ataxia stained Purkinje cells strongly. Less intense staining was seen in some but not all sera from patients with newly diagnosed celiac disease without neurologic dysfunction. At high dilutions (1:800) staining was seen only with sera from patients with gluten ataxia but not in control subjects. Sera from patients with gluten ataxia also stained some brainstem and cortical neurons in rat CNS tissue. Commercial anti-gliadin antibody stained human Purkinje cells in a similar manner. Adsorption of the antigliadin antibodies using crude gliadin abolished the staining in patients with celiac disease without neurologic dysfunction, but not in those with gluten ataxia. CONCLUSIONS: Patients with gluten ataxia have antibodies against Purkinje cells. Antigliadin antibodies cross-react with epitopes on Purkinje cells.

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Garvey J: Diet in autism and associated disorders. J Fam Health Care 2002;12(2):34-8.

Abstract:

Royal Free Hospital, London.

A dietitian discusses the theory that peptides with opioid activity may cause or trigger autism. The use of an exclusion diet to treat autism is explained, weighing the potential benefits against some of the practical difficulties of keeping to a strict exclusion diet. The use of nutritional supplements is described. An abnormal gut flora has also been implicated in autism and the use of probiotics and prebiotics in improving the integrity of the gut mucosa is also discussed.

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Cornish E: Gluten and casein free diets in autism: a study of the effects on food choice and nutrition. J Hum Nutr Diet 2002 Aug;15(4):261-9.

Abstract:

Senior Community Dietitian, Community Nutrition Service, South Derbyshire Community Health NHS Trust, Dar es Salaam, Tanzania.

BACKGROUND: There is growing interest in possible dietary involvement in the aetiology and treatment of Autistic Spectrum Disorders (ASD). Research has focused on the physiological and behavioural effects of dietary change but has not examined the effect of exclusion diets on nutritional intake. AIMS: The aim of this study was to examine whether the removal of major dietary staples placed children with autism at risk of nutrient deficiency and compares their food choice with ASD children not following gluten and/or casein free diets. METHODS: A postal questionnaire was sent to parents of children aged 3-16 years, diagnosed with ASD belonging to the National Autistic Society in Leicestershire and southern Derbyshire. Detailed dietary information and a 3-day food diary were collected. The sample size was small: those using gluten/casein free diets (n = 8) and those not following diet (n = 29). RESULTS: Nutrient intakes fell below the Lower Reference Nutrient Intake (LRNI) in 12 children (32%) for zinc, calcium, iron, vitamin A, vitamin B12 and riboflavin in the nondiet group and four children (50%) for zinc and calcium in the diet group. Fruit and vegetable intakes were higher and cereal, bread and potato consumption were lower in those children using gluten and/or casein free diets. CONCLUSION: No significant differences in the energy, protein and micronutrient intakes were found between the two groups of children. A longitudinal prospective study is suggested to examine whether differences in food choice are the result of dietary intervention or the prerequisite for the successful application of diet in this special group of children.

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Wakefield AJ, Puleston JM, Montgomery SM, Anthony A, O'Leary JJ, Murch SH: Review article: the concept of entero-colonic encephalopathy, autism and opioid receptor ligands. Aliment Pharmacol Ther. 2002 Apr;16(4):663-74.

Inflammatory Bowel Disease Study Group, Centre for Gastroenterology, Department of Medicine, Royal Free and University College Medical School, London, UK. wakers@aol.com

There is growing awareness that primary gastrointestinal pathology may play an important role in the inception and clinical expression of some childhood developmental disorders, including autism. In addition to frequent gastrointestinal symptoms, children with autism often manifest complex biochemical and immunological abnormalities. The gut-brain axis is central to certain encephalopathies of extra-cranial origin, hepatic encephalopathy being the best characterized. Commonalities in the clinical characteristics of hepatic encephalopathy and a form of autism associated with developmental regression in an apparently previously normal child, accompanied by immune-mediated gastrointestinal pathology, have led to the proposal that there may be analogous mechanisms of toxic encephalopathy in patients with liver failure and some children with autism. Aberrations in opioid biochemistry are common to these two conditions, and there is evidence that opioid peptides may mediate certain aspects of the respective syndromes. The generation of plausible and testable hypotheses in this area may help to identify new treatment options in encephalopathies of extra-cranial origin. Therapeutic targets for this autistic phenotype may include: modification of diet and entero-colonic microbial milieu in order to reduce toxin substrates, improve nutritional status and modify mucosal immunity; anti-inflammatory/immunomodulatory therapy; and specific treatment of dysmotility, focusing, for example, on the pharmacology of local opioid activity in the gut.

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Knivsberg AM, Reichelt KL, Nodland M: Reports on dietary intervention in autistic disorders. Nutr Neurosci 2001;4(1):25-37.

Center for Reading Research, Stavanger College, Norway. ann-mari.knivsberg@slf.his.no

Abstract:

Autism is a developmental disorder for which no cure currently exists. Gluten and/or casein free diet has been implemented to reduce autistic behaviour, in addition to special education, since early in the eighties. Over the last twelve years various studies on this dietary intervention have been published in addition to anecdotal, parental reports. The scientific studies include both groups of participants as well as single cases, and beneficial results are reported in all, but one study. While some studies are based on urinary peptide abnormalities, others are not. The reported results are, however, more or less identical; reduction of autistic behaviour, increased social and communicative skills, and reappearance of autistic traits after the diet has been broken.

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Jyonouchi H, Sun S, Le H. Proinflammatory and regulatory cytokine production associated with innate and adaptive immune responses in children with autism spectrum disorders and developmental regression. J Neuroimmunol 2001 Nov 1;120(1-2):170-9

Abstract:
Department of Pediatrics, University ofMinnesota, MMC 610 FUMC, 420 Delaware Street SE, Minneapolis, MN55455, USA. jyono001@tc.umn.edu

We determined innate and adaptive immune responses in children with developmental regression and autism spectrum disorders (ASD, N=71), developmentally normal siblings (N=23), and controls (N=17). With lipopolysaccharide (LPS), a stimulant for innate immunity, peripheral blood mononuclear cells (PBMCs) from 59/71 (83.1%) ASD patients produced >2 SD above the control mean (CM) values of TNF-alpha, IL-1beta, and/or IL-6 produced by control PBMCs. ASD PBMCs produced higher levels of proinflammatory/counter-regulatory cytokines without stimuli than controls. With stimulants of phytohemagglutinin (PHA), tetanus, IL-12p70, and IL-18, PBMCs from 47.9% to 60% of ASD patients produced >2 SD above the CM values of TNF-alpha depending on stimulants. Our results indicate excessive innate immune responses in a number of ASD children that may be most evident in TNF-alpha production.

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Hadjivassiliou M, Grunewald RA, Lawden M, Davies-Jones GA, Powell T, Smith CM: Headache and CNS white matter abnormalities associated with gluten sensitivity. Neurology 2001 Feb 13;56(3):385-8.

Abstract:

Department of Clinical Neurology, The Royal HallamshireHospital, Sheffield,UK. m.hadjivassiliou@sheffield.ac.uk

The authors describe 10 patients with gluten sensitivity and abnormal MRI. All experienced episodic headache, six had unsteadiness, and four had gait ataxia. MRI abnormalities varied from confluent areas of high signal throughout the white matter to foci of high signal scattered in both hemispheres. Symptomatic response to gluten-free diet was seen in nine patients.  

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Dubynin VA , Ivleva IuA, Malinovskaia IV, Kamenskii AA, Andreeva LA, Alfeeva LIu, Miasoedov NF: Changes in beta-casomorphine-7 effect on behavior of albino rat pups in postnatal development. [Article in Russian]. Zh Vyssh Nerv Deiat Im I P Pavlova 2001 May-Jun;51(3):386-9.  

Abstract:

Lomonosov State University, Institute of Molecular Genetics, Russian Academy of Sciences, Moscow.

The analgetic effect of heptapeptide beta-casomorphine-7 in newborn albino rats (20 mg/kg, i.p.) was recorded already 14 days after birth in the "hot plate" test. The first signs of a possible influence of the peptide on motor activity were observed only at the age of 28 days. They are expressed in impairment of motor coordination and change in locomotion level ("Opto-Varimex" test). The obtained evidence probably reflect the processes of discrete maturation of different components of the opioid system of the rat brain.

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Furlano RI, Anthony A, Day R, Brown A, McGarvey L, Thomson MA, Davies SE, Berelowitz M, Forbes A, Wakefield AJ, Walker-Smith JA, Murch SH. Colonic CD8 and gamma delta T-cell infiltration with epithelial damage in children with autism. J Pediatr. 2001 Mar;138(3):366-72.

University Department of Paediatric Gastroenterology, the Inflammatory Bowel Diseases Study Group, Royal Free and University College School of Medicine, London, United Kingdom.

OBJECTIVES: We have reported colitis with ileal lymphoid nodular hyperplasia (LNH) in children with regressive autism. The aims of this study were to characterize this lesion and determine whether LNH is specific for autism. METHODS: Ileo-colonoscopy was performed in 21 consecutively evaluated children with autistic spectrum disorders and bowel symptoms. Blinded comparison was made with 8 children with histologically normal ileum and colon, 10 developmentally normal children with ileal LNH, 15 with Crohn's disease, and 14 with ulcerative colitis. Immunohistochemistry was performed for cell lineage and functional markers, and histochemistry was performed for glycosaminoglycans and basement membrane thickness. RESULTS: Histology demonstrated lymphocytic colitis in the autistic children, less severe than classical inflammatory bowel disease. However, basement membrane thickness and mucosal gamma delta cell density were significantly increased above those of all other groups including patients with inflammatory bowel disease. CD8(+) density and intraepithelial lymphocyte numbers were higher than those in the Crohn's disease, LNH, and normal control groups; and CD3 and plasma cell density and crypt proliferation were higher than those in normal and LNH control groups. Epithelial, but not lamina propria, glycosaminoglycans were disrupted. However, the epithelium was HLA-DR(-), suggesting a predominantly T(H)2 response. INTERPRETATION: Immunohistochemistry confirms a distinct lymphocytic colitis in autistic spectrum disorders in which the epithelium appears particularly affected. This is consistent with increasing evidence for gut epithelial dysfunction in autism.

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Cavataio F, Carroccio A, Iacono G. Milk-induced reflux in infants less than one year of age. J Pediatr Gastroenterol Nutr 2000;30 Suppl:S36-44

Abstract:

1st Divisione Pediatria, Gastroenterologia, Ospedale dei Bambini G. Di Cristina, Palermo, Italy.

Cow's milk allergy (CMA) and gastroesophageal reflux are considered to be among the most common disturbances in infants less than 1 year of age. In recent years, the relationship existing between these two entities has been investigated and some important conclusions have been reached: In just under half the cases of GER in infants less than 1 year of age there is an association with CMA; in a high proportion of cases, GER is not only CMA-associated but also CMA-induced; the frequency of this association should induce pediatricians to screen for possible concomitant CMA in all infants with GER less than 1 year old; with the exception of some patients with mild typical CMA manifestations (diarrhea, dermatitis, or rhinitis), the symptoms of GER associated with CMA are the same as those observed in primary GER; immunologic tests are useful in a suspected association between GER and CMA; and subjects with GER secondary to CMA show a typical pH-monitoring tracing pattern, characterized by a progressive, slow decrease in esophageal pH between feedings. This article reviews the main features of the two diseases, stressing the aspects in common between them and comments on all the listed points.

NOTE: Reflux has been reported in infants later dx'd with autism.  

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Wakefield AJ, Anthony A, Murch SH, Thomson M, Montgomery SM, Davies S, O'Leary JJ, Berelowitz M, Walker-Smith JA: Enterocolitis in children with developmental disorders. Am J Gastroenterol. 2000 Sep;95(9):2285-95. University Department of Medicine, Royal Free and University College Medical School, London, United Kingdom.

OBJECTIVE: Intestinal pathology, i.e., ileocolonic lymphoid nodular hyperplasia (LNH) and mucosal inflammation, has been described in children with developmental disorders. This study describes some of the endoscopic and pathological characteristics in a group of children with developmental disorders (affected children) that are associated with behavioral regression and bowel symptoms, and compares them with pediatric controls. METHODS: Ileocolonoscopy and biopsy were performed on 60 affected children (median age 6 yr, range 3-16; 53 male). Developmental diagnoses were autism (50 patients), Asperger's syndrome (five), disintegrative disorder (two), attention deficit hyperactivity disorder (ADHD) (one), schizophrenia (one), and dyslexia (one). Severity of ileal LNH was graded (0-3) in both affected children and 37 developmentally normal controls (median age 11 yr, range 2-13 yr) who were investigated for possible inflammatory bowel disease (IBD). Tissue sections were reviewed by three pathologists and scored on a standard proforma. Data were compared with ileocolonic biopsies from 22 histologically normal children (controls) and 20 children with ulcerative colitis (UC), scored in an identical manner. Gut pathogens were sought routinely. RESULTS: Ileal LNH was present in 54 of 58 (93%) affected children and in five of 35 (14.3%) controls (p < 0.001). Colonic LNH was present in 18 of 60 (30%) affected children and in two of 37 (5.4%) controls (p < 0.01). Histologically, reactive follicular hyperplasia was present in 46 of 52 (88.5%) ileal biopsies from affected children and in four of 14 (29%) with UC, but not in non-IBD controls (p < 0.01). Active ileitis was present in four of 51 (8%) affected children but not in controls. Chronic colitis was identified in 53 of 60 (88%) affected children compared with one of 22 (4.5%) controls and in 20 of 20 (100%) with UC. Scores of frequency and severity of inflammation were significantly greater in both affected children and those with UC, compared with controls (p < 0.001). CONCLUSIONS: A new variant of inflammatory bowel disease is present in this group of children with developmental disorders.

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Sandler RH, Finegold SM, Bolte ER, Buchanan CP, Maxwell AP, Vaisanen ML, Nelson MN, Wexler HM. Short-term benefit from oral vancomycin treatment of regressive-onset autism. J Child Neurol. 2000 Jul;15(7):429-35.

Section of Pediatric Gastroenterology and Nutrition, Rush Children's Hospital, Rush Medical College, Chicago, IL 60612, USA. rushstudy@aol.com

In most cases symptoms of autism begin in early infancy. However, a subset of children appears to develop normally until a clear deterioration is observed. Many parents of children with "regressive"-onset autism have noted antecedent antibiotic exposure followed by chronic diarrhea. We speculated that, in a subgroup of children, disruption of indigenous gut flora might promote colonization by one or more neurotoxin-producing bacteria, contributing, at least in part, to their autistic symptomatology. To help test this hypothesis, 11 children with regressive-onset autism were recruited for an intervention trial using a minimally absorbed oral antibiotic. Entry criteria included antecedent broad-spectrum antimicrobial exposure followed by chronic persistent diarrhea, deterioration of previously acquired skills, and then autistic features. Short-term improvement was noted using multiple pre- and post-therapy evaluations. These included coded, paired videotapes scored by a clinical psychologist blinded to treatment status; these noted improvement in 8 of 10 children studied. Unfortunately, these gains had largely waned at follow-up. Although the protocol used is not suggested as useful therapy, these results indicate that a possible gut flora-brain connection warrants further investigation, as it might lead to greater pathophysiologic insight and meaningful prevention or treatment in a subset of children with autism.

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Carroccio A, Montalto G, Custro N, Notarbartolo A, Cavataio F, D'Amico D, Alabrese D, Iacono G: Evidence of very delayed clinical reactions to cow's milk in cow's milk-intolerant patients. Allergy 2000 Jun;55(6):574-9.  

Abstract:
 
Internal Medicine, University Hospital of Palermo, Italy.

BACKGROUND: In patients with cow's milk protein intolerance (CMPI), delayed clinical reactions to cow's milk (CM) ingestion may be misdiagnosed if the clinical symptoms are not "classical" and there is a long time lapse between ingestion of CM and the clinical reaction. The aim was to evaluate the clinical outcome of CMPI in a cohort of CM-intolerant children, with particular attention to the occurrence of clinical manifestations beyond 72 h after CM challenge. METHODS: Eighty-six consecutive patients (44 boys, 42 girls) with new CMPI diagnoses were enrolled; median age at diagnosis was 4 months. Patients were followed up for a mean period of 40 months. In all patients, CMPI diagnosis was made on the observation of symptoms, their disappearance after elimination diet, and their reappearance on double-blind CM challenge. At CMPI diagnosis, immunologic tests to demonstrate IgE-mediated hypersensitivity were performed. After 12 months of CM-free diet, CM tolerance was re-evaluated with a CM challenge continued at home for up to 30 days, according to a double-blind, placebo-controlled method. Patients who did not achieve CM tolerance continued a CM-free diet and subsequently underwent yearly CM challenge. RESULTS: The percentages of CMPI patients who became CM-tolerant after 1, 2, and 3 years of CM-free diet were 30%, 54.5%, and 70%, respectively. At the end of the follow-up period, 26/86 subjects showed persistent CMPI; these patients had a higher percentage of positivity of total serum IgE (P<0.05), RAST (P<0.01), and cutaneous prick tests for CM antigens (P<0.001) than all the others. At CMPI diagnosis, all patients had a clinical reaction within 72 h from the beginning of the CM challenge; at the subsequent "cure" challenges, we observed patients who first reacted to CM more than 72 h after ingestion. In total, 10 out of 86 patients showed "very delayed reactions"; in these patients, the mean time between the beginning of CM challenge and the onset of a clinical symptom was 13.3 days (range 4-26 days). The number of "very late reactors" increased from the first to the third of the "cure" CM challenges, performed at yearly intervals. The "very delayed" CMPI manifestations in these subjects were constipation (five cases), wheezing (two cases), dermatitis plus constipation (two cases), and dermatitis alone (one case); in 6/10 patients, the symptoms observed at the "cure challenge" were different from those at CMPI onset. CONCLUSIONS: Very delayed clinical reactions to reintroduction of CM in the diet can occur in CMPI patients; thus, accurate follow-up and frequent outpatient observation in patients with a long history of CMPI are probably more useful and safer than prolonged CM challenge.

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Kawashima H, Mori T, Kashiwagi Y, Takekuma K, Hoshika A, Wakefield A. Detection and sequencing of measles virus from peripheral mononuclear cells from patients with inflammatory bowel disease and autism. Dig Dis Sci 2000 Apr;45(4):723-9.

Abstract:

Department of Paediatrics, Tokyo Medical University , Japan .

It has been reported that measles virus may be present in the intestine of patients with Crohn's disease. Additionally, a new syndrome has been reported in children with autism who exhibited developmental regression and gastrointestinal symptoms (autistic enterocolitis), in some cases soon after MMR vaccine. It is not known whether the virus, if confirmed to be present in these patients, derives from either wild strains or vaccine strains. In order to characterize the strains that may be present, we have carried out the detection of measles genomic RNA in peripheral mononuclear cells (PBMC) in eight patients with Crohn's disease, three patients with ulcerative colitis, and nine children with autistic enterocolitis. As controls, we examined healthy children and patients with SSPE, SLE, HIV-1 (a total of eight cases). RNA was purified from PBMC by Ficoll-paque, followed by reverse transcription using AMV; cDNAs were subjected to nested PCR for detection of specific regions of the hemagglutinin (H) and fusion (F) gene regions. Positive samples were sequenced directly, in nucleotides 8393-8676 (H region) or 5325-5465 (from noncoding F to coding F region). One of eight patients with Crohn disease, one of three patients with ulcerative colitis, and three of nine children with autism, were positive. Controls were all negative. The sequences obtained from the patients with Crohn's disease shared the characteristics with wild-strain virus. The sequences obtained from the patients with ulcerative colitis and children with autism were consistent with being vaccine strains. The results were concordant with the exposure history of the patients. Persistence of measles virus was confirmed in PBMC in some patients with chronic intestinal inflammation.

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Cade R, Privette M, Fregly M, Rowland N, Sun Z, Zele V, Wagemaker H, Edlestein C. Autism and schizophrenia: intestinal disorders. Nutritional Neuroscience 3: 57-72, 2000. [No abstract available]  

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Horvath K, Papadimitriou JC, Rabsztyn A, Drachenberg C, Tildon JT.  Gastrointestinal abnormalities in children with autistic disorder. J Pediatr 1999 Nov;135(5):559-63

Abstract:
Department of Pediatrics, University of Maryland School of Medicine , Baltimore , USA .

OBJECTIVES: Our aim was to evaluate the structure and function of the upper gastrointestinal tract in a group of patients with autism who had gastrointestinal symptoms. STUDY DESIGN: Thirty-six children (age: 5.7 +/- 2 years, mean +/- SD) with autistic disorder underwent upper gastrointestinal endoscopy with biopsies, intestinal and pancreatic enzyme analyses, and bacterial and fungal cultures. The most frequent gastrointestinal complaints were chronic diarrhea, gaseousness, and abdominal discomfort and distension. RESULTS: Histologic examination in these 36 children revealed grade I or II reflux esophagitis in 25 (69.4%), chronic gastritis in 15, and chronic duodenitis in 24. The number of Paneth's cells in the duodenal crypts was significantly elevated in autistic children compared with non-autistic control subjects. Low intestinal carbohydrate digestive enzyme activity was reported in 21 children (58.3%), although there was no abnormality found in pancreatic function. Seventy-five percent of the autistic children (27/36) had an increased pancreatico-biliary fluid output after intravenous secretin administration. Nineteen of the 21 patients with diarrhea had significantly higher fluid output than those without diarrhea. CONCLUSIONS: Unrecognized gastrointestinal disorders, especially reflux esophagitis and disaccharide malabsorption, may contribute to the behavioral problems of the non-verbal autistic patients. The observed increase in pancreatico-biliary secretion after secretin infusion suggests an upregulation of secretin receptors in the pancreas and liver. Further studies are required to determine the possible association between the brain and gastrointestinal dysfunctions in children with autistic disorder.

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Pedersen OS, Liu Y, Reichelt KL. Serotonin uptake stimulating peptide found in plasma of normal individuals and in some autistic urines. J Pept Res 1999 Jun;53(6):641-6  

Abstract:  

Research Institute, University of Oslo, Rikshospitalet, Norway.

We have isolated a tripeptide from normal plasma and autistic urines which stimulates the uptake of serotonin (5-HT) into platelets. This peptide was purified by high-performance liquid chromatography (HPLC) and characterized by sequenation and mass-spectrometry. Synthetic peptide showed co-chromatography with the biological sample in the HPLC systems used. Close to 60% of the autistic children diagnosed using the Diagnostic Statistical Manual III-R had an increased HPLC peak eluting like this peptide in their urines compared with controls.  

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Ek J, Stensrud M, Reichelt KL. Gluten-free diet decreases urinary peptide levels in children with celiac disease. J Pediatr Gastroenterol Nutr 1999 Sep;29(3):282-5.  

Abstract:  

Department of Pediatrics, Buskerud Central Hospital, Drammen, Norway.

BACKGROUND: Increased urine secretion of peptides has been found in celiac disease, probably resulting from increased intestinal uptake of peptides caused by damage to the small gut mucosa. METHODS: High-performance liquid chromatography of low-molecular-weight peptides in the urine was performed over 6 months, before and after a gluten-free diet was instituted in children who clinically improved while consuming the diet. RESULTS: A significant decrease of peptide levels was observed in children consuming the gluten-free diet. Certain peptide peaks thought to be gluten related decreased the most after the patients began the diet. CONCLUSIONS: Because the peptides decrease in patients consuming a gluten-free diet, it is reasonable to conclude that such peptides have a mostly dietary origin.

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Cade JR et al: Autism and schizophrenia linked to malfunctioning enzyme for milk protein digestion. Autism, Mar 1999. 

Sun Z, Cade JR, Fregly MJ, Privette RM. Caesomorphine induces Fos-like reactivity in discrete brain regions relevant to schizophrenia and autism. Autism 1999;3:67-84

Sun Z, Cade JR. A peptide found in schizophrenia and autism causes behavioral changes in rats. Autism 1999;3:85

Cade JR, Privette RM, Fregly M, Rowland N, Sun Z, Zele V, Wagemaker H Edelstein C: Autism and schizophrenia: Intestinal disorders. Nutritional Neuroscience 1999, 2, 57-72.

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Alberti A, Pirrone P, Elia M, Waring RH, Romano C: Sulphation deficit in "low-functioning" autistic children: a pilot study. Biol Psychiatry 1999 Aug 1;46(3):420-4.

Abstract:

Department of Pediatrics, Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Troina, Italy.

BACKGROUND: Parents of autistic children and autism support groups often report that autistic episodes are exacerbated when the children eat certain foodstuffs such as dairy products, chocolates, wheat, corn sugar, apples, and bananas. The hypothesis that autistic behavior might be related to metabolic dysfunctions has led us to investigate in a group of "low functioning" autistic children and in an age-matched control group each made up of 20 subjects, the sulphation capacity available. METHODS: Utilizing the biochemical characteristics of paracetamol we evaluated by high performance liquid chromatography, the urine paracetamol-sulfate/paracetamol-glucuronide (PS/PG) ratio in all subjects following administration of this drug. RESULTS: The PS/PG ratio in the group of autistic subjects gave a significantly lower results than the control group with p < .00002. CONCLUSIONS: The inability to effectively metabolize certain compounds particularly phenolic amines, toxic for the CNS, could exacerbate the wide spectrum of autistic behavior.

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Iacono G, Cavataio F, Montalto G, Florena A, Tumminello M, Soresi M, Notarbartolo A, Carroccio A: Intolerance of cow's milk and chronic constipation in children. New England Journal of Medicine 1998 / 339 (16) / 1100-1104.

Abstract:

Divisione di Pediatria, Ospedale G. Di Cristina, Palermo, Italy.

BACKGROUND: Chronic diarrhea is the most common gastrointestinal symptom of intolerance of cow's milk among children. On the basis of a prior open study, we hypothesized that intolerance of cow's milk can also cause severe perianal lesions with pain on defecation and consequent constipation in young children. METHODS: We performed a double-blind, crossover study comparing cow's milk with soy milk in 65 children (age range, 11 to 72 months) with chronic constipation (defined as having one bowel movement every 3 to 15 days). All had been referred to a pediatric gastroenterology clinic and had previously been treated with laxatives without success; 49 had anal fissures and perianal erythema or edema. After 15 days of observation, the patients received cow's milk or soy milk for two weeks. After a one-week washout period, the feedings were reversed. A response was defined as eight or more bowel movements during a treatment period. RESULTS: Forty-four of the 65 children (68 percent) had a response while receiving soy milk. Anal fissures and pain with defecation resolved. None of the children who received cow's milk had a response. In all 44 children with a response, the response was confirmed with a double-blind challenge with cow's milk. Children with a response had a higher frequency of coexistent rhinitis, dermatitis, or bronchospasm than those with no response (11 of 44 children vs. 1 of 21, P=0.05); they were also more likely to have anal fissures and erythema or edema at base line (40 of 44 vs. 9 of 21, P<0.001), evidence of inflammation of the rectal mucosa on biopsy (26 of 44 vs. 5 of 21, P=0.008), and signs of hypersensitivity, such as specific IgE antibodies to cow's-milk antigens (31 of 44 vs. 4 of 21, P<0.001). CONCLUSIONS: In young children, chronic constipation can be a manifestation of intolerance of cow's milk.

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Iacono G, Cavataio F, Montalto G, Soresi M, Notarbartolo A, Carroccio A: Persistent cow's milk protein intolerance in infants: the changing faces of the same disease. Clin Exp Allergy 1998 Jul;28(7):817-23.

Abstract:

II Divisione di Pediatria, Ospedale Di Cristina, Universita di Palermo, Italy.

BACKGROUND: Recent research has shown that cow's milk protein intolerance (CMPI) often persists beyond 4 years of age. AIMS: To evaluate the clinical and immunological characteristics of a group of infants with persistent CMPI. PATIENTS AND METHODS: Twelve infants (6 m, 6f) with persistent CMPI were followed up from birth until a median age of 5 years. The patients underwent CMP challenge each year to evaluate CMP-tolerance. As controls we followed 26 infants (12 m, 14 f) with CMPI that resolved within 1-2 years. RESULTS: A family history of atopic disease was found in 10/12 patients with persistent CMPI and in 10/26 controls (P<0.01). Clinical presentation changed over time: at onset symptoms were prevalently gastrointestinal, while at the end of the study there was an increased frequency of wheezing and constipation and a higher frequency of delayed reactions to CMP-challenge than at study commencement (9/12 vs 2/12; P<0.007). 11/12 infants with persistent CMPI and 3/26 controls (P<0.0001) presented multiple food intolerance. During the observation period 9/12 infants with persistent CMPI and 2/26 controls showed atopic disease: asthma, rhinitis, eczema (P < 0.0001). CONCLUSIONS: Persistent CMPI forms are characterized by: (a) considerable importance of familial atopic disease; (b) change in CMPI manifestations over time and more prolonged delay between CMP consumption and manifestation of symptoms; (c) very high frequency of multiple food intolerance and allergic diseases.

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Teschemacher, H. et al: Milk protein-derived opioid receptor ligands. Biopolymers. 1997 / 43 (2) / 99-117.

Abstract:

Rudolf-Buchheim-Institut fur Pharmakologie, Justus-Liebig-Universitat, Giessen, Germany.

Milk is mammalian characteristic and is of particular importance for humans: Mother's milk or its substitutes from cows' milk are absolutely essential nutriments for the neonate and cows' milk also represents a basic foodstuff for adults. However, in addition to their well-known nutritive role, milk constituents apparently are also able to carry specific information from the milk producer's to the milk receiver's organism: Thus, a number of milk protein fragments has been shown to behave like opioid receptor ligands able to address opioidergic systems in the adult's or in the neonate's organism. With respect to the proteins, which they are derived off these peptides have been named alpha-casein exorphins or casoxin D (alpha-casein), beta-casomorphins or beta-casorphin (beta-casein), casoxin or casoxin A, B, or C (k-casein), alpha-lactorphins (alpha-lactalbumin), beta-lactorphin (beta-lactoglobulin) or lactoferroxins (lactoferrin). Only casoxins and lactoferroxins display antagonistic properties; the other peptides behave like opioid receptor agonists. Most of the information available so far has been collected about beta-casomorphins. These peptides obviously can be released from beta-casein in the adult's or in the neonate's organism, where they might elicit opioid effects in the frame of a regulatory role as "food hormones". Several synthetic beta-casomorphin derivatives have been shown to be highly specific and potent mu-type opioid receptor ligands which frequently have been used as standard tools in opioid research.

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Fukudome, S. et al. Release of opioid peptides, gluten exorphins by the action of pancreatic elastase. FEBS Lett. 1997 / 412 (3) / 475-479.

Abstract:

Food Research Laboratory, Nisshin Flour Milling Co. Ltd., Saitama, Japan.

The release of opioid peptides, gluten exorphins A, which have been isolated from the pepsin-thermolysin digest of wheat gluten, with gastrointestinal proteases was examined. High levels of gluten exorphin A5 (Gly-Tyr-Tyr-Pro-Thr) immunoreactive materials were detected in the pepsin-pancreatic elastase digest by a competitive ELISA. From this digest, gluten exorphin A5, B5 and B4 were isolated. This means that these peptides are released in the gastrointestinal tracts after ingestion of wheat gluten. The yield of gluten exorphin A5 in the pepsin-elastase digest was larger than that in the pepsin-thermolysin digest. The gluten exorphin A5 sequence is found 15 times in the primary structure of the high molecular weight glutenin. The region from which gluten exorphin A5 was released by the action of pancreatic elastase was identified using synthetic fragment peptides.

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D'Eufemia P., Celli M., Finocchiaro R., Pacifico L., Viozzi L., Zaccagnini M., Cardi E., Giardini O. Abnormal Intestinal Permeability in Children with Autism. Acta Paediatrica,1996; 85: 1076-1079.

Abstract:

Institute of Pediatrics, La Sapienza University of Rome, Italy .

We determined the occurrence of gut mucosal damage using the intestinal permeability test in 21 autistic children who had no clinical and laboratory findings consistent with known intestinal disorders. An altered intestinal permeability was found in 9 of the 21 (43%) autistic patients, but in none of the 40 controls. Compared to the controls, these nine patients showed a similar mean mannitol recovery, but a significantly higher mean lactulose recovery (1.64% +/- 1.43 vs 0.38% +/- 0.14; P < 0.001). We speculate that an altered intestinal permeability could represent a possible mechanism for the increased passage through the gut mucosa of peptides derived from foods with subsequent behavioural abnormalities.

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Scifo R, Cioni M, Nicolosi A, Batticane N, Tirolo C, Testa N, Quattropani MC, Morale MC, Gallo F, Marchetti B: Opioid-immune interactions in autism: behavioural and immunological assessment during a double-blind treatment with naltrexone. Ann Ist Super Sanita 1996;32(3):351-9.

Abstract:

Servizio di Psichiatria, Istituto OASI per lo Studio del Ritardo Mentale e l'Involuzione Cerebrale, Troina (Enna), Italy.

The emerging concept of opioid peptides as a new class of chemical messengers of the neuroimmune axis and the presence of a number of immunological abnormalities in infantile autism prompted us to correlate biological (hormonal and immunological) determinations and behavioural performances during treatment with the potent opiate antagonist, naltrexone (NAL). Twelve autistic patients ranging from7 to 15 years, diagnosed according to DSM-III-R, entered a double-blind crossover study with NAL at the doses of 0.5, 1.0 and 1.5 mg/kg every 48 hours. The behavioural evaluation was conducted using the specific BSE and CARS rating scales NAL treatment produced a significant reduction of the autistic symptomatology in seven ("responders") out of 12 children. The behavioural improvement was accompanied by alterations in the distribution of the major lymphocyte subsets, with a significant increase of the T-helper-inducers (CD4+CD8-) and a significant reduction of the T-cytotoxic-suppressor (CD4-CD8+) resulting in a normalization of the CD4/CD8 ratio. Changes in natural killer cells and activity were inversely related to plasma beta-endorphin levels. It is suggested that the mechanisms underlying opioid-immune interactions are altered in this population of autistic children and that an immunological screening may have prognostic value for the pharmacological therapy with opiate antagonists.

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Hadjivassiliou M, Gibson A, Davies-Jones GA , Lobo AJ, Stephenson TJ, Milford-Ward A. Does cryptic gluten sensitivity play a part in neurological illness? Lancet 1996 Feb 10;347(8998):369-71.

Abstract:

Department of Neurology, Royal Hallamshire Hospital, Sheffield, UK.

BACKGROUND: Antigliadin antibodies are a marker of untreated coeliac disease but can also be found in individuals with normal small-bowel mucosa. Because neurological dysfunction is a known complication of coeliac disease we have investigated the frequency of antigliadin antibodies, as a measure of cryptic gluten sensitivity, and coeliac disease in neurological patients. METHODS: Using ELISA, we estimated serum IgG and IgA antigliadin antibodies in 147 neurological patients who were divided into two groups. There were 53 patients with neurological dysfunction of unknown cause despite full investigation (25 ataxia, 20 peripheral neuropathy, 5 mononeuritis multiplex, 4 myopathy, 3 motor neuropathy, 2 myelopathy). The remaining 94 patients were found to have a specific neurological diagnosis (16 stroke, 12 multiple sclerosis, 10 Parkinson's disease, 56 other diagnoses) and formed the neurological control group. 50 healthy blood donors formed a third group. FINDINGS: The proportions of individuals with positive titres for antigliadin antibodies in the three groups were 30/53, 5/94, and 6/50 respectively (57, 5, and 12%). The difference in proportion between group 1 and the combined control groups was 0.49 (95% CI 0.35-0.63). Distal duodenal biopsies in 26 out of 30 antigliadin-positive patients from group 1 revealed histological evidence of coeliac disease in nine (35%), non-specific duodenitis in ten (38%), and no lesion in seven (26%) individuals. INTERPRETATION: Our data suggest that gluten sensitivity is common in patients with neurological disease of unknown cause and may have aetiological significance.

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D'Eufemia P., Celli M., Finocchiaro R., Pacifico L., Viozzi L., Zaccagnini M., Cardi E., Giardini O. Abnormal Intestinal Permeability in Children with Autism. Acta Paediatrica,1996; 85: 1076-1079.

Abstract:

Institute ofPediatrics, La Sapienza University of Rome, Italy.

We determined the occurrence of gut mucosal damage using the intestinal permeability test in 21 autistic children who had no clinical and laboratory findings consistent with known intestinal disorders. An altered intestinal permeability was found in 9 of the 21 (43%) autistic patients, but in none of the 40 controls. Compared to the controls, these nine patients showed a similar mean mannitol recovery, but a significantly higher mean lactulose recovery (1.64% +/- 1.43 vs 0.38% +/- 0.14; P < 0.001). We speculate that an altered intestinal permeability could represent a possible mechanism for the increased passage through the gut mucosa of peptides derived from foods with subsequent behavioural abnormalities.

Lucarelli, S., Frediani, T., Zingoni, A.M., Ferruzzi, F.,Giardini, O., Quintieri, F., Barbato, M., D'Eufemia, P., Cardi, E. Food allergy and infantile autism. Panminerva Med., 1995 Sep; 37(3): 137-41.

Abstract:

Department of Paediatrics, University of Rome La Sapienza, Italy.

The etiopathogenesis of infantile autism is still unknown. Recently some authors have suggested that food peptides might be able to determine toxic effects at the level of the central nervous system by interacting with neurotransmitters. In fact a worsening of neurological symptoms has been reported in autistic patients after the consumption of milk and wheat. The aim of the present study has been to verify the efficacy of a cow's milk free diet (or other foods which gave a positive result after a skin test) in 36 autistic patients. We also looked for immunological signs of food allergy in autistic patients on a free choice diet. We noticed a marked improvement in the behavioural symptoms of patients after a period of 8 weeks on an elimination diet and we found high levels of IgA antigen specific antibodies for casein, lactalbumin and beta-lactoglobulin and IgG and IgM for casein. The levels of these antibodies were significantly higher than those of a control group which consisted of 20 healthy children. Our results lead us to hypothesise a relationship between food allergy and infantile autism as has already been suggested for other disturbances of the central nervous system.

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Lensing P, Schimke H, Klimesch W, Pap V, Szemes G, Klingler D, Panksepp J. Clinical case report: opiate antagonist and event-related desynchronization in 2 autistic boys. Neuropsychobiology 1995;31(1):16-23.

Abstract:

Department of Physiological Psychology, University of Salzburg, Austria.

Event-related desynchronization and visual orientational behavior were examined in 2 autistic boys to determine if blockade of endogenous opioid activity facilitates cognitive processing at a cortical level. Before naltrexone, the boys showed no selective alpha blocking during exposure to either mother's pictures or white light. Unlike normals, they exhibited strong alpha band enhancement at temporocentral recording sites. Two hours after administering 0.5 mg/kg naltrexone, mother-as well as light-related alpha blocking appeared at occipital, occipitotemporal, and prefrontal sites. These effects were gone 24 h after dosing in one child, but persisted in the other. A parallel increase in visual pursuit in a social context was observed. These results affirm that autistic gaze aversion can be caused by excessive opioid activity interfering with corticothalamocortical processing of visual stimuli.

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Kurek M, Czerwionka-Szaflarska M, Doroszewska G. Pseudoallergic skin reactions to opiate sequences of bovine casein in healthy
children. Rocz Akad Med Bialymst 1995;40(3):480-5.

Abstract:

Department of Gastroenterology, Academy of Medicine, Gdansk.

Skin tests with opioid peptides naturally occurring in cow's milk: beta-casomorphin-7 and alpha-casein (90-95), were performed in 25 healthy children. Wheal and flare reactions, similiar to histamine and codeine were observed in all children. The area of these reactions was concentration dependent. Pretreatment with H1 antagonist--cetirizine significantly inhibited the skin response to both peptides. Beta-casomorphin-7 and alpha-casein (90-95) are noncytotoxic histamine releasers in humans.

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Knivbserg A.M., Reichelt K.L., Nodland M., Hoien T. Autistic syndromes and diet. A four year follow-up study. Scand J Educat. Res. 1995, 39: 223-236.

Abstract:

Dietary intervention was applied to 15 subjects with autistic syndromes, with pathological urine patterns, and increased levels of peptides found in their twenty-four-hour urine samples. The peptides, some of which are probably derived from gluten and casein, are thought to have a negative pharmacological effect on attention, brain maturation, social interaction and learning. Our hypothesis was that a diet without these proteins would facilitate learning. Social behaviour, as well as cognitive and communicative skills, were assessed before diet. The subjects were closely followed for a year, after which their urine was retested blind, and the assessment of behaviors and skills was repeated. Further retesting was made four years after the onset of dietary intervention. Normalization of urine patterns and peptide levels was found after one year. Likewise, a decrease in odd behaviour and an improvement in the use of social, cognitive and communicative skills were registered. This positive development continued through the next three years, though at a lower rate. These promising results encourage further research on the effect of dietary intervention.

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Bouvard MP, Leboyer M, Launay JM, Recasens C, Plumet MH, Waller-Perotte D, Tabuteau F, Bondoux D, Dugas M, Lensing P, et al. Low-dose naltrexone effects on plasma chemistries and clinical symptoms in autism: a double-blind, placebo-controlled study. Psychiatry Res 1995 Oct 16;58(3):191-201.

Abstract:

Service de Psychopathologie de l'Enfant et de l'Adolescent, Hopital Robert Debre, Paris, France.

The effect of month-long naltrexone (NTX) treatment at a daily oral dose of 0.5 mg/kg/day was contrasted with placebo (PLC) in a double-blind study with conjoint clinical and biochemical evaluations of therapeutic effects. Modest clinical benefits were achieved with both PLC and NTX, with marginally better overall results following NTX, and degree of improvement appeared to be related to plasma chemical profiles. Massively elevated levels of beta-endorphin were observed in all children with assays using C-terminal antibody but not with an N-terminal antibody assay. In addition, 70% of the children exhibited abnormally low levels of adrenocorticotropic hormone, and smaller subsets exhibited elevated norepinephrine (60%), arginine-vasopressin (50%), and serotonin (20%). The best clinical responders exhibited the clearest normalization of the elevated plasma chemistries, especially in C-terminal-beta-endorphin and serotonin. There was some evidence of therapeutic carry-over effects in both clinical and biochemical measures in those children who received NTX before PLC. The results suggest that NTX only benefits a subgroup of autistic children, who may be identified by the presence of certain plasma abnormalities. These results suggest a possible linkage between abnormal plasma chemistries, especially those related to the pro-opiomelanocortin system, and autistic symptoms.

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Reichelt K.L. Knivsberg AM, Nodland M, Lind G. Nature and consequences of hyperpeptiduria and bovine casomorphin found in autistic syndromes. Develop Brain Dysfunct. 1994, 7: 71-85. [No abstract available]

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Gardner M.L.G.: Absorption of intact proteins and peptides. Physiol of gastrointestinal Tract 3rd edit (edit: LR Johnson) Raven press, New York 1994: 1795-1820.

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Leboyer M, Bouvard MP, Launay JM, Recasens C, Plumet MH, Waller-Perotte D, Tabuteau F, Bondoux D, Dugas M. Opiate hypothesis in infantile autism? Therapeutic trials with naltrexone [Article in French]. Encephale 1993 Mar-Apr;19(2):95-102.

Abstract:

Service de Psychiatrie Adulte, Hopital Pitie-Salpetriere, Paris.

The opioid hypothesis suggests that childhood autism may result from excessive brain opioid activity during neonatal period which may constitutionally inhibit social motivation, yielding autistic isolation and aloofness (Panksepp, 1979). This hypothesis has now received strong support and is currently based on three types of arguments: (1) similarity between autistic symptomatology and abnormal behaviors induced in young animals by injections of exogenous opioids, such as increasing social aloofness and decreasing social vocalization; (2) direct biochemical evidence of abnormalities of peripheral endogenous opioids being reported in autism and (3) therapeutic effects of the long lasting opioid receptor blocking agent naltrexone in autism. In this article, we give description of open and double-blind studies of naltrexone in autism. Naltrexone has been tested in several open studies. We performed an open trial with naltrexone in 2 autistic girls, displaying serious self-injurious behavior, reduced crying and a marked preference for salty and spicy foods, symptoms that could be related to a dysfunction of the opioid system. With dosages of 1 mg/kg/day, we observed an immediate reduction of hyperactivity, self-injurious behavior and aggressiveness, while attention improved. In addition, social behaviors, smiling, social seeking behaviors and play interactions increased (Leboyer, Bouvard et Dugas, 1988). Campbell et al. (1988) has also reported a tranquilizing and a stimulating effect in 6 out of 8 children with autism. We did confirm these preliminary results in a double-blind study performed on 4 children with autism. In a cross-over double-blind study, three dosages of naltrexone (0.5, 1 and 2 mg/kg/day) and placebo were compared. (ABSTRACT TRUNCATED AT 250 WORDS)

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Fukudome S, Yoshikawa M. Gluten exorphin C, A novel opioid peptide derived from wheat gluten. FEBS 1993; 316: 17-19.

Abstract:

Research Control Department, Nisshin Flour Milling Co., Ltd., Nihonbashi, Tokyo, Japan.

A novel opioid peptide, Tyr-Pro-Ile-Ser-Leu, was isolated from the pepsin-trypsin-chymotrypsin digest of wheat gluten. Its IC50 values were 40 microM and 13.5 microM in the GPI and MVD assays, respectively. This peptide was named gluten exorphin C. Gluten exorphin C had a structure quite different from any of the endogenous and exogenous opioid peptides ever reported in that the N terminal Tyr was the only aromatic amino acid. The analogs containing Tyr-Pro-X-Ser-Leu were synthesized to study its structure-activity relationship. Peptides in which X was an aromatic amino acid or an aliphatic hydrophobic amino acid had opioid activity.  

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Bidet B, Leboyer M, Descours B, Bouvard MP, Benveniste J. Allergic sensitization in infantile autism. J Autism Dev Disord 1993 Jun;23(2):419-20. [No abstract available.]

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Leboyer M, Bouvard MP, Launay JM, Recasens C, Plumet MH, Waller-Perotte D, Tabuteau F, Bondoux D, Dugas M. [Opiate hypothesis in infantile autism? Therapeutic trials with naltrexone] [Article in French]. Encephale. 1993 Mar-Apr;19(2):95-102.

Service de Psychiatrie Adulte, Hôpital Pitié-Salpêtrière, Paris.

Abstract

The opioid hypothesis suggests that childhood autism may result from excessive brain opioid activity during neonatal period which may constitutionally inhibit social motivation, yielding autistic isolation and aloofness (Panksepp, 1979). This hypothesis has now received strong support and is currently based on three types of arguments: (1) similarity between autistic symptomatology and abnormal behaviors induced in young animals by injections of exogenous opioids, such as increasing social aloofness and decreasing social vocalization; (2) direct biochemical evidence of abnormalities of peripheral endogenous opioids being reported in autism and (3) therapeutic effects of the long lasting opioid receptor blocking agent naltrexone in autism. In this article, we give description of open and double-blind studies of naltrexone in autism. Naltrexone has been tested in several open studies. We performed an open trial with naltrexone in 2 autistic girls, displaying serious self-injurious behavior, reduced crying and a marked preference for salty and spicy foods, symptoms that could be related to a dysfunction of the opioid system. With dosages of 1 mg/kg/day, we observed an immediate reduction of hyperactivity, self-injurious behavior and aggressiveness, while attention improved. In addition, social behaviors, smiling, social seeking behaviors and play interactions increased (Leboyer, Bouvard et Dugas, 1988). Campbell et al. (1988) has also reported a tranquilizing and a stimulating effect in 6 out of 8 children with autism. We did confirm these preliminary results in a double-blind study performed on 4 children with autism. In a cross-over double-blind study, three dosages of naltrexone (0.5, 1 and 2 mg/kg/day) and placebo were compared.

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McLaughlin P.J., Zagon I.S. Endogenous opiod systems and clinical implications for infantile autism. Proceedings of the International Symposium on Neurobiology of Infantile Autism, Tokyo , 1990, Neurobiology of Infantile Autism, Excerpta Medica 1992.

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Lensing P, Klingler D, Lampl C, Leboyer M, Bouvard M, Plumet MH, Panksepp J. Naltrexone open trial with a 5-year-old-boy. A social rebound reaction. Acta Paedopsychiatr 1992;55(3):169-73.

Abstract:

School Psychology of Upper Austria, Linz.

The neurobiological rationale for an opiate antagonist pharmacotherapy of autism is presented. Naltrexone efficacy in decreasing autistic behaviour and in increasing social-affiliative behaviour was explored in a 5-year-old autistic boy. Naltrexone (0.5 mg/kg 3 times peer week) was effective in immediately decreasing gross motor activity and stereotyped behaviour and caused a delayed increase of crying, smiling and rough-and-tumble play. This single case presents preliminary evidence that a therapeutically valuable rebound reaction is possible and that the human opioid system modulates social-affective processes. The possibility of psychological factors being instrumental in achieving this effect is discussed as being suitable for future clinical trials.

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Kurek M, Przybilla B, Hermann K, Ring J. A naturally occurring opioid peptide from cow's milk, beta-casomorphine-7, is a direct histamine releaser in man. Int Arch Allergy Immunol 1992;97(2):115-20.

Abstract:

Department of Dermatology, Ludwig-Maximilian-University, Munich.

beta-Casomorphine-7, a naturally occurring product of cow's milk with opiate-like activity, was studied for possible direct histamine liberation activities in humans. It was found to cause concentration-dependent in vitro histamine release from peripheral leukocytes of healthy adult volunteers. Intradermal injection of beta-casomorphine-7 induced a wheal and flare reaction in the skin similar to histamine or codeine. Oral pretreatment with the H1 antagonist terfenadine significantly inhibited the skin responses to beta-casomorphine-7. The intradermal injection of an opiate receptor antagonist, naloxone, inhibited in vitro histamine release and skin reactions only in a 100-fold excess over beta-casomorphine-7. These findings suggest that beta-casomorphine-7 can be regarded as a noncytotoxic, direct histamine releaser in humans. The clinical relevance of these findings deserves further studies.

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Fukudome S, Yoshikawa M. Opioid peptides derived from wheat gluten: their isolation and characterization. Federation of European Biochemical Societies (FEBS) 1992; 296: 107-111.

Abstract:

Research Control Department, Nisshin Flour Milling Co., Ltd., Tokyo, Japan.

Four opioid peptides were isolated from the enzymatic digest of wheat gluten. Their structures were Gly-Tyr-Tyr-Pro-Thr, Gly-Tyr-Tyr-Pro,Tyr-Gly-Gly-Trp-Leu and Tyr-Gly-Gly-Trp, which were named gluten exorphins A5, A4, B5 and B4, respectively. The gluten exorphin A5 sequence was found at 15 sites in the primary structure of the high molecular weight glutenin and was highly specific for delta-receptors. The structure-activity relationships of gluten exorphins A were unique in that the presence of Gly at their N-termini increased their activities. Gluten exorphin B5, which corresponds to [Trp4,Leu5]enkephalin, showed the most potent activity among these peptides. Its IC50 values were 0.05 microM and 0.017 microM, respectively, on the GPI and the MVD assays.

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Dubynin VA, Maklakova AS, Nezavibat'ko VN, Alfeeva LA, Kamenskii AA, Ashmarin IP: Effects of systemically-administered beta-casomorphin-7 on nociception in rats. [Article in Russian] Biull Eksp Biol Med 1992 Sep;114(9):284-6.  

Abstract:  

The influence of food-derived heptapeptide beta-casomorphin-7 (beta-CM-7) on pain sensibility of white rats was studied by tail flick test. As shown for doses 10 and 20 mg/kg intraperitoneally, injected beta-CM-7 induced significant analgesia; lower peptide concentration (5 mg/kg) was ineffective. As a whole, there is a significant positive correlation between the intensity of analgesia and the quantity of administered exorphine. These changes of pain sensibility were observed for one hour after injection of heptapeptide; further measurements showed no significant difference of time reaction between control and experimental groups of rats. It was found out that animals with high native level of pain sensibility (4-8 sec) made the main contribution to manifestation of analgesia.

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Bouvard M.P., Leboyer M., Launay J.M., Kerdelhue B., Dugas M. The opiod excess hypothesis of autism: A double-blind study of naltrexone. Proc. of the Intern. Symp. on Neurob. of Inf. Autism, 1990, Neurobiology of Infantile Autism, Exerpta Medica 1992.

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Teschemacher H, Koch G: Opioids in the milk. Endocr Regul 1991 Sep;25(3):147-50.  

Abstract:

Rudolf-Buchheim-Institut fur Pharmakologie, Justus-Liebig-Universitat Giessen, Germany.

In various studies, the milk has been screened for the presence of free or precursor-bound opioids. In fact, various opioid receptor ligands with agonistic or even antagonistic activity were found. Besides the alkaloid morphine, peptides derived from alpha-casein (alpha-casein exorphins), beta-casein (beta-casomorphins; beta-casorphin), alpha-lactalbumin (alpha-lactorphins) and beta-lactoglobulin (beta-lactorphin) were among the agonists. In addition, certain peptides derived from k-casein (casoxins) or from lactoferrin (lactoferroxins) were found to behave like opioid antagonists. Although a functional role in the mammalian organism for all of these compounds appears to be well possible, evidence has only been presented for the functional significance of beta-casomorphins, so far. These peptides might play a role in reproduction or nutrition in the female, in the newborn's or in a milk consumer's organism, respectively. Thus, opioids related to milk might represent essential exogenous extensions of the endogenous opiodergic systems.  

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Risebro, B. Gluten-free diet in infantile autism. Tidsskr Nor Laegeforen 1991 Jun 10;111(15):1885-6 [Article in Norwegian]

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Reichelt K.L., Knivsberg A.M., Lind G., Nodland M. The probable etiology and possible treatment of childhood autism. Brain Dysfunct. 1991, 4: 308-319. [No abstract available]

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Longoni R, Spina L, Mulas A, Carboni E, Garau L, Melchiorri P, Di Chiara G. (D-Ala2)deltorphin II: D1-dependent stereotypies and stimulation of dopamine release in the nucleus accumbens. J Neurosci 1991 Jun;11(6):1565-76.  

Abstract:

Institute of Experimental Pharmacology and Toxicology, University of Cagliari, Italy.

In order to investigate the relative role of central delta- and mu-opioid receptors in behavior, the effects of (D-Ala2)deltorphin II, a natural delta-opioid peptide, and PL017, a beta-casomorphin derivative specific for mu receptors, were compared after local intracerebral and intraventricular administration. Intracerebral infusion of the two peptides was done bilaterally in the limbic nucleus accumbens and in the ventral and dorsal caudate putamen of freely moving rats through chronic intracerebral cannulas. After intra-accumbens infusion, the two peptides elicited marked but opposite behavioral effects: while (D-Ala2)deltorphin II evoked dose-dependent motor stimulation characterized by locomotion, sniffing, and oral stereotypies, PL017 elicited motor inhibition with rigidity and catalepsy. These effects were site specific because they could not be evoked from the ventral or from the dorsal caudate. Low doses of naloxone (0.1 mg/kg, s.c. ) blocked the effects of PL017 but not those of (D-Ala2)deltorphin II, which instead were reduced by high doses of naloxone (1.0 mg/kg) and by the putative delta-antagonist naltrindole; this drug failed to affect the catalepsy induced by PL017. Therefore, while (D-Ala2)deltorphin II effects were delta-mediated, PL017 effects were mu-mediated. Blockade of dopamine D1 receptors by SCH 23390 abolished (D-Ala2)deltorphin II effects, while blockade of dopamine D2 receptors by raclopride or by haloperidol was without effect. Local application by reverse dialysis of (D-Ala2)deltorphin II (5 microM) to the accumbens resulted in a naloxone-sensitive increase of extracellular dopamine concentrations; these effects could not be evoked from the caudate, nor by PL017 in the accumbens. Intracerebroventricular administration of (D-Ala2)deltorphin II or of PL017 elicited behavioral effects qualitatively similar to those obtained from the accumbens.

If deltorphin II is indeed present in the urine, this may explain why low doses of naloxone are often only moderately effective at reducing autistic behaviors.

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Fukudome S.-I. and Yoshikawa M.: Opioid peptides derived from wheat gluten: Their isolation and characterization. FEBS Letters 1991, 296: 107-111.

Abstract:

Four opioid peptides were isolated from the enzymatic digest of wheat gluten. Their structures were Gly-Tyr-Tyr-Pro-Thr, Gly-Tyr-Tyr-Pro, Tyr-Gly-Gly-Trp-Leu and Tyr-Gly-Gly-Trp, which were named gluten exorphins A5, A4, B5 and B4, respectively. The gluten exorphin A5 sequence was found at 15 sites in the primary structure of the high molecular weight glutenin and was highly specific for delta-receptors. The structure-activity relationships of gluten exorphins A were unique in that the presence of Gly at their N-termini increased their activities. Gluten exorphin B5, which corresponds to [Trp4,Leu5]enkephalin, showed the most potent activity among these peptides. Its IC50 values were 0.05 microM and 0.017 microM, respectively, on the GPI and the MVD assays.

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Shattock P. Kennedy A, Rowell F, Berney T:  Role of neuropeptides in autism and their relationships with classical neurotransmitters. Brain Dysfunct 1990, 3: 328-346. [No abstract available]

Reichelt K.L., Ekrem J., Scott H.: Gluten, milk proteins and autism: Dietary interventions effects on behavior and peptide secretion. J Appl Nutrition 1990, 42: 1-11. [No abstract available]

Marchetti B, Scifo R, Batticane N, Scapagnini U: Immunological Significance of Opioid Peptide Dysfunction in Infantile Autism. Brain Dysfunction,3: 346-354,1990. [No abstract available]

Leboyer M, Bouvard MP, Lensing P, Launay JM, Tabuteau F, Arnaud P, Waller D, Plumet MH, Recasens C, Kerdelhue B, Dugas M, Panksepp J: Opioid Excess Hypothesis of Autism. Brain Dysfunction 1990; 3: 285-298. [No abstract available]

Knivsberg A.M., Wiig K., Lind G., Nodland M., Reichelt K.L.: Dietary intervention in autistic syndromes. Brain Dysfunc. 1990, 3: 315-327. [No abstract available]

Cade R. et al.: The effects of dialysis and diet in schizophrenia. Psychiatry: A World perspective 1990, 3: 494-500. [No abstract available]

Barthelemy C, Bruneau N, Adrien J, Roux S, Lelord G: Clinical, Biological and Therapeutic Applications of the Functional Analysis of Autistic Disorders. Brain Dysfunction, 3: 271-284, 1990. [No abstract available]

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Herrera-Marschitz M, Terenius L, Grehn L, Ungerstedt U: Rotational behaviour produced by intranigral injections of bovine and human beta-casomorphins in rats. Psychopharmacology (Berl) 1989;99(3):357-61.  

Abstract:

Department of Pharmacology, Karolinska Institutet, Stockholm, Sweden.

The biological activity of beta-casein derived beta-casomorphin peptides was evaluated by injecting bovine beta-casomorphin-5 (Tyr-Pro-Phe-Pro-Gly), the homologous sequence in human beta-casein (Tyr-Pro-Phe-Val-Glu) and the corresponding N-terminal tetrapeptides into the left substantia nigra of rats. Their ability to produce rotational behaviour was compared to that produced by three reference compounds, morphine, D-ala2D-leu5 enkephalin and U50,488H, ligands for mu, delta and kappa types of opioid receptors, respectively. The relative potencies of beta-casomorphins and morphine were compared to those tested in two in vitro assays for opioid activity: (1) inhibition of the electrically induced contraction of the isolated myenteric plexus-longitudinal muscle of the guinea-pig ileum and (2) displacement of 3H-dihydromorphine binding to brain membranes. The same ranking order of potency was found in all three assays, the peptides from human beta-casein being about 10-fold less potent than those from bovine beta-casein. The effects of both morphine and bovine beta-casomorphin-5 in producing rotational behaviour were antagonized by naloxone; however, approximately 10-fold more naloxone was required to antagonize the beta-casomorphin-5 effect than that of morphine. The present data are discussed in the light of the recent observation that high concentrations of beta-casomorphin-like peptides are found in the cerebrospinal fluid and plasma of women with postpartum psychosis.  

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Ramabadran K, Bansinath M: Opioid peptides from milk as a possible cause of sudden infant death syndrome. Med Hypotheses 1988 Nov;27(3):181-7.  

Abstract:  

Department of Anesthesiology, New York University Medical Center, NY 10016.

Milk from breast or baby formula is the exclusive source of nutrition for newborn infants. Short chain opioid peptides such as beta-casomorphins have been isolated from breast milk as well as baby formula. These biologically active peptides are absorbed from the gastrointestinal tract. In infants predisposed to respiratory apnea because of abnormal autonomic nervous system development and respiratory control mechanisms, opioid peptides derived from milk might be one of the etiological factors for sudden infant death syndrome and near miss sudden infant death syndrome.

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Paroli E: Opioid Peptides from Food (the Exorphins). World Review of Nutrition and Dietetics 1988; 55: 58-97. [No abstract available]

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Hole K. et al.: Attention deficit disorders: A study of peptide-containing urinary complexes. J Develop Behav Pediatrics 1988, 9: 205-212.

Abstract:

Department of Physiology, University of Bergen, Norway.

In several behavioral disorders, we have observed that abnormal amounts of peptides and protein-associated peptide complexes are excreted in the urine. The gel filtration patterns of these excreted substances have some specificity for the different disorders. The urinary excretion of peptide-containing complexes was studied in 91 boys and 13 girls (mean age 9.4 years, range 1-23) with the clinical diagnosis of attention deficit disorder (ADD), with or without hyperactivity. The gel filtration of urine precipitate showed patterns in all patients that were different from those seen in 36 normal controls. Sixty-four patients had increased benzoic acid-glycoprotein-peptide complexes in the late peaks. The symptoms of all these patients fit the criteria for diagnosis of attention deficit disorder with hyperactivity (ADDH). Thirty-five patients showed reduced amounts of uric acid complexes in the late peaks. Clinically, this group, with the exception of three patients, fit the criteria for diagnosis of attention deficit disorder without hyperactivity. Five patients showed reduced amounts of all urinary complexes; four of these were hyperactive. Moderate exercise in control children did not change the urinary pattern. One urinary peptide fraction from hyperactive patients, purified to homogeneity, increased the uptake of 14C[5-HT] in platelets. Strict clinical, neuropsychological, and psychophysiological selection of the patients reduced the heterogeneity of the patterns. Although more studies are needed, the findings seem promising for the possibility of developing biochemical tests that may be helpful diagnostically.

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Dohan, FC: Genetic hypothesis of idiopathic schizophrenia: its exorphin connection. Schizophr. Bull. 1988 / 14 (4) / 489-494.

Abstract:

Medical College of Pennsylvania, Eastern Pennsylvania, Psychiatric Institute, Philadelphia, 19129.

This brief overview proposes a testable oligogenic model of the inheritance of susceptibility to idiopathic schizophrenia: "abnormal" genes at each of a few complementary loci. The model is based on my assumptions as to the likely genetic abnormalities at possibly four or five interacting loci that would permit exorphins, the opioid peptides from some food proteins, especially glutens and possibly caseins, to go from gut to brain and cause symptoms of schizophrenia. Exorphins may reach the brain cerebrospinal fluid (CSF) in harmful amounts because of their genetically increased, receptor-mediated transcellular passage across the gut epithelial barrier plus decreased catabolism by genetically defective enzymes. A schizophrenia-specific, genetically enhanced affinity for exorphins by opioid receptors influencing dopaminergic and other neurons would permit sustained dysfunction at low CSF exorphin concentrations. Tests of each postulated genetic abnormality are suggested. This model is supported by a variety of evidence, including a significant effect of gluten or its absence on relapsed schizophrenic patients, the high correlation of changes in first admission rates for schizophrenia with changes in grain consumption rates, and the rarity of cases of schizophrenia where grains and milk are rare.

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Sahley TL, Panksepp J: Brain opioids and autism: an updated analysis of possible linkages. J Autism Dev Disord 1987 Jun;17(2):201-16.

Abstract:

Considerable clinical evidence suggests that autistic children lack the normal ability or desire to engage others socially, as indicated by their poor social skills and inappropriate use of language for communicative purposes. Specifically, these children seem to lack normal amounts of social-emotional interest in other people, leading perhaps to a decreased initiative to communicate. This paper summarizes experimental evidence supporting a neurological theory, which posits that autism, at least partially, represents in the brain, such as brain opioids. These substances modulate social-emotional processes, and the possibility that blockade of opioid activity in the brain may be therapeutic for early childhood autism is discussed.

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Kahn A, Rebuffat E, Blum D, Casimir G, Duchateau J, Mozin MJ, Jost R: Difficulty in initiating and maintaining sleep associated with cow's milk allergy in infants. Sleep 1987 Apr;10(2):116-21.

Abstract:

To confirm that sleeplessness in infants can be related to an undiagnosed allergy to cow's milk proteins, 71 infants were studied. Group I consisted of 20 infants referred for chronic insomnia that had appeared in the early days of life. Group II was made up of 31 infants admitted for skin or digestive symptoms attributed to cow's milk intolerance; 13 of these infants were shown to sleep as poorly as the infants of group I. Group III consisted of 20 infants with no history of sleep disturbance or milk allergy. The three groups of infants were comparable for sex and age. Laboratory tests revealed immunologic reactions to milk in all the infants in groups I and II. The sleep of the insomniac infants (group I, and the 13 "poor sleepers" in group II) became normal after cow's milk was eliminated from the diet. Insomnia reappeared when the infants in group I were challenged with milk. We conclude that infants with clinically evident milk allergy may suffer from sleeplessness and that when no evident cause for a chronic insomnia can be found in an infant the possibility of milk allergy should be given serious consideration.

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Meisel, H: Chemical characterization and opioid activity of an exorphin isolated from in vivo digests of casein. FEBS Lett. 1986 / 196 (2) / 223-227.

Abstract:

The in vivo formation of an opioid peptide (exorphin) derived from beta-casein has been proved for the first time. It was isolated from duodenal chyme of minipigs after feeding with the milk protein casein. The exorphin has been identified as a beta-casein fragment by end-group determinations and qualitative amino acid analysis of the purified peptide. This peptide, named beta-casomorphin-11, displayed substantial opioid activity in an opiate receptor-binding assay.

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Alpers DH: Uptake and fate of absorbed amino acids and peptides in the mammalian intestine. Federation Proc. 1986; 45:2261-2267.

Abstract:

Intraluminal and brush-border digestion of proteins results in a mixture of amino acids and small peptides. Thirteen brush-border peptidases have been described. Despite all of these enzymes, some peptides escape digestion and are absorbed intact. The assimilated products of protein digestion can follow multiple paths: absorption into the blood as amino acids or small peptides, metabolism within the enterocyte, incorporation into proteins of the enterocyte, and incorporation into proteins to be secreted into plasma. Unlike other tissues, the intestinal mucosa is not very responsive to metabolic regulation as regards amino acid uptake or regulation of protein synthesis. Most effects after dietary manipulation or drug or hormonal stimulation are modes (two-to fivefold increases). This constitutive metabolism of amino acids in the intestinal mucosa is consistent with its essential role in absorption. The mucosa also is a major contributor to apolipoproteins, which are probably the quantitatively most important proteins secreted from the intestine. Alterations in apoprotein secretion have been noted after fat feeding, and are both transcriptionally and translationally regulated. Although the fractional renewal rate of protein in the intestine is the highest of any tissue in the body, the quantitative importance of alterations in protein synthesis or secretion to the fate of intracellular amino acids is not known.

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Svedberg, J.et al: Demonstration of beta-casomorphin immunoreactive materials in in vitro digests of bovine milk and in small intestine contents after bovine milk ingestion in adult humans. Peptides 1985 / 6 / pag.825-830.

Abstract:

Healthy young volunteers ingested one liter of cows' milk; then the contents of the small intestine were aspirated through an intestinal tube at various times and assayed for the presence of bovine beta-casomorphin immunoreactive materials. Considerable amounts of beta-casomorphin-7, but no beta-casomorphin-5 and only small amounts of beta-casomorphin-4 or -6 immunoreactive materials were found. Chromatographical characterization showed that most of the beta-casomorphin-7 immunoreactive material was not identical with beta-casomorphin-7, whereas the major part of the beta-casomorphin-4 or -6 immunoreactive materials might be identical with their corresponding beta-casomorphins. Analogous results were obtained for in vitro digestion of bovine milk which had been designed as a rough imitation of the gastrointestinal digestion process. A regulatory influence of beta-casomorphins as "food hormones" on intestinal functions is suggested.

Saelid G, et. al.: Peptide-Containing Fractions in Depression. Biol Psychiatry 1985, 20: 245-256.

Abstract:

A mixture of peptides and glycoproteins has been found in benzoic acid-precipitable material from urines of psychomotorically agitated and retarded endogenous depressive patients. This complex mixture of compounds is fractionated on a Sephadex G-25 gel, from which the different peaks are further separated on Biogel P2. The G-25 elution profiles ultraviolet absorbance, 280 nm) from depressive patients deviated from the normal pattern. The increase in hydrolyzable ninhydrin-colorable material of the P2 fractionation step encountered in psychotic depression was several-fold that of the normal population. Neurochemically active peptide-containing fractions were found. As explanation of these findings, it is probable that a genetically determined peptidase insufficiency is present, causing a peptide overflow when the secretion outstrips the breakdown. This model could easily combine more psychodynamic models with the genetic-biological models. The variability of the peptide patterns could possibly reflect the considerable clinical variability of the syndrome. Furthermore, the presence of a group of active compounds with different neuropharmacological activities might reflect the composite nature of the depressive syndrome.

Rix KJ, Ditchfield J, Freed DL, Goldberg DP, Hillier VF: Food antibodies in acute psychoses. Psychol Med 1985 May;15(2):347-54.

Abstract:

Antibodies to a variety of foods, and in particular cereals, were measured in serum from 100 patients with acute psychoses and 100 elective surgical patients. For 13 out of 14 foods to which non-IgE antibodies were detected the schizophrenics had slightly more antibodies than the controls. There was an association between a possible secondary mania and the presence of IgE antibodies to wheat or rye. However, neither the schizophrenia nor the mania findings can be regarded as evidence for food allergy causing psychiatric disorder, since the immunological findings in both cases may represent consequences of the illnesses or their treatment, rather than causes of the illness.

Chang, KJ, Su YF, Brent DA, Chang JK: Isolation of a specific mu-opiate receptor peptide, morphiceptin, from an enzymatic digest of milk proteins. J. Biol. Chem. 1985 / 260 (17) / pag. 9706-9712.

Abstract:

Specific radioimmunoassays have been developed for the measurement of naturally occurring morphiceptin and beta-casomorphin. These peptides and related exorphins were isolated from an enzymatic digest of caseins by chromatographic techniques including gel filtration, hydrophobic column and multiple-step high pressure liquid chromatography. Three exorphins were purified and characterized in their radioimmunological, biological, and chemical properties. They were identified as morphiceptin, beta-casomorphin, and 8-prolyl-beta-casomorphin. Since morphiceptin is a highly specific mu-agonist and can be derived from a milk protein, it is possible that morphiceptin is an exogenous opioid ligand specific for mu-receptors in the brain and gastrointestinal tract.

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Takahashi M, Fukunaga H, Kaneto H, Fukudome S, Yoshikawa M: Behavioral and pharmacological studies on gluten exorphin A5, a newly isolated bioactive food protein fragment, in mice. Jpn J Pharmacol 2000 Nov;1984(3):259-65.

Abstract:

Department of Pharmacoinformatics, School of Pharmaceutical Sciences, Nagasaki University, Japan. takahashi@net.nagasaki-u.ac.jp

Central effects of gluten exorphin A5 (Gly-Tyr-Tyr-Pro-Thr), a fragment from wheat gluten, were studied on the pain-inhibitory system, emotionality and learning/memory processes in mice. Orally administered gluten exorphin A5 produced neither an antinociceptive effect nor an effect on morphine analgesia. Intracerebroventricularly (i.c.v.) administered gluten exorphin A5 produced mild but significant antinociception in a dose-depepndent manner, while not affecting the morphine analgesia. On the other hand, oral gluten exorphin A5 suppressed the endogenous pain-inhibitory system, i.e., antinociception induced by socio-psychological- (PSY-) stress (SIA) using a communication box; intraperitoneal gluten exorphin A5 abolished both footshock- (FS-) stress-induced antinociception (SIA) and PSY-SIA; and i.c.v. gluten exorphin A5 suppressed FS-SIA, but rather potentiated PSY-SIA. This peptide given by these routes was without effect on forced swim-SIA. In addition, oral gluten exorphin A5 tended to prolong the retention time on open arms in the elevated plus-maze test. Finally, oral gluten exorphin A5 when given during the post-training period of learning/memory processes significantly increased the latency into the dark compartment in the one-trail step-though type passive avoidance test, indicating that the peptide also facilitates the acquire/consolidation process of learning/memory. Thus, gluten exorphin A5 has been found to produce various effects not only in the peripheral nervous systems but also in the central nervous system.

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Pfeiffer CC: Schizophrenia and wheat gluten enteropathy. Biol Psychiatry 1984 Mar;19(3):279-80. [No abstract available]

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Lindstrom LH, Nyberg F, Terenius L, Bauer K, Besev G, Gunne LM, Lyrenas S, Willdeck-Lund G, Lindberg B: (1984) CSF and plasma beta-casomorphin-like opioid peptides in post-partum psychosis. Amer. J. Psychiat. 1984, 141: 1059-1066.

Abstract:

The authors measured opioid receptor-active components in the CSF of 11 women with postpartum psychosis, 11 healthy lactating women, and 16 healthy women who were not lactating. Activity that eluted with 0.2 M acetic acid 0.7-0.9 times the total volume of the column (fraction II activity) was significantly higher in the CSF of both healthy and psychotic women in the puerperium than in that of the lactating women. Very high levels of fraction II activity were seen in four psychotic patients. Material from these patients was further characterized by electrophoresis and high-performance liquid chromatography: The material migrated as bovine beta-casomorphin. Receptor-active material with the same characteristics was also found in the plasma of these four patients. The authors conclude that certain cases of postpartum psychosis are associated with the occurrence in plasma and CSF of unique opioid peptides probably related to bovine beta-casomorphin.

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Huebner FR, Lieberman KW, Rubino RP, Wall JS: Demonstration of high opioid-like activity in isolated peptides from wheat gluten hydrolysates. Peptides 1984 Nov-Dec;5(6):1139-47.

Abstract:

Because of a possible relationship between schizophrenia and celiac disease, a condition in some individuals who are sensitive to wheat gluten proteins in the diet, there has been interest in observations that peptides derived from wheat gluten proteins exhibit opioid-like activity in in vitro tests. To determine the origin of the peptides exhibiting opioid activity, wheat proteins were fractionated by size (gel filtration), by charge differences (ion exchange chromatography) and by differences in hydrophobicity (reversed-phase HPLC). These fractions were hydrolyzed by pepsin or pepsin and trypsin and the resulting peptides separated by gel filtration chromatography. The separated peptides were tested for opioid-like activity by competitive binding to opioid receptor sites in rat brain tissue in the presence of tritium-labeled dihydromorphine. The peptides showed considerable differences in activity; while some peptides exhibited no activity, 0.5 mg of the most active peptides were equivalent to 1 nM of morphine in the binding assay. The most active peptides were derived from the gliadin fraction of the gluten complex.

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Dohan et. al: "Is Schizophrenia Rare if Grain is Rare?" Biol Psychiat 1984; 19(3): 385-399.

Abstract:

If, as hypothesized, neuroactive peptides from grain glutens are the major agents evoking schizophrenia in those with the genotype(s), it should be rare if grain is rare. To test this, we analyzed the results of our clinical examinations (e.g., kuru) and observations of anthropologists on peoples consuming little or no grain. Only two overtly insane chronic schizophrenics were found among over 65,000 examined or closely observed adults in remote regions of Papua New Guinea (PNG, 1950-1967) and Malaita, Solomon Islands (1980-1981), and on Yap, Micronesia (1947-1948). In preneuroleptic Europe over 130 would have been expected. When these peoples became partially westernized and consumed wheat, barley beer, and rice, the prevalence reached European levels. Our findings agree with previous epidemiologic and experimental results indicating that grain glutens are harmful to schizophrenics.

Loukas, S. et al: Opioid activities and structures of alpha-casein-derived exorphins. Biochemistry 1983 / 22 (19) / 4567-4573.

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Gardner MLG: Evidence for, and implications of, passage of intact peptides across the intestinal mucosa. Biochemical Society Transactions 1983; 11: 810-812. [no abstract available]

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Morley, JE: Food peptides. A new class of hormones? J. Am. Med. Assoc. 1982 / 247 (17) / 2379-2380. [No abstract available]

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Reichelt KL, Hole K, Hamberger A, Saelid G, Edminson PD, Braestrup CB, Lingjaerde O, Ledaal P, Orbeck H: Biologically active peptide-containing fractions in schizophrenia and childhood autism. Adv Biochem Psychopharmacol 1981; 28: 627-643.

Abstract:

It is well documented that peptides have a major role in the effective functioning of higher animals at all levels from enzyme stabilization to homeostatic mechanisms governing essential functions such as eating, sexual behavior, and temperature regulation. The effects of exogenously administered peptides on neurotransmitter release, uptake, metabolism and behavioral consequences are also well established. We have attempted to extend these findings by postulating peptidergic neurons as transducers of multisignal inputs, and that development of pathological states may be due to genetically-determined reduced levels of activity of key peptidases, leading to excretion of regulatory peptides into the circulation. We have been able to demonstrate that, in schizophrenia and autism (in well defined clinical cases), the patterns of peptides and associated proteins from urinary samples differ considerably from each other and from normal controls. In addition to this, further purification of the material obtained has led to the discovery of a number of factors capable of modulating the function of major neurotransmitters. Some of these are in the final stages of characterization as peptides, while the remainder are also probably peptides, as purification has been followed by both biological testing and chemical analysis for peptidic material. We have outlined a number of parameters which we consider relevant in any attempt to put psychiatric disorders on a biological foundation. Any new advances in the neurochemical understanding of such disorders must take into consideration the observations of several different disciplines including genetics and psychology. However, at this stage of research it is far too early to speculate on the relevance of the various biological activities to the etiology and symptomatology of schizophrenia and childhood autism.

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Trygstad OE, et al: Patterns of peptides and protein-associated-peptide complexes in psychiatric disorders. Br J Psychiatry 1980 Jan;136:59-72.

Abstract:

Peptidic neurones may be considered as multisignal intergrators and transducers. When formation or release of peptide outstrips genetically determined breakdown capacity, overflow of peptides to the body fluids and urine may be expected. In this paper, pathological urinary chromatographic patterns of peptides are shown for genetic, functional and mixed disorders. Part symptoms of the disorders may be induced with the biologically isolated and purified peptides as well as with chemically synthesized peptides.

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Ross-Smith, P, Jenner FA: Diet (gluten) and Schizophrenia. J. Hum. Nutr. 1980 / 34 (2) / 107-112.

Four aspects of clinical evidence for an association between gluten and schizophrenia are examined. The scientific evidence for the role of gluten is set out. Finally, reference is made to other dietary approaches.

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Zioudrou C, Streaty RA, Klee WA: Opioid peptides derived from food proteins. The exorphins. J. Biol. Chem.1979 / 254 (7) / 2446-2449.

Abstract:

Peptides with opioid activity are found in pepsin hydrolysates of wheat gluten and alpha-casein. The opioid activity of these peptides was demonstrated by use of the following bioassays: 1) naloxone-reversible inhibition of adenylate cyclase in homogenates of neuroblastoma X-glioma hybrid cells; 2) naloxone-reversible inhibition of electrically stimulated contractions of the mouse vas deferens; 3) displacement of [3H]dihydromorphine and [3H-Tyr, dAla2]met-enkephalin amide from rat brain membranes. Substances which stimulate adenylate cyclase and increase the contractions of the mouse vas deferens but do not bind to opiate receptors are also isolated from gluten hydrolysates. It is suggested that peptides derived from some food proteins may be of physiological importance.

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Panksepp J: A neurochemical theory of autism. Point of View, North-Holland Biomedical Press, Jul 1979.

Hole K, Bergslien AA, Jørgensen H, Berge O-G, Reichelt KL & Trygstad OE:(1979) A peptide containing fraction from schizophrenia which stimulates opiate receptors and inhibits dopamine uptake. Neuroscience, 4, 1139-1147. [No abstract available]

Dohan FC: Schizophrenia and neuroactive peptides from food. Lancet 1979 May 12;1(8124):1031. [No abstract available]

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Brantl V, Teschemacher H: Naunyn Schmiedebergs  A material with opioid activity in bovine milk and milk products. Arch Pharmacol 1979 Apr 30;306(3):301-4.

Abstract:

Chloroform-methanol extracts of lyophilized milk, of commercially available dried milk or baby food and of casein digests were tested for opioid activity on the guinea-pig ileum longitudinal muscle-myenteric plexus preparation. Compounds with opioid activity--which proved to be resistant to peptidases--were detected in certain batches of baby food, casein digest, and cow milk in considerably varying amounts.

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Ashkenazi et. al: "Immunologic reaction of psychotic patients to fractions of gluten" Am J Psychiat 1979; 136: 1306-1309.

Abstract:

Production of a leukocyte migration inhibition factor by peripheral blood lymphocytes in response to challenge with gluten fractions was studied in hospitalized patients with schizophrenia and other psychoses compared with normal individuals and with children and adolescents with celiac disease. The schizophrenic and other psychotic patients could be subdivided into two groups, one that responded in the leukocyte migration inhibition factor test as the celiac patients did and one that responded as the normal control subjects did. The psychotic and schizophrenic patients did not show any evidence of malabsorption. The authors speculate that gluten may be involved in biological processes in the brain in certain psychotic individuals.

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O'Banion D, Armstrong B, Cummings RA, Stange J.: Disruptive behavior: a dietary approach. J Autism Child Schizophr 1978 Sep;8(3):325-37.  

Abstract: The effect of particular foods on levels of hyperactivity, uncontrolled laughter, and disruptive behaviors was studied in an 8-year-old autistic boy. The floor of the child's room was taped off into six equal-sized rectangles to measure general activity level. Frequency data were recorded on screaming, biting, scratching, and object throwing. A time-sample technique was used to record data on laughing. Data were gathered during four phases. During an initial 4-day period the child was fed a normal American diet. A 6-day fasting period followed, during which time only spring water was allowed. The third phase lasted 18 days and involved the presentation of individual foods. During the final phase of the study the child was given only foods that had not provoked a reaction in the third phase. Results showed that foods such as wheat, corn, tomatoes, sugar, mushrooms, and dairy products were instrumental in producing behavioral disorders with this child.

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Singh MM, Kay SR: Wheat gluten as a pathogenic factor in schizophrenia. Science 1976 Jan 30;191(4225):401-2.

Abstract:

Schizophrenics maintained on a cereal grain-free and milk-free diet and receiving optimal treatment with neuropleptics showed an interruption or reversal of their therapeutic progress during a period of "blind" wheat gluten challenge. The exacerbation of the disease process was not due to variations in neuroleptic doses. After termination of the gluten challenge, the course of improvement was reinstated. The observed effects seemed to be due to a primary schizophrenia-promoting effect of wheat gluten.

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Dohan FC, Grasberger JC: Relapsed schizophrenics: earlier discharge from the hospital after cereal-free, milk-free diet. Am J Psychiatry. 1973 Jun;130(6):685-8. [No abstract available]  

Goodwin MS, Cowen MA, Goodwin TC: Malabsorption and cerebral dysfunction: a multivariate and comparative study of autistic children. J Autism Child Schizophr 1971 Jan-Mar;1(1):48-62. [No abstract available]

Dohan FC: "Is celiac disease a clue to pathogenesis of schizophrenia?" Mental Hyg 1969; 53: 525-529. [No abstract available]

Dohan FC: Wheat "consumption" and hospital admissions for schizophrenia during World War II. A preliminary report. Am J Clin Nutr. 1966 Jan;18(1):7-10. [No abstract available]

Cooke WT, Smith WT: Neurological disorders associated with adult celiac disease. Brain 1966, 89: 683-722. [No abstract available]

Dohan FC: Cereals and schizophrenia: data and hypothesis. Acta Psychiat Scand 1966; 42: 125-152. [No abstract available] Autism  spectrum disorders and intestinal  microbiota.

De Angelis M1,  Francavilla R,  Piccolo M,  De Giacomo A,  Gobbetti M.