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Research has mainly centered on vagal afferent and efferent neurotransmission along the gastrointestinal tract, followed by the integration of luminal information in the nodose ganglia and transmission to vagal integral sites in the brain. The physiological and cellular mechanisms of nutrient sensing by enterocytes and enteroendocrine cells have been well established; however, the roles of the enteric nervous system (ENS) remain elusive. Recent advances in targeting specific neuronal subpopulations and imaging techniques unravel the plausible roles of the ENS in nutrient sensing. In this review, we highlight physiological, cellular, and molecular insights that direct toward direct and indirect roles of the ENS in luminal nutrient sensing and vagal neurotransmission along the gut\u2013brain axis and discuss functional maladaptations observed during metabolic insults, as observed during obesity and associated comorbidities, including type 2 diabetes.<\/jats:p>","DOI":"10.1096\/fj.202500220rr","type":"journal-article","created":{"date-parts":[[2025,5,3]],"date-time":"2025-05-03T06:11:22Z","timestamp":1746252682000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The Enteric Neuronal Circuitry: A Key Ignored Player in Nutrient Sensing Along the Gut\u2013Brain Axis"],"prefix":"10.1096","volume":"39","author":[{"given":"Ester","family":"Nikolla","sequence":"first","affiliation":[{"name":"Department of Physiology, College of Graduate Studies Midwestern University  Downers Grove Illinois 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