Autism spectrum disorder (ASD) comprises a set of complex neurodevelopmental disabilities characterized by repetitive/stereotypic behaviors and deficits in communication and social interaction. Recent studies highlight striking neural and peripheral immune dysregulation in ASD. Moreover, a significant subset of ASD children exhibit gastrointestinal (GI) complications, including increased intestinal permeability and altered composition of intestinal microbiota. The potential connections between GI abnormalities, intestinal bacteria, and behavioral deficits have not yet been convincingly investigated. To examine the hypothesis that GI pathology is associated with, and contributes to behavioral symptoms, we employ a mouse model of an ASD risk factor, maternal immune activation (MIA). Our results show that these mice, which display cardinal ASD-like behaviors and neuropathology, also exhibit GI pathology. This includes changes in expression of tight junction components in the intestinal epithelium and a 'leaky gut', or diminished epithelial barrier function, which is reported in a significant subset of ASD children. Remarkably, this leaky gut is associated with an altered metabolite profile in the serum of the MIA mice, suggesting that GI permeability results in translocation of bacterial products into the circulation. Furthermore, we show that administration of a probiotic bacterium, Bacteroides fragilis, to these mice cures several behavioral abnormalities while restoring GI barrier function. Our central hypothesis is that correcting GI abnormalities with probiotic bacteria may be a safe and effective treatment for some of the abnormal behaviors in ASD.
The specific aims that will test this hypothesis are: 1) in mechanistic experiments, determine if a cytokine relevant to MIA induces leaky gut;2) determine whether putative metabolites that leak from the gut contribute to or modify behavioral abnormalities;3) extending our results from the mouse model of an environmental ASD risk factor, test if this probiotic treatment corrects GI and behavioral abnormalities in genetic models of ASD;4) determine if human ASD subjects with GI complications display altered serum metabolites. Based on compelling preliminary evidence, this project aims to explore the potential connection between GI barrier defects and altered behavior in preclinical models of autism, and extend these findings to humans. Our long-term goal is to explore possible serum biomarkers for ASD diagnosis, and potentially develop a novel probiotic therapy for at least a subset of children with ASD with GI issues.

Public Health Relevance

Autism spectrum disorder (ASD) is a rapidly growing medical and social burden with limited therapeutic options, often involving gastrointestinal abnormalities along with behavioral deficits. We have modeled these features together for the first time in animals, and have further discovered a metabolite signature in the serum of the mice that may be applicable for early diagnosis in humans. Based on data that a probiotic bacterium ameliorates gut dysfunction, corrects serum metabolites and cures many behavioral deficits, this project aims to develop a diagnostic profile for ASD with GI problems, and eventually a safe and effective treatment for ASD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH100556-01
Application #
8484091
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Desmond, Nancy L
Project Start
2013-07-15
Project End
2018-04-30
Budget Start
2013-07-15
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$558,136
Indirect Cost
$219,301
Name
California Institute of Technology
Department
None
Type
Schools of Arts and Sciences
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Mayer, Emeran A; Knight, Rob; Mazmanian, Sarkis K et al. (2014) Gut microbes and the brain: paradigm shift in neuroscience. J Neurosci 34:15490-6