Gastrointestinal Findings in Autism and Other ASDs

Advances in Autism Research
April 2010

Given that not all peer-reviewed journals are indexed in Pubmed and that not all articles are indexed into Pubmed immediately upon publication, on March 21, 2010, a fairly thorough Pubmed search for 2008, 2009, and 2010 brought forth 98 citations:

(gastrointestinal OR intestinal OR ileal OR ileum OR intestin* OR constipation OR diarrhea)
AND (autis* OR PDD OR PDD* OR adhd OR ASD OR asds OR Asperge*)
AND (2010[dp] OR 2009[dp] OR 2008[dp])

One of the most noteworthy advances in autism occurred in early 2010 when the journal "Pediatrics" published two reviews focused upon evaluation and treatment of gastrointestinal pathologies often present in autistic children. Each review is free online (1-2). In my opinion, these two reviews would not have been published or would have been published years from now were it not for the pioneering efforts of D'Eufemia, Horvath, Knivsberg, Jyonouchi, their various colleagues, and other pioneers such as Steve Walker & Arthur Krigsman (eg, 3-10).

Ironically, as Pediatrics is promoting progress by printing the Buie et al reviews (1-2), that journal previously published a flawed study wherein Ibrahim et al used an odd methodology to find that gastrointestinal pathologies are as common in non-autistic children as those pathologies are in autistic children. A critique of Ibrahim et al can be enjoyed here.

Additional studies are listed (14-38), and their abstracts can be viewed by clicking on the blue-text in each. Some are free online.

1. Evaluation, Diagnosis, and Treatment of Gastrointestinal Disorders in Individuals With ASDs: A Consensus Report
Buie T et al.
Pediatrics 2010;125:S1–S18.
http://pediatrics.aappublications.org/cgi/content/full/125/Supplement_1/S1

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. Amultidisciplinary 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.

2. Recommendations for Evaluation and Treatment of Common Gastrointestinal Problems in Children With ASDs
Buie T et al.
Pediatrics 2010;125:S19–S29
http://pediatrics.aappublications.org/cgi/content/full/125/Supplement_1/S19

Children with autism spectrum disorders (ASDs) can benefit from adaptation of general pediatric guidelines for the diagnostic evaluation of abdominal pain, chronic constipation, and gastroesophageal reflux disease. These guidelines help health care providers determine when gastrointestinal symptoms are self-limited and when evaluation beyond a thorough medical history and physical examination should be considered. Children with ASDs who have gastrointestinal disorders may present with behavioral manifestations. Diagnostic and treatment recommendations for the general pediatric population are useful to consider until the development of evidence-based guidelines specifically for patients with ASDs.

3. Food allergy and infantile autism.
Lucarelli S et al.
Panminerva Med. 1995 Sep;37(3):137-41.

4. Abnormal intestinal permeability in children with autism.
D'Eufemia P et al.
Acta Paediatr. 1996 Sep;85(9):1076-9.

5. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children

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


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.

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

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

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

10. Autistic enterocolitis: Fact or fiction?
{excellent, brief overview free online}
P Galiatsatos, A Gologan, E Lamoureux
Can J Gastroenterol. 2009 Feb;23(2):95-8.

11. Clinical Presentation and Histologic Findings at Ileocolonoscopy in Children with Autistic Spectrum Disorder and Chronic Gastrointestinal Symptoms
{free online}
Arthur Krigsman, Marvin Boris, Allan Goldblatt and Carol Stott
Autism Insights 2010:2 1-11; 27 Jan 2010

12. Gastrointestinal Pathology in Autism Spectrum Disorders: The Venezuelan Experience
{conference report, free online}
AutismOne 2009, 2010
Lenny G. Gonzalez, M.D.

13. Incidence of Gastrointestinal Symptoms in Children With Autism: A Population-Based Study
{a study with major flaws, critiqued here)
Samar H. Ibrahim, Robert G. Voigt, Slavica K. Katusic, Amy L. Weaver, William Barbaresi.
Departments of Pediatric and Adolescent Medicine and Health Sciences Research
Mayo Clinic, Rochester, Minnesota
Pediatrics 2009;124;680-686. Epub 2009 Jul 27.
$ http://pediatrics.aappublications.org/cgi/content/full/124/2/680

14. Digestive Enzyme Supplementation for Autism Spectrum Disorders: A Double-Blind Randomized Controlled Trial.

Munasinghe SA, Oliff C, Finn J, Wray JA.
J Autism Dev Disord. 2010 Mar 5. [Epub ahead of print]

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

16. A longitudinal study of gastrointestinal diseases in individuals diagnosed with infantile autism as children.
Mouridsen SE, Rich B, Isager T.
Child Care Health Dev. 2009 Nov 2. [Epub ahead of print]

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

18. Syndrome of allergy, apraxia, and malabsorption: characterization of a neurodevelopmental phenotype that responds to omega 3 and vitamin E supplementation.
Morris CR, Agin MC.
Altern Ther Health Med. 2009 Jul-Aug;15(4):34-43.

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

20. 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.
Smith RA, Farnworth H, Wright B, Allgar V.
Autism. 2009 Jul;13(4):343-55.

21. Gene expression profiling of lymphoblasts from autistic and nonaffected sib pairs: altered pathways in neuronal development and steroid biosynthesis.
Hu VW, Nguyen A, Kim KS, Steinberg ME, Sarachana T, Scully MA, Soldin SJ, Luu T, Lee NH.
PLoS One. 2009 Jun 3;4(6):e5775.

22. Food allergy and autism spectrum disorders: is there a link?
Jyonouchi H.
Curr Allergy Asthma Rep. 2009 May;9(3):194-201.

23. Autism and immunity: revisited study.
Castellani ML et al.
Int J Immunopathol Pharmacol. 2009 Jan-Mar;22(1):15-9.

24. Association of MET with social and communication phenotypes in individuals with autism spectrum disorder
Campbell DB, Warren D, Sutcliffe JS, Lee EB, Levitt P.
Department of Pharmacology, Vanderbilt University, Nashville, Tennessee.
Am J Med Genet B Neuropsychiatr Genet. 2009 Jun 22. [Epub ahead of print]
$ http://www3.interscience.wiley.com/journal/122462380/abstract

Autism is a complex neurodevelopmental disorder diagnosed by impairments in social interaction, communication, and behavioral flexibility. Autism is highly heritable, but it is not known whether a genetic risk factor contributes to all three core domains of the disorder or autism results from the confluence of multiple genetic risk factors for each domain. We and others reported previously association of variants in the gene encoding the MET receptor tyrosine kinase in five independent samples. We further described enriched association of the MET promoter variant rs1858830 C allele in families with co-occurring autism and gastrointestinal conditions. To test the contribution of this functional MET promoter variant to the domains of autism, we analyzed its association with quantitative scores derived from three instruments used to diagnose and describe autism phenotypes: the Autism Diagnostic Interview-Revised (ADI-R), the Autism Diagnostic Observation Schedule (ADOS), and both the parent and the teacher report forms of the Social Responsiveness Scale (SRS). In 748 individuals from 367 families, the transmission of the MET C allele from parent to child was consistently associated with both social and communication phenotypes of autism. Stratification by gastrointestinal conditions revealed a similar pattern of association with both social and communication phenotypes in 242 individuals with autism from 118 families with co-occurring gastrointestinal conditions, but a lack of association with any domain in 181 individuals from 96 families with ASD and no co-occurring gastrointestinal condition. These data indicate that the MET C allele influences at least two of the three domains of the autism triad.

25. Gastrointestinal symptoms in children with an autism spectrum disorder and language regression.
Valicenti-McDermott MD, McVicar K, Cohen HJ, Wershil BK, Shinnar S.
Pediatr Neurol. 2008 Dec;39(6):392-8.

26. Autism, gut-blood-brain barrier, and mast cells.
Theoharides TC, Doyle R.
J Clin Psychopharmacol. 2008 Oct;28(5):479-83.

27. Gastrointestinal symptoms in a sample of children with pervasive developmental disorders.
Nikolov RN et al.
J Autism Dev Disord. 2009 Mar;39(3):405-13.

28. Novel therapeutic targets for autism.
Theoharides TC, Doyle R, Francis K, Conti P, Kalogeromitros D.
Trends Pharmacol Sci. 2008 Aug;29(8):375-82.

29. Regression, developmental trajectory and associated problems in disorders in the autism spectrum: the SNAP study.
Baird G, Charman T, Pickles A, Chandler S, Loucas T, Meldrum D, Carcani-Rathwell I, Serkana D, Simonoff E.
J Autism Dev Disord. 2008 Nov;38(10):1827-36.

30. Discerning the Mauve Factor, Part 1.
McGinnis WR, Audhya T, Walsh WJ, Jackson JA, McLaren-Howard J, Lewis A, Lauda PH, Bibus DM, Jurnak F, Lietha R, Hoffer A.
Altern Ther Health Med. 2008 Mar-Apr;14(2):40-50.


31. Discerning the Mauve factor, Part 2.
McGinnis WR, Audhya T, Walsh WJ, Jackson JA, McLaren-Howard J, Lewis A, Lauda PH, Bibus DM, Jurnak F, Lietha R, Hoffer A.
Altern Ther Health Med. 2008 May-Jun;14(3):56-62.

32. Regression in autism: prevalence and associated factors in the CHARGE Study.
Hansen RL, Ozonoff S, Krakowiak P, Angkustsiri K, Jones C, Deprey LJ, Le DN, Croen LA, Hertz-Picciotto I.
Ambul Pediatr. 2008 Jan-Feb;8(1):25-31.

33. Autism spectrum disorders: concurrent clinical disorders.
Xue Ming, Brimacombe M, Chaaban J, Zimmerman-Bier B, Wagner GC.
J Child Neurol. 2008 Jan;23(1):6-13.

34. Psychiatric disorders and family functioning in children and adolescents with functional abdominal pain syndrome.
Ghanizadeh A, Moaiedy F, Imanieh MH, Askani H, Haghighat M, Dehbozorgi G, Dehghani SM.
J Gastroenterol Hepatol. 2008 Jul;23(7 Pt 1):1132-6.

35. Therapy and epidemiology of autism--clostridial spores as key elements.

Finegold SM.
Med Hypotheses. 2008;70(3):508-11.

36. Intestinal anaerobic bacteria and autistic mind...
Martirosian G et al.
Med Sci Monit. 2009 Mar;15(3):LE2-3.
http://www.medscimonit.com/fulltxt.php?ICID=869564

excerpt: "In 1998, Ellen Bolte published hypothesis that Clostridium tetani (or other bacteria in the gut) might play a role in late onset of autism..."


This document prepared by
Teresa Binstock
Researcher in Developmental & Behavioral Neuroanatomy
April 2010