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Cell. 2019 May 30;177(6):1600-1618.e17. doi: 10.1016/j.cell.2019.05.004.

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

Author information

1
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address: gsharon@caltech.edu.
2
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
3
Biodesign Swette Center for Environmental Biotechnology, Arizona State University, Tempe, AZ 85287, USA; Biodesign Center for Fundamental and Applied Microbiomics, Arizona State University, Tempe, AZ 85287, USA.
4
Center for Autism Research and Treatment, Program in Neurobehavioral Genetics, Semel Institute, University of California Los Angeles, Los Angeles, CA 90095, USA; Department of Neurology, Semel Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Psychiatry, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
5
Earth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, WA 99352, USA.
6
Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.
7
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
8
National Security Directorate, Pacific Northwest National Laboratory, Richland, WA 99352, USA.
9
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
10
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Department of Computer Science and Engineering, University of Washington, Seattle, WA 98195, USA; Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv 6997801, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; Santa Fe Institute, Santa Fe, NM 87501, USA.
11
Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA 92093, USA; Department of Biongineering, University of California, San Diego, La Jolla, CA 92093, USA.
12
Center for Autism Research and Treatment, Program in Neurobehavioral Genetics, Semel Institute, University of California Los Angeles, Los Angeles, CA 90095, USA; Department of Neurology, Semel Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
13
Biodesign Swette Center for Environmental Biotechnology, Arizona State University, Tempe, AZ 85287, USA; Biodesign Center for Fundamental and Applied Microbiomics, Arizona State University, Tempe, AZ 85287, USA; School of Sustainable Engineering and the Built Environment, Arizona State University, Tempe, AZ 85287, USA.
14
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address: sarkis@caltech.edu.

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.

KEYWORDS:

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

PMID:
31150625
DOI:
10.1016/j.cell.2019.05.004

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