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Neuronal Activation of the Gastrointestinal Tract Shapes the Gut Environment in Mice

Yoo, Bryan B. and Griffiths, Jessica A and Thuy-Boun, Peter and Cantu, Victor and Weldon, Kelly and Challis, Collin and Sweredoski, Michael J. and Chan, Ken Y. and Thron, Taren M. and Sharon, Gil and Moradian, Annie and Humphrey, Gregory and Zhu, Qiyun and Shaffer, Justin and Wolan, Dennis W. and Dorrestein, Pieter C. and Knight, Rob and Gradinaru, Viviana and Mazmanian, Sarkis K. (2021) Neuronal Activation of the Gastrointestinal Tract Shapes the Gut Environment in Mice. . (Unpublished)

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The enteric nervous system (ENS) coordinates responses that shape the intestinal milieu, and participates in bi-directional communication with various organs including the brain. Tools to study, and knowledge of, ENS development and function lag behind brain research. Herein, we deploy recombinant adeno-associated viral (rAAV) vectors with enhanced tropism for the gut to map and activate gut associated neurons in mice with spatial and temporal resolution. rAAV-mediated fluorescent labelling coupled with whole-tissue clearing methods in the small intestine and colon reveal novel neuronal architectures in the gut of mice. Viral delivery of genetically-encoded calcium indicators enable in vivo measurement of ENS activity. Further, we employed chemogentics to specifically activate gut neurons that express choline acetyltransferase (ChAT⁺) or tyrosine hydroxylase (TH⁺). Targeted activation of ChAT⁺ or TH⁺ neuronal populations associated with the gastrointestinal (GI) tract alters the intestinal transcriptome, mouse and microbial proteomes, metagenome, and fecal metabolome. We reveal previously unknown and broad roles for enteric neurons in modulating GI physiology, mucosal immunity, and microbiome structure, and provide evidence for novel functions by the ENS such as regulating fungal colonization and shaping of bile acid profiles in the gut. These advanced experimental tools and rich datasets with multi-parameter characterization of the gut ecosystem may facilitate expanded understanding and study of the ENS.

Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription Paper ItemData ItemCode
Yoo, Bryan B.0000-0003-1450-2696
Griffiths, Jessica A0000-0002-5586-1567
Thuy-Boun, Peter0000-0003-3285-4273
Weldon, Kelly0000-0003-1064-8153
Challis, Collin0000-0003-4716-6086
Sweredoski, Michael J.0000-0003-0878-3831
Chan, Ken Y.0000-0002-8853-5186
Thron, Taren M.0000-0001-9577-2617
Sharon, Gil0000-0002-4605-9943
Moradian, Annie0000-0002-0407-2031
Shaffer, Justin0000-0002-9371-6336
Wolan, Dennis W.0000-0001-9879-8353
Dorrestein, Pieter C.0000-0002-3003-1030
Knight, Rob0000-0002-0975-9019
Gradinaru, Viviana0000-0001-5868-348X
Mazmanian, Sarkis K.0000-0003-2713-1513
Alternate Title:Targeted Neuronal Activation of the Gastrointestinal Tract Shapes the Environment of the Gut in Mice
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. Version 1 - April 13, 2021; Version 2 - October 15, 2021. We thank members in the Mazmanian’s laboratory for discussions throughout the research and critical reading of the manuscript. We thank Dr. Andres Collazo and Caltech’s Biological Imaging Facility for training access to microscopy capabilities and the Caltech Proteome Exploration Laboratory for access to LC-MS/MS capabilities. This research was funded in whole or in part by Aligning Science Across Parkinson’s ASAP-000375 through the Michael J. Fox Foundation for Parkinson’s Research (MJFF). For the purpose of open access, the author has applied a CC BY 4.0 public copyright license to all Author Accepted Manuscripts arising from this submission. This work was supported by grants to S.K.M. from the Heritage Medical Research Institute, Emerald Foundation, Caltech Center for Environmental and Microbial Interactions (CEMI), the National Institutes of Health (GM007616 and DK078938), and the Department of Defense (PD160030). Author Contributions: B.B.Y. and S.K.M. designed experiments. B.B.Y. performed experiments. J.A.G., K.Y.C., C.C. (supervised by V.G.) helped in AAV-mediated ENS characterization. J.A.G. performed analysis of GCaMP6F fluorescence. P.T.B (supervised by D.W.W.), M.J.S., A.M. performed acquisition and analysis of proteomic data. V.C., G.H., G.S., Q.Z., J.S., and (supervised by R.K.) performed acquisition and analysis of metagenomic data. K.W. (supervised by P.C.D.) performed acquisition and analysis of metabolomic data. T.M.T. assisted in animal-related work. B.B.Y. and S.K.M wrote the manuscript with input from all authors. The authors have declared no competing interest.
Group:Heritage Medical Research Institute, Caltech Center for Environmental Microbial Interactions (CEMI)
Funding AgencyGrant Number
Aligning Science Across Parkinson’s FoundationASAP-000375
Michael J. Fox FoundationUNSPECIFIED
Heritage Medical Research InstituteUNSPECIFIED
Emerald FoundationUNSPECIFIED
Caltech Center for Environmental Microbial Interactions (CEMI)UNSPECIFIED
NIH Predoctoral FellowshipGM007616
Department of DefensePD160030
Record Number:CaltechAUTHORS:20210414-072514678
Persistent URL:
Official Citation:Neuronal Activation of the Gastrointestinal Tract Shapes the Gut Environment in Mice. Bryan B. Yoo, Jessica A. Griffiths, Peter Thuy-Boun, Victor Cantu, Kelly Weldon, Collin Challis, Michael J. Sweredoski, Ken Y. Chan, Taren M. Thron, Gil Sharon, Annie Moradian, Gregory Humphrey, Qiyun Zhu, Justin Shaffer, Dennis W. Wolan, Pieter C. Dorrestein, Rob Knight, Viviana Gradinaru, Sarkis K. Mazmanian. bioRxiv 2021.04.12.439539; doi:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:108724
Deposited By: Tony Diaz
Deposited On:16 Apr 2021 19:11
Last Modified:16 Nov 2021 19:32

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