A Cellular Basis for Heightened Gut Sensitivity in Females

Visceral pain disorders, such as irritable bowel syndrome, exhibit a marked female prevalence. Enhanced signaling between enterochromaffin (EC) cells in the gut epithelium and mucosal sensory nerve fibers likely contributes to this sex bias. Here, we identify a novel estrogen-responsive paracrine pathway in which two enteroendocrine cell types, PYY-expressing L-cells and serotonergic EC cells, communicate to increase gut sensitivity in females. We demonstrate that ERa estrogen signaling upregulates the bacterial metabolite SCFA receptor Olfr78 on colonic L-cells, increasing PYY release and their sensitivity to acetate. Elevated PYY acts on neighboring EC cells via NPY1R, thereby enhancing serotonin release and gut pain. We propose that hormonal fluctuations, in conjunction with internal (stress) or environmental (diet) factors, amplify this local estrogen-responsive colonic circuit, resulting in maladaptive gut sensitivity. Overall design: RNA-seq was performed on L-cells and EC cells isolated from colons of 10–14-week-old ovariectomized (OVX) female mice. L-cells were obtained from OVX Cck-Cre;R26LSL-tdTomato mice treated with sesame oil vehicle (VEH) or estradiol benzoate (EB) 4 hours prior to isolation. Approximately 7,000 L-cells were collected per treatment group (OVX + VEH and OVX + EB). EC cells were obtained from OVX ECFLTG mice treated with VEH or EB, with at least 500 EC cells isolated per sample and processed in the same manner.