Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice

Gil Sharon*, Nikki Jamie Cruz, Dae Wook Kang, Michael J. Gandal, Bo Wang, Young Mo Kim, Erika M. Zink, Cameron P. Casey, Bryn C. Taylor, Christianne J. Lane, Lisa M. Bramer, Nancy G. Isern, David W. Hoyt, Cecilia Noecker, Michael J. Sweredoski, Annie Moradian, Elhanan Borenstein, Janet K. Jansson, Rob Knight, Thomas O. MetzCarlos Lois, Daniel H. Geschwind, Rosa Krajmalnik-Brown, Sarkis K. Mazmanian

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Autism spectrum disorder (ASD) manifests as alterations in complex human behaviors including social communication and stereotypies. In addition to genetic risks, the gut microbiome differs between typically developing (TD) and ASD individuals, though it remains unclear whether the microbiome contributes to symptoms. We transplanted gut microbiota from human donors with ASD or TD controls into germ-free mice and reveal that colonization with ASD microbiota is sufficient to induce hallmark autistic behaviors. The brains of mice colonized with ASD microbiota display alternative splicing of ASD-relevant genes. Microbiome and metabolome profiles of mice harboring human microbiota predict that specific bacterial taxa and their metabolites modulate ASD behaviors. Indeed, treatment of an ASD mouse model with candidate microbial metabolites improves behavioral abnormalities and modulates neuronal excitability in the brain. We propose that the gut microbiota regulates behaviors in mice via production of neuroactive metabolites, suggesting that gut-brain connections contribute to the pathophysiology of ASD. Repetitive and social behavioral abnormalities in mice with microbiomes from patients with autism spectrum disorder can be corrected by the administration of specific metabolites.

Original languageEnglish
Pages (from-to)1600-1618.e17
JournalCell
Volume177
Issue number6
DOIs
StatePublished - 30 May 2019

Funding

FundersFunder number
Autism Speaks Postdoctoral Fellowship in Translational Research 9718 and Human Frontiers Science Program Long-TermFellowship 2012/65
Axial Biotherapeutics
Caltech Office of Laboratory Animal Resources
National Biomedical Computation Resource
U.S. Department of Energy Office of Biological and Environmental Research
National Institutes of HealthMH100556, HD055784, NS104925, GM124312-01, MH100027
U.S. Department of EnergyDE-AC05-76RLO 1830
National Institute of Mental HealthU01MH105578
Autism SpeaksPostdoctoral Fellowship in Translational Research 9718
Simons Foundation
Brenen Hornstein Autism Research & Education Foundation
Laboratory Directed Research and Development
Autism Research Institute
Emch Foundation
Pacific Northwest National Laboratory
Heritage Medical Research Institute
Simons Foundation Autism Research InitiativeBridge to Independence Award
National Biomedical Computation Resource
Norges Idrettshøgskole

    Keywords

    • autism
    • autism spectrum disorder
    • bacterial metabolites
    • gut microbiome
    • gut-brain axis
    • metabolome
    • microbiota
    • mouse model

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