Gut Microbiota Structure and Function in Children with Autism (ASUF 30005952) Gut Microbiota Structure and Function in Children with Autism Individuals with autism spectrum disorder (ASD) have extremely heterogeneous gastrointestinal (GI) symptoms, ranging from none to extremely severe (chronic constipation, diarrhea, reflux, ulcerative colitis, etc.). Discomfort and pain from these symptoms affect mood, behavior, attention, and learning capacity. Patients with more severe GI symptoms often have more severe autism symptoms 1. There is a growing body of evidence for a gut to brain connection for ASDs, where the complex consortia of microorganisms that colonize the gut (the microbiota) affect autistic symptoms. The gut microbiota is mostly composed of beneficial microorganisms that influence digestion and extraction of nutrients from food 2, generate vitamins and neurotransmitters, and provide a protective barrier against pathogenic bacteria that can produce toxins and create inflammation 3. A microbial etiology for ASDs was potentially demonstrated by treating children with regressiveonset autism with the minimally absorbed antibiotic Vancomycin, which resulted in short-term improvement only during vancomycin treatment in 8 of 10 children 4. The few studies of GI microbiota composition in autism conducted to date, however, have yielded conflicting results in the nature and or extent of GI microbiota differences in children with ASDs compared to controls 5-8. For instance, the recent report by co-PI Krajmalnik-Brown of a decreased incidence of Prevotella (among other species) in children with ASD7 was not replicated in another recent study which found no difference in the gut microbiota with ASD 9. Other studies that did detect a difference in gut microbiota with ASDs highlighted taxa that were not found to diverge in co-PI Krajmalnik-Browns cohort (e.g. Clostridium bolteae as reported in 10). These differences may reflect different degrees to which the studies considered potentially confounding factors such as diet, oral antibiotic use, prebiotics, probiotics, GI problems, and autistic symptoms or divided their ASD cohort into subtypes (e.g. early versus regressive onset or by severity). Differences between cohorts may also reflect the natural human microbial diversity both within and between individuals, or differences in sequencing methods; to address this requires larger cohorts using the same sequencing methodology and studies that longitudinally correlate behavioral symptoms with gut microbial composition. Despite inconsistency in the degree and nature of microbiota divergence with ASDs, an altered functional profile of ASD-associated gut microbiota has been evidenced by profiles of urinary 11 and fecal (unpublished data; Krajmalnik-Brown) metabolites. Urinary metabolites that positively correlate with ASD symptoms include 1) 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), a probable metabolite of a tyrosine analog that depletes catecholamines and causes symptoms of autism, such as stereotypical behavior, hyperactivity, and hyper-reactivity in experimental animals 12 and 2) p-cresol, which can compete with neurotransmitters for enzymes and co-factors essential for sulfonation reactions in the liver (preliminary data; 13,14). Gut bacteria may also play a role in an observed B vitamin deficiency in individuals with ASDs 15. Unfortunately, patient correlations between urinary and/or fecal metabolic phenotypes and gut microbiota over time have not been performed to date. This limits our ability to determine which bacteria are potentially generating which metabolites. In this work, we will further characterize gut microbiota differences with ASDs and correlate these differences with metabolite production by carrying out the following specific aims: Aim 1: Correlate the taxonomic and gene composition of the gut microbiota (as assessed with 16S rRNA and shotgun metagenomic sequencing of fecal samples) of ASD patients and controls over time from individuals from two geographically distinct cohorts (Arizona and Colorado) with measures of behavior, GI symptoms and diet. Aim 2: Perform metabolomic analysis of matched urine and stool samples and correlate the presence and abundance of metabolites significantly enriched in ASD populations with the presence/absence of bacterial taxa or functional genes in stool. Potential Impact on Autism Research One of the most complex issues with ASD is the heterogeneity of the disease itself and GI symptoms. In this light it is not surprising that different studies have revealed inconsistent results with regard to the degree and nature of gut microbiota differences with ASDs. Combining samples from two independently recruited cohorts and processing and analyzing them with consistent methods will allow for results to be directly compared without the confounding factor of differences in experimental protocol. Furthermore, collecting rich metadata and sampling longitudinally across individuals over time
|Effective start/end date||1/1/14 → 7/31/16|
- Arizona State University Foundation (ASUF): $52,000.00
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