美国加州大学旧金山分校David Julius团队宣布他们提出了沿着肠隐窝-绒毛轴的应力传感器的拓扑分离。该研究于2025年2月12日发表于国际一流学术期刊《自然》杂志上。

在这里，该课题组研究人员通过开发一种报告小鼠模型，定量测量活体肠道中EC细胞释放的血清素及其传播情况。隐窝EC细胞表现出一种强直性低水平模式，激活上皮5-HT4受体调节基底离子分泌，以及一种刺激诱导的高水平模式，激活感觉神经纤维上的5-HT3受体。这两种模式都可以由刺激受体TRPA1启动，TRPA1局限于隐窝EC细胞。当保护性粘膜层受损时，腔内刺激物对TRPA1的激活增强。绒毛EC细胞也通过一种独特的机制发出损伤信号，即氧化应激激活TRPM2通道，导致血清素和ATP的释放，并随之刺激感觉神经纤维。这种沿粘膜结构的EC细胞功能的拓扑分离构成了在不同生理条件下监测、维持和保护肠道完整性的机制。

据悉，小肠的隐窝-绒毛结构是一个重要的保护屏障。这一屏障的完整性由肠道复杂的感觉系统监测，其中5 -羟色胺能肠色素（EC）细胞起着重要作用。这些罕见的感觉上皮细胞监视粘膜环境以获得腔内刺激，并在肠内外传递信号。然而，隐窝和绒毛中的EC细胞是否检测到不同的刺激或产生不同的生理反应尚不清楚。

附：英文原文

Title: Topological segregation of stress sensors along the gut crypt–villus axis

Author: Touhara, Kouki K., Rossen, Nathan D., Deng, Fei, Castro, Joel, Harrington, Andrea M., Chu, Tifany, Garcia-Caraballo, Sonia, Brizuela, Mariana, ODonnell, Tracey, Xu, Jinhao, Cil, Onur, Brierley, Stuart M., Li, Yulong, Julius, David

Issue&Volume: 2025-02-12

Abstract: The crypt–villus structure of the small intestine serves as an essential protective barrier. The integrity of this barrier is monitored by the complex sensory system of the gut, in which serotonergic enterochromaffin (EC) cells play an important part1,2. These rare sensory epithelial cells surveil the mucosal environment for luminal stimuli and transmit signals both within and outside the gut3,4,5,6. However, whether EC cells in crypts and villi detect different stimuli or produce distinct physiological responses is unknown. Here we address these questions by developing a reporter mouse model to quantitatively measure the release and propagation of serotonin from EC cells in live intestines. Crypt EC cells exhibit a tonic low-level mode that activates epithelial serotonin 5-HT4 receptors to modulate basal ion secretion and a stimulus-induced high-level mode that activates 5-HT3 receptors on sensory nerve fibres. Both these modes can be initiated by the irritant receptor TRPA1, which is confined to crypt EC cells. The activation of TRPA1 by luminal irritants is enhanced when the protective mucus layer is compromised. Villus EC cells also signal damage through a distinct mechanism, whereby oxidative stress activates TRPM2 channels, which leads to the release of both serotonin and ATP and consequent excitation of sensory nerve fibres. This topological segregation of EC cell functionality along the mucosal architecture constitutes a mechanism for the surveillance, maintenance and protection of gut integrity under diverse physiological conditions.

DOI: 10.1038/s41586-024-08581-9

Source: https://www.nature.com/articles/s41586-024-08581-9