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The ENS is optimally positioned and together with the intestinal epithelium, is well\u2010equipped to monitor the luminal contents such as microbial metabolites and to coordinate appropriate responses accordingly. Despite the heightened interest in the gut microbiota and its influence on intestinal physiology and pathophysiology, how they interact with the host ENS remains unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Using full\u2010thickness proximal colon preparations from transgenic Villin\u2010CreERT2;R26R\u2010GCaMP3 and Wnt1\u2010Cre;R26R\u2010GCaMP3 mice, which express a fluorescent Ca<jats:sup>2+<\/jats:sup> indicator in their intestinal epithelium or in their ENS, respectively, we examined the effects of key luminal microbial metabolites (SCFAs and 5\u2010HT) on the mucosa and underlying enteric neurons.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>We show that the SCFAs acetate, propionate, and butyrate, as well as 5\u2010HT can, to varying extents, acutely elicit epithelial and neuronal Ca<jats:sup>2+<\/jats:sup> responses. Furthermore, SCFAs exert differential effects on submucosal and myenteric neurons. Additionally, we found that submucosal ganglia are predominantly aligned along the striations of the transverse mucosal folds in the proximal colon.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions &amp; Inferences<\/jats:title><jats:p>Taken together, our study demonstrates that different microbial metabolites, including SCFAs and 5\u2010HT, can acutely stimulate Ca<jats:sup>2+<\/jats:sup> signaling in the mucosal epithelium and in enteric neurons.<\/jats:p><\/jats:sec>","DOI":"10.1111\/nmo.14186","type":"journal-article","created":{"date-parts":[[2021,6,14]],"date-time":"2021-06-14T08:10:11Z","timestamp":1623658211000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Luminal short\u2010chain fatty acids and 5\u2010HT acutely activate myenteric neurons in the mouse proximal colon"],"prefix":"10.1111","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4277-3664","authenticated-orcid":false,"given":"Candice","family":"Fung","sequence":"first","affiliation":[{"name":"Laboratory for Enteric NeuroScience (LENS) Translational Research Center for Gastrointestinal Disorders (TARGID) University of Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bert","family":"Cools","sequence":"additional","affiliation":[{"name":"Laboratory for Enteric NeuroScience (LENS) Translational Research Center for Gastrointestinal Disorders (TARGID) University of Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Malagola","sequence":"additional","affiliation":[{"name":"Laboratory for Enteric NeuroScience (LENS) Translational Research Center for Gastrointestinal Disorders (TARGID) University of Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Martens","sequence":"additional","affiliation":[{"name":"Laboratory for Enteric NeuroScience (LENS) Translational Research Center for Gastrointestinal Disorders (TARGID) University of Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3206-6704","authenticated-orcid":false,"given":"Jan","family":"Tack","sequence":"additional","affiliation":[{"name":"Translational Research Center for Gastrointestinal Disorders (TARGID) University of Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6284-225X","authenticated-orcid":false,"given":"Youcef","family":"Kazwiny","sequence":"additional","affiliation":[{"name":"Laboratory for Enteric NeuroScience (LENS) Translational Research Center for Gastrointestinal Disorders (TARGID) University of Leuven Leuven 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