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Targeted Neuronal Activation of the Gastrointestinal Tract Shapes the Environment of the Gut 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) Targeted Neuronal Activation of the Gastrointestinal Tract Shapes the Environment of the Gut in Mice. . (Unpublished)

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The enteric nervous system (ENS) integrates cues from the brain and from local signals in the gut to coordinate responses that shape the intestinal milieu. Tools to study, and knowledge of, the ENS lag behind brain research. Herein, we deploy novel recombinant adeno-associated viral (rAAV) vectors with enhanced tropism for the gut to map and activate enteric neurons with spatial and temporal resolution. rAAV-mediated fluorescent labelling coupled with whole-tissue clearing methods in the small intestine and colon of mice enables efficient and thorough characterization of the neuronal architecture of the ENS. We also delivered ‘designer receptors exclusively activated by designer drugs’ (DREADDs) to specifically activate gut neurons that express choline acetyltransferase (ChAT⁺) and tyrosine hydroxylase (TH⁺). Targeted activation of ChAT⁺ or TH⁺ neuronal populations associated with the gastrointestinal (GI) tract altered the intestinal transcriptome of mice, host and microbial proteome, metagenome, and fecal metabolome. We reveal previously unknown and broad roles for neurons in modulating intestinal physiology, mucosal immunity, and gut microbiome structure, and propose novel interactions for the ENS such as regulating fungal colonization and shaping of bile acid profiles. Experimental tools and rich datasets with multi-parameter characterization of the gut ecosystem may enable further study of the ENS.

Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription Paper ItemData/Code
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
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This version posted April 13, 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 work was supported by grants from the Heritage Medical Research Institute, Emerald Foundation, Caltech Center for Environmental and Microbial Interactions (CEMI), Aligning Science Across Parkinson’s Foundation, 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
Heritage Medical Research InstituteUNSPECIFIED
Emerald FoundationUNSPECIFIED
Caltech Center for Environmental Microbial Interactions (CEMI)UNSPECIFIED
Aligning Science Across Parkinson’s FoundationUNSPECIFIED
NIH Predoctoral FellowshipGM007616
Department of DefensePD160030
Record Number:CaltechAUTHORS:20210414-072514678
Persistent URL:
Official Citation:Targeted Neuronal Activation of the Gastrointestinal Tract Shapes the Environment of the Gut 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, Greg Humphrey, Qiyun Zhu, Justin Shaffer, Dennis W. Wolan, Pieter Dorrestein, Rob Knight, Viviana Gradinaru, Sarkis 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:19 Apr 2021 18:20

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