Microbiota Modulate Behavioral and Physiological Abnormalities Associated with Neurodevelopmental Disorders
Abstract
Neurodevelopmental disorders, including autism spectrum disorder (ASD), are defined by core behavioral impairments; however, subsets of individuals display a spectrum of gastrointestinal (GI) abnormalities. We demonstrate GI barrier defects and microbiota alterations in the maternal immune activation (MIA) mouse model that is known to display features of ASD. Oral treatment of MIA offspring with the human commensal Bacteroides fragilis corrects gut permeability, alters microbial composition, and ameliorates defects in communicative, stereotypic, anxiety-like and sensorimotor behaviors. MIA offspring display an altered serum metabolomic profile, and B. fragilis modulates levels of several metabolites. Treating naive mice with a metabolite that is increased by MIA and restored by B. fragilis causes certain behavioral abnormalities, suggesting that gut bacterial effects on the host metabolome impact behavior. Taken together, these findings support a gut-microbiome-brain connection in a mouse model of ASD and identify a potential probiotic therapy for GI and particular behavioral symptoms in human neurodevelopmental disorders.
Additional Information
© 2013 Elsevier Inc. Received: August 20, 2013; Revised: October 3, 2013; Accepted: November 18, 2013; Published: December 5, 2013. We acknowledge Reyna Sauza, Jaime Rodriguez, and Taren Thron for caring for the animals; Dr. Michael Fischbach (UCSF) for advising on pathways of 4EPS and indolepyruvate synthesis; Dr. Nadim Ajami (Baylor) for providing helpful comments on the manuscript; Greg Donaldson (Caltech) for conducting experiments on microbial viability; Dr. Kym Faull (UCLA) for conducting pilot GC/MS experiments; Dr. Alessio Fasano (Massachusetts General) for conducting pilot microbiota sequencing experiments; and Dr. Jerrold Turner (U Chicago) for providing histological analysis of intestinal sections. This work was supported by a Caltech Innovation Fellowship (to E.Y.H.), Autism Speaks Weatherstone Fellowship (to E.Y.H.), NIH/NRSA Predoctoral Fellowship (to E.Y.H.), Human Frontiers Science Program Fellowship (to G.S.), DOD Graduate Fellowship (to J.A.C.), NSF Graduate Research Fellowship (to J.A.C.), Autism Speaks Trailblazer Award (to P.H.P. and S.K.M.), Caltech Innovation Initiative (to P.H.P. and S.K.M.), Caltech Grubstake Awards (to P.H.P. and S.K.M), Congressionally Directed Medical Research Award (to P.H.P. and S.K.M.), Weston Havens Award (to P.H.P. and S.K.M.), Callie D. McGrath Charitable Foundation awards (to P.H.P.) and NIMH grant MH100556 (to P.H.P. and S.K.M.).Attached Files
Accepted Version - nihms543590.pdf
Supplemental Material - mmc1.xlsx
Supplemental Material - mmc2.zip
Supplemental Material - mmc3.pdf
Files
mmc2.zip
Additional details
Additional titles
- Alternative title
- The microbiota modulates gut physiology and behavioral abnormalities associated with autism
Identifiers
- PMCID
- PMC3897394
- Eprint ID
- 42857
- Resolver ID
- CaltechAUTHORS:20131205-105756544
Funding
- Autism Speaks
- NIH Predoctoral Fellowship
- Human Frontier Science Program
- National Defense Science and Engineering Graduate (NDSEG) Fellowship
- NSF Graduate Research Fellowship
- Caltech Innovation Initiative (CI2)
- Caltech Grubstake Awards
- Congressionally Directed Medical Research Award
- Weston Havens Foundation
- Callie D. McGrath Charitable Foundation
- NIH
- MH100556
Dates
- Created
-
2013-12-05Created from EPrint's datestamp field
- Updated
-
2021-11-10Created from EPrint's last_modified field