The gut epithelium functions as a hormone-responsive sensory interface, continuously integrating dietary, microbial, and mechanical inputs into physiological signals that regulate gastrointestinal homeostasis and pain. Dysregulation of these epithelial pathways can produce chronic visceral hypersensitivity, a key physiological feature of irritable bowel syndrome (IBS), which exhibits marked sex differences. Enterochromaffin (EC) cells are specialized gut epithelial sensors that convert luminal stimuli into serotonergic output that engages 5-HT3 receptor-expressing mucosal afferents. While our prior work established that EC cells drive sex-specific nociceptive signaling, the cellular mechanisms that confer female-biased hypersensitivity remain unclear. Here, using ex vivo, in vitro, and in vivo physiological approaches, we identify an estrogen-dependent epithelial circuit that amplifies visceral sensitivity in females. We show that estrogen receptor-α (ERα) expression is confined to L cells, not EC cells, positioning L cells as the primary estrogen-responsive node within the intestinal epithelium. Estrogen enhances L cell responsiveness to the abundant colonic short-chain fatty acid (SCFA), acetate, by upregulating the SCFA receptor Olfr78. Through this enhanced Olfr78-mediated signaling, estrogen likely promotes peptide YY (PYY) release. PYY then acts in a paracrine manner on neighboring EC cells through NPY1R to potentiate serotonin (5-HT) secretion. Subsequently, 5-HT activates mucosal nociceptors, leading to intense visceral pain in females. These findings delineate a hormone-sensitive epithelial circuit linking estrogen signaling, nutrient-derived metabolites, and nociceptor activation. We identify PYY as a nociceptive hormone within this gut–brain physiological axis. We propose that fluctuations in estrogen, interacting with stress, diet, and microbial metabolites, may create an endocrine milieu that predisposes females to maladaptive visceral pain responses. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Venkataraman et al. (Fri,) studied this question.