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

Kouki K. Touhara (), Nathan D. Rossen, Fei Deng, Joel Castro, Andrea M. Harrington, Tifany Chu, Sonia Garcia-Caraballo, Mariana Brizuela, Tracey O’Donnell, Jinhao Xu, Onur Cil, Stuart M. Brierley (), Yulong Li () and David Julius ()
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Kouki K. Touhara: University of California San Franscisco
Nathan D. Rossen: University of California San Franscisco
Fei Deng: Peking University
Joel Castro: South Australian Health and Medical Research Institute (SAHMRI)
Andrea M. Harrington: South Australian Health and Medical Research Institute (SAHMRI)
Tifany Chu: University of California San Francisco
Sonia Garcia-Caraballo: South Australian Health and Medical Research Institute (SAHMRI)
Mariana Brizuela: South Australian Health and Medical Research Institute (SAHMRI)
Tracey O’Donnell: South Australian Health and Medical Research Institute (SAHMRI)
Jinhao Xu: University of California San Franscisco
Onur Cil: University of California San Francisco
Stuart M. Brierley: South Australian Health and Medical Research Institute (SAHMRI)
Yulong Li: Peking University
David Julius: University of California San Franscisco

Nature, 2025, vol. 640, issue 8059, 732-742

Abstract: 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 gut3–6. 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.

Date: 2025
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DOI: 10.1038/s41586-024-08581-9

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