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The digestion of food and absorption of nutrients, electrolytes, and water occurs in a hostile luminal environment that contains a large and diverse microbiota. At the core of regulatory control of the digestive and defensive functions of the gastrointestinal tract is the enteric nervous system (ENS), a complex system of neurons and glia in the gut wall. In this review, we discuss 1) the intrinsic neural control of gut functions involved in digestion and 2) how the ENS interacts with the immune system, gut microbiota, and epithelium to maintain mucosal defense and barrier function. We highlight developments that have revolutionized our understanding of the physiology and pathophysiology of enteric neural control. These include a new understanding of the molecular architecture of the ENS, the organization and function of enteric motor circuits, and the roles of enteric glia. We explore the transduction of luminal stimuli by enteroendocrine cells, the regulation of intestinal barrier function by enteric neurons and glia, local immune control by the ENS, and the role of the gut microbiota in regulating the structure and function of the ENS. Multifunctional enteric neurons work together with enteric glial cells, macrophages, interstitial cells, and enteroendocrine cells integrating an array of signals to initiate outputs that are precisely regulated in space and time to control digestion and intestinal homeostasis.<\/jats:p>","DOI":"10.1152\/physrev.00018.2022","type":"journal-article","created":{"date-parts":[[2022,12,15]],"date-time":"2022-12-15T15:29:02Z","timestamp":1671118142000},"page":"1487-1564","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":411,"title":["The enteric nervous system"],"prefix":"10.1152","volume":"103","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9560-1711","authenticated-orcid":false,"given":"Keith A.","family":"Sharkey","sequence":"first","affiliation":[{"name":"Hotchkiss Brain Institute and Snyder Institute for Chronic Diseases, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8876-8468","authenticated-orcid":false,"given":"Gary M.","family":"Mawe","sequence":"additional","affiliation":[{"name":"Department of Neurological Sciences, Larner College of Medicine, University of Vermont, Burlington, Vermont"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1104816"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/nature11550"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2974"},{"key":"B4","unstructured":"Furness JB, Costa M. 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