A cellular basis for heightened gut sensitivity in females

• 成果类型: Article
• 署名作者: Venkataraman, Archana; Figueroa, Eric E.; Castro, Joel; Navarro, Fernanda Castro; Soota, Deepanshu; Brierley, Stuart M.; Julius, David; Ingraham, Holly A.
• 署名单位: University of California System; University of California San Francisco; University of California System; University of California San Francisco; Adelaide University; University of Adelaide
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adz1398
• 发表日期: 2025-12-18
• 页码: 1285-1291
• 关键词: IRRITABLE-BOWEL-SYNDROME; PEPTIDE-YY; SOMATIC PAIN; PYY3-36; inhibition; secretion; stimuli; release; cells; cycle

摘要

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. We identified an estrogen-responsive paracrine pathway in which two enteroendocrine cell types, peptide YY (PYY)-expressing L cells and serotonergic EC cells, communicate to increase gut sensitivity in females. We demonstrate that estrogen signaling up-regulates the bacterial metabolite short-chain fatty acid receptor Olfr78 on colonic L cells, increasing PYY release and their sensitivity to acetate. Elevated PYY acts on neighboring EC cells by means of 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.