@article{60371878014c498b8b180552a73026db,
title = "Microbiota modulate sympathetic neurons via a gut–brain circuit",
abstract = "Connections between the gut and brain monitor the intestinal tissue and its microbial and dietary content1, regulating both physiological intestinal functions such as nutrient absorption and motility2,3, and brain-wired feeding behaviour2. It is therefore plausible that circuits exist to detect gut microorganisms and relay this information to areas of the central nervous system that, in turn, regulate gut physiology4. Here we characterize the influence of the microbiota on enteric-associated neurons by combining gnotobiotic mouse models with transcriptomics, circuit-tracing methods and functional manipulations. We find that the gut microbiome modulates gut-extrinsic sympathetic neurons: microbiota depletion leads to increased expression of the neuronal transcription factor cFos, and colonization of germ-free mice with bacteria that produce short-chain fatty acids suppresses cFos expression in the gut sympathetic ganglia. Chemogenetic manipulations, translational profiling and anterograde tracing identify a subset of distal intestine-projecting vagal neurons that are positioned to have an afferent role in microbiota-mediated modulation of gut sympathetic neurons. Retrograde polysynaptic neuronal tracing from the intestinal wall identifies brainstem sensory nuclei that are activated during microbial depletion, as well as efferent sympathetic premotor glutamatergic neurons that regulate gastrointestinal transit. These results reveal microbiota-dependent control of gut-extrinsic sympathetic activation through a gut–brain circuit.",
author = "Muller, {Paul A.} and Marc Schneeberger and Fanny Matheis and Putianqi Wang and Zachary Kerner and Anoj Ilanges and Kyle Pellegrino and {del M{\'a}rmol}, Josefina and Castro, {Tiago B.R.} and Munehiro Furuichi and Matthew Perkins and Wenfei Han and Arka Rao and Picard, {Amanda J.} and Cross, {Justin R.} and Kenya Honda and {de Araujo}, Ivan and Daniel Mucida",
note = "Funding Information: Acknowledgements We thank all members of the Mucida laboratory, past and present, for assistance with experiments, fruitful discussions and critical reading of the manuscript. In particular we thank: A. Rogoz for maintaining gnotobiotic mice; S. Gonzalez for maintaining SPF mice; T. Rendon and B. Lopez for genotyping; C. Nowosad for setting up the ASF; A. North, C. Pyrgaki, T. Tong, C. Rico and P. Ariel of The Rockefeller University Bio-imaging Research Center for assistance with light-sheet microscopy and image analysis; The Rockefeller University Genomics Center for RNA sequencing; Rockefeller University employees for continuous assistance; T. Y. Oliveira for valuable discussions on TRAP-seq approaches and help with initial analysis; S. Poliak (Kallyope) for help in setting up tracing experiments and valuable input throughout the project; K. Loh and A. Ilanges for fruitful experimental discussions; J. Friedman and V. Ruta for the use of laboratory equipment; A. Lockhart, V. Jov{\'e} and V. Ruta for critical reading of the manuscript; V. Jov{\'e} for critical reading of reviewer responses; L. Vosshall, M. Nussenzweig, G. Victora and J. Lafaille and their respective laboratory members for fruitful discussions and suggestions; D. Littman and M. Xu for providing faeces from SFB monocolonized mice; D. Artis and G. Sonnenberg for providing germ-free mice and Clostridium consortium colonized mice; N. Arpaia for Gpr43−/− mice; S. Mehandru for Gpr109a−/− Gpr43−/− mice; J. Pluznick, J. Gordon and M. Yanagisawa for Gpr41−/− mice; I. Chiu and J. Wood for Nav1.8Cre mice; C. Woolf and R. Kuhner for SNSCre mice; A. Ramer-Tait for ASF caeca; J. Faith for germ-free mice; G. Donaldson for A. muciniphilia and B. fragilis monocolonized mice; and C. Nowosad for OligoMM12 mice. We finally thank R. U. Muller for his inspiration. This work was supported by National Institute of Diabetes and Digestive Kidney Diseases (NIDDK) grant K99 DK120869 (to M.S.); NIH Virus Center grant P40 OD010996; a NIH F31 Kirchstein Fellowship (to P.A.M.); National Center for Advancing Translational Sciences (NCATS) NIH grant UL1TR001866 (to P.A.M. and D.M.); a Philip M. Levine Fellowship (to P.A.M.); a Kavli Graduate Fellowship (to P.A.M.); a Kavli Postdoctoral Fellowship (to M.S.); an Anderson Graduate Fellowship (to F.M.); a Leon Levy Fellowship in Neuroscience (to J.d.M.); the Leona M. and Harry B. Helmsley Charitable Trust (to D.M.); the Kenneth Rainin Foundation (to D.M.); a Burroughs Wellcome Fund PATH Award (to D.M.); and Transformative grant R01DK116646 (to D.M). Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2020",
month = jul,
day = "16",
doi = "10.1038/s41586-020-2474-7",
language = "English",
volume = "583",
pages = "441--446",
journal = "Nature Cell Biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "7816",
}