Peripheral neuronal activation shapes the microbiome and alters gut physiology
Jessica A. Griffiths,
Bryan B. Yoo,
Peter Thuy-Boun,
Victor J. Cantu,
Kelly C. Weldon,
Collin Challis,
Michael J. Sweredoski,
Ken Y. Chan,
Taren M. Thron,
Gil Sharon,
Annie Moradian,
Gregory Humphrey,
Qiyun Zhu,
Justin P. Shaffer,
Dennis W. Wolan,
Pieter C. Dorrestein,
Rob Knight,
Viviana Gradinaru,
Sarkis K. Mazmanian
Affiliations
Jessica A. Griffiths
Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA
Bryan B. Yoo
Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
Peter Thuy-Boun
Departments of Molecular Medicine and Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
Victor J. Cantu
Department of Pediatrics, University of California, San Diego, San Diego, CA, USA
Kelly C. Weldon
Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, San Diego, CA, USA; UCSD Center for Microbiome Innovation, University of California, San Diego, San Diego, CA, USA
Collin Challis
Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
Michael J. Sweredoski
Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
Ken Y. Chan
Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
Taren M. Thron
Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
Gil Sharon
Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
Annie Moradian
Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
Gregory Humphrey
Department of Pediatrics, University of California, San Diego, San Diego, CA, USA
Qiyun Zhu
Department of Pediatrics, University of California, San Diego, San Diego, CA, USA
Justin P. Shaffer
Department of Pediatrics, University of California, San Diego, San Diego, CA, USA
Dennis W. Wolan
Departments of Molecular Medicine and Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
Pieter C. Dorrestein
Department of Pediatrics, University of California, San Diego, San Diego, CA, USA; Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, San Diego, CA, USA; UCSD Center for Microbiome Innovation, University of California, San Diego, San Diego, CA, USA
Rob Knight
Department of Pediatrics, University of California, San Diego, San Diego, CA, USA; UCSD Center for Microbiome Innovation, University of California, San Diego, San Diego, CA, USA; Department of Computer Science and Engineering, University of California, San Diego, San Diego, CA, USA; Shu Chien-Gene Lay Department of Engineering, University of California, San Diego, San Diego, CA, USA; Halıcıoğlu Data Science Institute, University of California, San Diego, San Diego, CA, USA
Viviana Gradinaru
Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA
Sarkis K. Mazmanian
Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA; Corresponding author
Summary: The gastrointestinal (GI) tract is innervated by intrinsic neurons of the enteric nervous system (ENS) and extrinsic neurons of the central nervous system and peripheral ganglia. The GI tract also harbors a diverse microbiome, but interactions between the ENS and the microbiome remain poorly understood. Here, we activate choline acetyltransferase (ChAT)-expressing or tyrosine hydroxylase (TH)-expressing gut-associated neurons in mice to determine effects on intestinal microbial communities and their metabolites as well as on host physiology. The resulting multi-omics datasets support broad roles for discrete peripheral neuronal subtypes in shaping microbiome structure, including modulating bile acid profiles and fungal colonization. Physiologically, activation of either ChAT+ or TH+ neurons increases fecal output, while only ChAT+ activation results in increased colonic contractility and diarrhea-like fluid secretion. These findings suggest that specific subsets of peripherally activated neurons differentially regulate the gut microbiome and GI physiology in mice without involvement of signals from the brain.
