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When the system fails, the outcome can be acute or chronic disease, often labeled as \u201cidiopathic\u201d in nature (e.g., irritable bowel syndrome, inflammatory bowel disease). Here we underscore the importance of a holistic approach to gut physiology, placing an emphasis on intercellular connectedness, using enteric neuroimmunophysiology as the paradigm. The goal of this opinion piece is to acknowledge the pace of change brought to our field via single-cell and -omic methodologies and other techniques such as cell lineage tracing, transgenic animal models, methods for culturing patient tissue, and advanced imaging. We identify gaps in the field and hope to inspire and challenge colleagues to take up the mantle and advance awareness of the subtleties, intricacies, and nuances of intestinal physiology in health and disease by defining communication pathways between gut resident cells, those recruited from the circulation, and \u201cexternal\u201d influences such as the central nervous system and the gut microbiota.<\/jats:p>","DOI":"10.1152\/ajpgi.00075.2024","type":"journal-article","created":{"date-parts":[[2024,4,16]],"date-time":"2024-04-16T16:31:20Z","timestamp":1713285080000},"page":"G712-G725","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Neuroimmunophysiology of the gastrointestinal tract"],"prefix":"10.1152","volume":"326","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0557-8210","authenticated-orcid":false,"given":"Derek M.","family":"McKay","sequence":"first","affiliation":[{"name":"Snyder Institute for 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