Research on Dietary Interventions in ASD

July 7th, 2010

Below are some abstracts of research done on the link between dietary issues and autism.


Williams, B. L., Hornig, M., Buie, T., Bauman, M. L., Cho Paik, M., Wick, I., Bennett, A., et al. (2011). Impaired Carbohydrate Digestion and Transport and Mucosal Dysbiosis in the Intestines of Children with Autism and Gastrointestinal Disturbances. (S. Jacobson, Ed.) PLoS ONE, 6(9), e24585. doi:10.1371/journal.pone.0024585.t008

Abstract

Gastrointestinal disturbances are commonly reported in children with autism, complicate clinical management, and may contribute to behavioral impairment. Reports of deficiencies in disaccharidase enzymatic activity and of beneficial responses to probiotic and dietary therapies led us to survey gene expression and the mucoepithelial microbiota in intestinal biopsies from children with autism and gastrointestinal disease and children with gastrointestinal disease alone. Ileal transcripts encoding disaccharidases and hexose transporters were deficient in children with autism, indicating impairment of the primary pathway for carbohydrate digestion and transport in enterocytes. Deficient expression of these enzymes and transporters was associated with expression of the intestinal transcription factor, CDX2. Metagenomic analysis of intestinal bacteria revealed compositional dysbiosis manifest as decreases in Bacteroidetes, increases in the ratio of Firmicutes to Bacteroidetes, and increases in Betaproteobacteria. Expression levels of disaccharidases and transporters were associated with the abundance of affected bacterial phylotypes. These results indicate a relationship between human intestinal gene expression and bacterial community structure and may provide insights into the pathophysiology of gastrointestinal disturbances in children with autism.

 

Food Allergy and Autism Spectrum Disorders: Is There a Link? Current Allergy and Asthma Reports 2009;9:194–201

Jyonouchi H

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

OBJECTIVE: Gastrointestinal (GI) symptoms are common comorbidities in children with autism spectrum disorders (ASDs). Parents often attribute these GI symptoms to food allergy (FA), although an evaluation for IgE-mediated FA is often unrevealing. Our previous studies indicated a high prevalence of non–IgE-mediated FA in young children with ASDs. Therefore, non–IgE-mediated FA may account for some but not all GI symptoms observed in children with ASDs. This raises the question of what treatment measures are applicable to ASD children with GI symptoms. A wide variety of dietary supplements and dietary intervention measures for ASD children have been promoted by medical professionals practicing complementary and alternative medicine despite the lack of rigorous scientifi c validation in most instances. This review summarizes possible (or proposed) etiologies of GI symptoms in ASD children and discusses risks and possible benefi ts of intervention measures promoted by complementary and alternative practitioners, with emphasis on FA.

RESULTS: In summary, convincing data support the presence of chronic GI inflammation in ASD children, but the etiology of this GI infl ammation is not well understood and is likely affected by multiple genetic and environmental factors. NFA can partially explain the GI symptoms and apparent beneficial effects of dietary interventions in some ASD children, especially young ASD children. Apparent effects of oral vancomycin and altered commensal flora reported in ASD children may be explained partially by dysbiosis, which is likely associated with multiple environmental and, possibly, genetic factors. Further studies are required to understand the etiology of GI symptoms observed in ASD children.

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.

Jyonouchi H, Geng L, Ruby A, Zimmerman-Bier B.

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. Copyright 2005 S. Karger AG, Basel.

Immune response to dietary proteins, gliadin and cerebellar peptides in children with autism. Nutr Neurosci. 2004 Jun;7(3):151-61.

Vojdani A, O'Bryan T, Green JA, Mccandless J, Woeller KN, Vojdani E, Nourian AA, Cooper EL.

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.

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.

Vojdani A, Bazargan M, Vojdani E, Samadi J, Nourian AA, Eghbalieh N, Cooper EL.

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.

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.

Jyonouchi H, Geng L, Ruby A, Reddy C, Zimmerman-Bier B.

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.

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.

Ashwood P, Anthony A, Torrente F, Wakefield AJ.

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.

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.

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.

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

Vojdani A, Pangborn JB, Vojdani E, Cooper EL., Infections, toxic chemicals and dietary peptides binding to lymphocyte receptors and tissue enzymes are major instigators of autoimmunity in autism. Int J Immunopathol Pharmacol. 2003 Sep-Dec;16(3):189-99.

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.

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.

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.

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.

Gluten- and casein-free diets for autistic spectrum disorder. Cochrane Database Syst Rev. 2004;(2):CD003498.

Millward C, Ferriter M, Calver S, Connell-Jones G.

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.

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.

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.

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.

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.

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]

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.

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.

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.

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.

 

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.

 

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.

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.

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.

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 appears to be common in infants later diagnosed with autism.

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.

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]

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.

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.

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.

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.

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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