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

• 成果类型: Article
• 署名作者: Xiao, Yang; Louwies, Tijs; Mars, Ruben A. T.; Till, Lisa M.; Gupta, Yash; Mercado-Perez, Arnaldo; Bhagwate, Aditya V.; Bellampalli, Shreya S.; Stark Quiroz, Alejandro; Sekhon, Prabhjot K.; Singh, Vaidhvi; Liu, Rongfang; Heitman, Laura H.; Tienter, Dennis; Thompson, Michael A.; Kossick, Kimberlee F.; Krueger, Eugene W.; Kalari, Krishna R.; Hawkins, Kaitlyn R.; Lee, Jeong-Heon; Edwards, Brian S.; van der Es, Daan; Alcaino, Constanza; Willett, Julia L. E.; Wongkrasant, Preedajit; Guo, Chun-Jun; Prakash, Y. S.; Druliner, Brooke R.; Ordog, Tamas; Farrugia, Gianrico; Beyder, Arthur; Smith-Edwards, Kristen M.; Kashyap, Purna C.
• 署名单位: Mayo Clinic; Mayo Clinic; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Mayo Clinic; Mayo Clinic; Mayo Clinic; Mayo Clinic; Mayo Clinic; University of Cambridge; Cambridge University Hospitals NHS Foundation Trust; Addenbrooke's Hospital; University of Minnesota System; University of Minnesota Twin Cities; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2533336123
• 发表日期: 2026-09-01
• 页码: e2533336123
• 关键词: metabolites; motility; IBS; airway; A(1) ADENOSINE RECEPTOR; activation; mechanisms; binding

摘要

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.