Diet‐Induced Obesity Blunts Sensitivity of Intestinal Enteric Neurons: FIRST Evidence of Modulation of Activity of Enteric Neurons by Luminal Nutrients

The enteric nervous system (ENS) has well-established roles in gut motility, epithelial secretion, and blood flow. However, its role in luminal nutrient sensing remains elusive. Given that the nerve endings of enteric neurons terminate at the basolateral surface of epithelial cells and do not contact the luminal milieu, the involvement of enteric neurons in luminal sensing is thought to be indirect and secondary to epithelial nutrient absorption. Our study demonstrates that intestinal enteric neurons are activated by dietary glucose and oleic acid, in the absence of mucosal enterocytes and enteroendocrine cells (EECs). Using primary enteric neuronal cultures generated from the intestinal submucosa, after exclusion of the mucosa, muscle layers, glial, and smooth muscle cells, we studied neuronal activation using intracellular Ca²⁺ transients as a surrogate. We show that diet-induced obesity (DIO) blunts the sensitivity of enteric neurons, as evidenced by lower (42%-52%), delayed (22-34 s), and sustained peak fluorescence (1.5-3.7-fold), and prolonged decay time (1158-1432 s). These findings significantly advance the field of enteric neuronal circuitry by revealing an unexplored, critical physiological function with potential therapeutic roles in the amelioration of obesity and associated comorbidities, including type 2 diabetes.