Background: Although there is general consensus of greater prevalence of GI distress in individuals with Autism Spectrum Disorders (ASD), the nature of the link is unknown. There is preliminary evidence to suggest that GI distress in ASD may be associated with """"""""Leaky-Gut"""""""" (i.e. increased permeability of the intestinal mucosal barrier due to either delayed or abnormal development), as shown by a study showing higher-than-normal prevalence in ASD children 4 - 16 years of age (e.g., D'Eufemia et al., 1996). During normal digestion, the mucosal barrier is responsible for keeping digestive enzymes out of the intestinal wall. Our recent evidence shows that if these powerful degrading enzymes enter the wall of the intestine, they will cause major damage to the intestinal wall as well as central inflammation. Delayed sealing or dysfunction of the mucosal barrier during postnatal development could allow digestive enzymes in the intestinal lumen to move into the intestinal wall, degrade the intestinal wall itself (referred to as """"""""auto-digestion""""""""), and in turn, lead to inflammatory responses and GI distress. Additionally, dysfunctional development of the barrier system could lead to pancreatic enzymes and inflammatory mediators entering the bloodstream, where their presence could have far-reaching degrading effects. Objective/Hypothesis: We hypothesize that ASD may be associated with Leaky-Gut early in development, which combines, or interacts, with diet (breast-milk, formula, solid foods) to produce auto-digestion and inflammation in: 1) the intestine, which could explain the GI distress, and 2) in the bloodstream, which could reach and damage the developing brain, thus contributing to the onset of ASD itself.
Specific Aims : To test our hypotheses, the current proposal is designed to track key aspects of GI function in """"""""High-Risk"""""""" infants, i.e., infants who have an older sibling diagnosed with ASD: 1) signs of Leaky-Gut, 2) symptoms of GI distress (e.g., diarrhea, reflux, constipation), 3) diet (breast-milk vs. formula), 4) evidence of digestive enzymes and inflammatory markers of cell death in the bloodstream. These High-Risk infants have a 10- to 20-fold greater chance of developing ASD than the general population, and tracking early development in this cohort is an ideal way to """"""""catch the culprit"""""""" in ASD. Study Design: The study is designed to collect urine samples from High-Risk infants (and for comparison, from Low-Risk controls, defined as infants from families without ASD history) at multiple time points in the first two years and urine and blood samples before and after transition from breast milk to formula feeding. The urine samples are used for a direct test of Leaky-Gut. The plasma samples will be assayed for evidence of digestive enzymes and inflammatory mediators. GI Symptomatology will be tracked via parent questionnaires. Diet history questionnaires/logs will monitor use of breast-milk vs. formula-milk. As part of our protocol already in place, we will administer early detection cognitive, visual, and behavioral tests as well as the ADOS/ADI at two and three years of age to determine whether an infant develops ASD.
This project seeks to answer fundamental questions about the connection between early development of gastrointestinal (GI) problems (constipation, diarrhea, vomiting, etc.) and autism spectrum disorders (ASD). It will do so by examining the early history of GI problems and diet (breast-feeding vs. formula/solids) vs. the permeability of the intestine (leaky gut) in infants at high genetic risk for developing ASD (due to having an older sibling already diagnosed with the disorder). If a link is found between the onset of gastrointestinal problems or development of ASD, and a leaky gut, then leaky gut could serve as an early biomarker for the disorder. If leaky gut in combination with diet is associated with GI problems or ASD, it could lead to diet recommendations for the purposes of preventing new cases of ASD or easing the GI symptoms of individuals already diagnosed with ASD.
|Penn, Alexander H; Carver, Leslie J; Herbert, Carrie A et al. (2016) Breast Milk Protects Against Gastrointestinal Symptoms in Infants at High Risk for Autism During Early Development. J Pediatr Gastroenterol Nutr 62:317-27|
|Penn, Alexander H; Altshuler, Angelina E; Small, James W et al. (2014) Effect of digestion and storage of human milk on free fatty acid concentration and cytotoxicity. J Pediatr Gastroenterol Nutr 59:365-73|
|Stavropoulos, Katherine K M; Carver, Leslie J (2014) Reward anticipation and processing of social versus nonsocial stimuli in children with and without autism spectrum disorders. J Child Psychol Psychiatry 55:1398-408|
|Stavropoulos, Katherine K M; Carver, Leslie J (2014) Reward sensitivity to faces versus objects in children: an ERP study. Soc Cogn Affect Neurosci 9:1569-75|
|Stavropoulos, Katherine K M; Carver, Leslie J (2013) Research review: Social motivation and oxytocin in autism--implications for joint attention development and intervention. J Child Psychol Psychiatry 54:603-18|
|Penn, Alexander H; Altshuler, Angelina E; Small, James W et al. (2012) Digested formula but not digested fresh human milk causes death of intestinal cells in vitro: implications for necrotizing enterocolitis. Pediatr Res 72:560-7|
|Cornew, Lauren; Dobkins, Karen R; Akshoomoff, Natacha et al. (2012) Atypical social referencing in infant siblings of children with autism spectrum disorders. J Autism Dev Disord 42:2611-21|