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

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

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.

Additional Information

© 2019 Elsevier Inc. Received 6 February 2018, Revised 11 February 2019, Accepted 30 April 2019, Available online 30 May 2019. The authors would like to thank Drs. H. Chu, G. Lenz, C. Schretter, and D. Dar, and members of the Mazmanian laboratory for critical discussions. We thank the staff at the Caltech Office of Laboratory Animal Resources. We also thank Y. Huang for hypD reference sequences. We thank Dr. J. Adams for critical review on the manuscript. We also thank Dr. J. Maldonado and M. Bennett for their support on 16S rRNA gene sequencing. We thank G. Humphrey, J. DeRight Goldasich, T. Schwartz, R. Salido Benitez, and G. Ackermann for their support in shotgun sequencing. Metabolomics analyses were supported by the Microbiomes in Transition (MinT) Initiative as part of the Laboratory Directed Research and Development Program at PNNL. Metabolomics measurements were performed in the Environmental Molecular Sciences Laboratory, a national scientific user facility sponsored by the U.S. Department of Energy Office of Biological and Environmental Research and located at PNNL in Richland Washington. PNNL is a multi-program national laboratory operated by Battelle for the DOE under contract DE-AC05-76RLO 1830. This work was supported by Autism Speaks Postdoctoral Fellowship in Translational Research 9718 and Human Frontiers Science Program Long-Term Fellowship 2012/65 (to G.S,), SFARI Bridge to Independence Award (to M.J.G), The San Diego Diversity Fellowship and the National Biomedical Computation Resource (to B.C.T). Funding includes grants from NIH (GM124312-01 to E.B., NS104925 to C.L., HD055784, MH100027 to D.H.G, and MH100556 to S.K.M.), Autism Research Institute, the Emch Foundation, the Brenen Hornstein Autism Research & Education Foundation (to D.W.K. and R.K.B.), Lynda and Blaine Fetter, the Simons Foundation, and the Heritage Medical Research Institute (to S.K.M.). Author Contributions: Conceptualization, G.S. and S.K.M.; Methodology, G.S., D.-W.K., M.J.G., B.W., Y.-M.K., N.G.I., M.S., A.M., D.W.H., T.O.M., R.K.-B., and S.K.M.; Formal Analysis, G.S., C.L., D.-W.K., M.J.G., Y.-M.K., C.P.C., B.C.T., L.M.B., N.G.I., B.C.T., M.J.S., D.W.H., C.N., and T.O.M.; Investigation, G.S., N.J.C., D.-W.K., M.J.G., B.W., Y.-M.K., C.P.C., N.G.I., M.J.S., A.M., D.W.H., and T.O.M.; Data Curation, G.S., D.-W.K., M.J.G., B.W., Y.-M.K., B.C.T., L.M.B., and D.W.H.; Visualization, G.S. and C.N.; Resources, D.-W.K. and R.K.,-B.; Supervision, E.B., J.K.J., R.K., T.O.M., C.L., D.H.G., R.K.-B., and S.K.M.; Funding Acquisition, E.B., R.K., J.K.J., T.O.M., C.L., D.H.G., R.K.-B., and S.K.M.; Writing – Original Draft, G.S. and S.K.M.; Writing – Review & Editing, all authors. Declaration of Interests: D.-W.K. and R.K.-B. have pending/approved patent applications related to the use of FMT and/or probiotics for various conditions including ASD. G.S. and S.K.M. have filed a pending patent application for the use of specific microbes and metabolites for various neurodevelopmental conditions. S.K.M is a co-founder of Axial Biotherapeutics and member of its scientific advisory board.

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