Gut enterochromaffin cells drive visceral pain and anxiety

James R. Bayrer (), Joel Castro, Archana Venkataraman, Kouki K. Touhara, Nathan D. Rossen, Ryan D. Morrie, Jessica Maddern, Aenea Hendry, Kristina N. Braverman, Sonia Garcia-Caraballo, Gudrun Schober, Mariana Brizuela, Fernanda M. Castro Navarro, Carla Bueno-Silva, Holly A. Ingraham (), Stuart M. Brierley () and David Julius ()
Additional contact information
James R. Bayrer: University of California, San Francisco
Joel Castro: Flinders Health and Medical Research Institute
Archana Venkataraman: University of California
Kouki K. Touhara: University of California
Nathan D. Rossen: University of California
Ryan D. Morrie: University of California
Jessica Maddern: Flinders Health and Medical Research Institute
Aenea Hendry: Flinders Health and Medical Research Institute
Kristina N. Braverman: University of California, San Francisco
Sonia Garcia-Caraballo: Flinders Health and Medical Research Institute
Gudrun Schober: Flinders Health and Medical Research Institute
Mariana Brizuela: Flinders Health and Medical Research Institute
Fernanda M. Castro Navarro: University of California
Carla Bueno-Silva: University of California, San Francisco
Holly A. Ingraham: University of California
Stuart M. Brierley: Flinders Health and Medical Research Institute
David Julius: University of California

Nature, 2023, vol. 616, issue 7955, 137-142

Abstract: Abstract Gastrointestinal (GI) discomfort is a hallmark of most gut disorders and represents an important component of chronic visceral pain1. For the growing population afflicted by irritable bowel syndrome, GI hypersensitivity and pain persist long after tissue injury has resolved2. Irritable bowel syndrome also exhibits a strong sex bias, afflicting women three times more than men1. Here, we focus on enterochromaffin (EC) cells, which are rare excitable, serotonergic neuroendocrine cells in the gut epithelium3–5. EC cells detect and transduce noxious stimuli to nearby mucosal nerve endings3,6 but involvement of this signalling pathway in visceral pain and attendant sex differences has not been assessed. By enhancing or suppressing EC cell function in vivo, we show that these cells are sufficient to elicit hypersensitivity to gut distension and necessary for the sensitizing actions of isovalerate, a bacterial short-chain fatty acid associated with GI inflammation7,8. Remarkably, prolonged EC cell activation produced persistent visceral hypersensitivity, even in the absence of an instigating inflammatory episode. Furthermore, perturbing EC cell activity promoted anxiety-like behaviours which normalized after blockade of serotonergic signalling. Sex differences were noted across a range of paradigms, indicating that the EC cell–mucosal afferent circuit is tonically engaged in females. Our findings validate a critical role for EC cell–mucosal afferent signalling in acute and persistent GI pain, in addition to highlighting genetic models for studying visceral hypersensitivity and the sex bias of gut pain.

Date: 2023
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DOI: 10.1038/s41586-023-05829-8

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