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Published April 23, 2024 | Published
Journal Article Open

Peripheral neuronal activation shapes the microbiome and alters gut physiology

Abstract

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.

Copyright and License

Acknowledgement

We thank members of the Mazmanian laboratory and Dr. Jonathan Hoang for discussions throughout the research project and critical reading of the manuscript and Dr. Catherine Oikonomou for invaluable manuscript editing. We thank Dr. Andres Collazo and Caltech’s Biological Imaging Facility for training and access to microscopy capabilities and the Caltech Proteome Exploration Laboratory for access to LC-MS/MS capabilities. We thank Prof. Elisa Hill-Yardin for providing MATLAB scripts for CMMC heatmaps. This research was funded in part by Aligning Science Across Parkinson’s (ASAP-020495 and ASAP-000375) through the Michael J. Fox Foundation for Parkinson's Research (MJFF). For the purpose of open access, the authors have applied a CC BY 4.0 public copyright license to all Author Accepted Manuscripts arising from this submission. S.K.M. was supported by grants from the Heritage Medical Research InstituteEmerald FoundationCaltech Center for Environmental and Microbial Interactions (CEMI), National Institutes of Health (GM007616 and DK078938), and Department of Defense (PD160030). P.C.D. was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK136117 and U24DK133658).

Contributions

J.A.G., B.B.Y., and S.K.M. designed experiments. J.A.G. and B.B.Y. performed experiments. K.Y.C., C.C. (supervised by V.G.), and J.A.G. helped with AAV-mediated ENS characterization. P.T.-B. (supervised by D.W.W.), M.J.S., and A.M. performed acquisition and analysis of proteomics data. V.C., G.H., G.S., Q.Z., and J.S. (supervised by R.K.) performed acquisition and analysis of metagenomics data. K.W. (supervised by P.C.D.) performed acquisition and analysis of metabolomics data. T.M.T. assisted with animal-related work. J.A.G., B.B.Y., and S.K.M wrote the manuscript with input from all authors.

Conflict of Interest

B.B.Y. declares financial interests in Nuanced Health, which is not related to the present study. S.K.M. declares financial interests in Axial Therapeutics and Nuanced Health, which is not related to the present study. P.C.D. is an advisor and holds equity in Cybele and Sirenas and is a scientific co-founder and advisor and holds equity to Ometa, Enveda, and Arome with prior approval by University of California, San Diego. He also consulted for DSM animal health in 2023. R.K. is a scientific advisory board member and consultant for BiomeSense, Inc.; has equity, and receives income. He is a scientific advisory board member of and has equity in GenCirq. He is a consultant and scientific advisory board member for DayTwo and receives income. He has equity in and acts as a consultant for Cybele. He is a co-founder of Biota, Inc. and has equity. He is a cofounder of Micronoma, has equity, and is a scientific advisory board member. The terms of these arrangements have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies.

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Additional details

Created:
April 8, 2024
Modified:
April 8, 2024