1. Non-celiac Gluten Sensitivity and Autism Spectrum Disorders “Gluten Free for Life” Timothy Buie MD April 11, 2015

2. Conflict of interest  I am interested in bread, pasta, you name it  I am conflicted as to whether these foods are good for me or others  I have no financial conflicts 2

3. Gluten Concerns and Autism Go Way Back  Autism was described by Leo Kanner in 1943  A compendium of articles including one penned by Asperger (1951) suggested the link of autism behaviors to gluten exposures  Dohan (1961) demonstrated the remarkable increase in exposure to gluten in the diet post World War II and an increase in schizophrenia diagnosis (Autism was characterized as childhood schizophrenia at the time)  Since the 1970’s there are continued publications evaluating diets for autism and prominent among them are milk and gluten free diets  WHERE THERE’S SMOKE…… ??? 3

4. Considered Mechanisms  Celiac Disease  Wheat Allergy  Problems with other component of the food such as CHO maldigestion  Dealing with the non-digestible component of gluten 4

5. Celiac and Autism  Early studies did not differentiate Celiac Disease from any other gluten reactions and as you have heard only with the advent of current antibody testing can we attempt to stratify reactions to foods  Pavone (1997) suggested no link in a limited population of children with autism 5

6. Celiac and Autism  Ludvigsson et al (2013) in A Nationwide Study of the Association Between Celiac Disease and the Risk of Autistic Spectrum Disorders reported no higher frequency of celiac identified by intestinal biopsy in patients with ASD over the general population in Sweden However, there was a higher risk of positive screening markers (IgA/IgG gliadin, endomysium, or tissue transglutaminase) in patients with autism with normal biopsies  Does abnormal antibody response reflect OTHER RISK? 6

7. Wheat Allergy  Current data suggest the prevalence of food allergy in pediatrics to be approximately 5-8%  Food allergy may be 2X more common in boys (Liu 2010)  Eight foods account for 90% of all food-allergic reactions: milk, eggs, peanuts, tree nuts (e.g., walnuts, almonds, cashews, pistachios, pecans), wheat, soy, fish, and shellfish.  Wheat is not in the top 5 food allergens  Debate still continues regarding best measures to establish a supportable diagnosis of allergy: Skin testing, IgE based measures 7

8. Non-Digestibles  Gluten foods have a number of non-digestible components  The protein product itself cannot be completely digested by our digestive capabilities  Lectins which may be gut toxic and are associated with a variety of autoimmune conditions  Phytic Acid may be an anti-nutrient affecting absorption of a number of minerals in the gut  Carbohydrate digestion impairment is rare. 8

9. ASD and Gluten: What problems are we talking about?  It is reasonable to consider the IF gluten is a trigger for GI disturbance, IBS, permeability issues of the gut that have been discussed THEN individuals with autism have equal rights to have those same issues  The difficulty is autism is the clinical presentation  Non-verbal individuals may manifest underlying GI of other medical issues in a behavioral fashion simply because they cannot communicate what is wrong  In autism, the highest correlations of self injurious or aggressive behavior are non-verbal status and the presence of associated GI conditions Perhaps therefore GI conditions may worsen the “autism behaviors” without necessarily causing autism 9

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12. Could Gluten or Food Sensitivity Cause Autism or Autism Symptoms?  Mechanisms  Opioid peptide theory  Altered intestinal flora  Altered intestinal permeability 12

13. Opioid Peptide Theory  Early speculation linking the foods (milk and gluten) to the presence of urinary peptides that were shown in vitro to bind to opioid receptors  Several reports in selected children with autism where these peptides were identified  Suggestion that increased quantities of these peptides were noted when there was abnormal permeability, including in patients with celiac who did not have autism 13

14. Opioid Peptide Theory  Recent studies seeking to replicate previous findings did not identify these products as more common in autism (Elder et al 2006)  Cass (2008) showed no higher frequency of abnormality in children with autism and that peaks identified as consistent with casomorphin or gliadomorphin were not those substances on confirmatory studies  Many neurotransmitters have been implicated in autism, opioid receptor genetics are normal 14

15. Altered Intestinal Microbiota  Multiple studies in past several years show altered microbiome assessments in children with autism. Our own group with Columbia identified Sutterella (a potential pathogen) in intestinal biopsies of children with autism (Williams 2012), this was not present in unaffected children  Other studies are supporting the presence of excess clostridial species among others in children with autism  Lack of diversity and reduced lactose fermenters are a common report 15

16. Altered Intestinal Microbiota  Diminished presence of B Fragilis in children with autism has been noted and providing B Fragilis in animal model for autism corrected autism features (Hsiao 2013)  Altered microbiota may develop as a result of dietary selectivity or alteration  Altered microbiota likely lead to altered gut metabolome and these bacterial byproducts may alter nervous system communication 16

17. Intestinal Permeability  Altered intestinal permeability has been reported frequently in autism  This may be a result of food reactivity or immune modulation related to foods  A recent study we’ve presented in abstract form did not show that increased permeability issues were noted with greater frequency in our children with autism compared to unaffected comparisons and was not correlated to the inflammation noted by intestinal biopsy performed contiguously. 17

18. Gluten Free Trials  Knivsberg, 1990: Selected patients with high gluten opioid peptides in urine. 8/10 were reported to have behavioral improvements noted. Duplicated study in 2002  Sponheim 1991: Selected 4 children with autism for gluten-free diet, behavior worsened  Whiteley, 1999: Observation study of gluten free diet, 2/3 had behavioral improvements noted  Where else? Unraveling the Mystery of Autism, by Karen Seroussi (Simon and Schuster, N.Y.N.Y. 2000)

19. Gluten Free Trials  Elder et al* 2006 double-blind crossover trial Casein-free, Gluten-free diet in 15 children with autism showed no benefit of diet in a 12-week study  Blinded parents reported benefits not identified by testing. Perhaps subtle changes/benefits will not be retrieved through standard tests.  Similar trial from Susan Hyman’s group in Rochester reported in abstract form *J Autism Dev Disord. 2006 Apr;36(3):413-20

20. Critique on diet trials  Selection  Outcomes  Importance of timing of intervention  Linkage of diet to the alteration of microbiota before and after will be remarkably useful and are not published in this population as of now 20

21. Conclusions  I believe there will be a group of candidate individuals with autism who will have improvement in their GI status, behaviors and perhaps core autism features by gluten =/- other food restriction diets  We have not adequately identified a candidate sub-group to improve likelihood of response  Until such time, individual counseling is needed to determine the potential benefit of this diet or others for the management of autism 21