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Gastrointestinal Symptoms and Probiotic Treatment in a Mouse Model of an ASD Risk Factor

Friday, 3 May 2013: 15:15
Chamber Hall (Kursaal Centre)
P. H. Patterson, California Institute of Technology, Altadena, CA
Background: While autism is a neurodevelopmental disorder characterized by language and social deficits, recent studies have highlighted striking dysregulation in the neural, peripheral, and enteric immune systems of autistic individuals. There are also reports that subsets of children with autism spectrum disorder (ASD) display gastrointestinal (GI) abnormalities, including increased intestinal permeability and altered composition of GI microbiota.

 Objectives: To explore the potential connections between GI problems and the brain and behavior, we use a mouse model of an ASD risk factor, maternal immune activation (MIA). We also tested the efficacy of probiotic treatment in MIA offspring that display the cardinal ASD behaviors and neuropathology.

 Methods: Pregnant mice are injected with poly(I:C) or saline on E12.5. Offspring are fed the probiotic bacteria, Bacteroides fragilis, at weaning for one week. Young and adult offspring are assessed for (i) intestinal barrier integrity by measuring leakage of FITC-dextran through the intestinal epithelium and tight junction expression, (ii) GI inflammation by cytokine Luminex array and histology, (iii) serum metabolome profiles by GC-MS and LC-MS.

 Results: MIA offspring display decreased intestinal barrier integrity and corresponding changes in levels of tight junction proteins. These symptoms are associated with altered expression of colon cytokines and changes in serum metabolite levels. Postnatal B. fragilis treatment ameliorates these GI abnormalities, and normalizes certain serum metabolites and several ASD-related behaviors.

 Conclusions: These studies highlight the potential relevance of the gut-brain axis for ASD, where manipulation of the intestinal microbiome can influence GI physiology and behavioral performance. The results raise the possibility of testing a probiotic therapy in individuals with autism and co-morbid GI symptoms. Moreover, the altered serum metabolite profiles in the MIA mouse model raise the possibility of testing particular metabolites as candidate biomarkers for subsets of human ASD.

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