Enterochromaffin cells as a cellular integration hub for cooperative microbial signaling to modulate gut serotonin and motility.

Authors

Yang Xiao, Tijs Louwies, Ruben A T Mars, Lisa M Till, Yash Gupta, Arnaldo Mercado-Perez, Aditya V Bhagwate, Shreya S Bellampalli, Alejandro Stark Quiroz, Prabhjot K Sekhon, Vaidhvi Singh, Rongfang Liu, Laura H Heitman, Dennis Tienter, Michael A Thompson, Kimberlee F Kossick, Eugene W Krueger, Krishna R Kalari, Kaitlyn R Hawkins, Jeong-Heon Lee, Brian S Edwards, Daan van der Es, Constanza Alcaino, Julia L E Willett, Preedajit Wongkrasant, Chun-Jun Guo, Y S Prakash, Brooke R Druliner, Tamas Ordog, Gianrico Farrugia, Arthur Beyder, Kristen M Smith-Edwards, Purna C Kashyap

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 35. Pages e2533336123. Epub Aug 24, 2026.

Abstract

The intestinal epithelium is exposed to diverse combinations of microbiota-derived compounds; however, the mechanisms by which the host integrates these signals remain poorly defined. Studying two highly abundant microbial metabolites, we identified the purine metabolite hypoxanthine as an effector metabolite that directly drives signaling and the short-chain fatty acid butyrate as a regulatory metabolite that conditions host responsiveness. Specifically, hypoxanthine activates the adenosine A1 receptor-TRPC4 axis in enterochromaffin (EC) cells, triggering calcium influx and serotonin release resulting in accelerated gastrointestinal transit locally and increased platelet activation systemically. In contrast, butyrate epigenetically upregulates specific G protein-coupled receptors and ion channels to enhance response to hypoxanthine and the neurotransmitters norepinephrine and dopamine. These findings define a cooperative signaling framework and highlight the role of EC cells as a distinct epithelial signaling hub that senses and integrates microbial metabolite signals to drive physiological responses. Our findings provide a mechanistic foundation for therapeutic strategies that leverage combinatorial microbial signaling.

PMID:
42636369
Bibliographic data and abstract were imported from PubMed on 25 Aug 2026.

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