Enterochromaffin cells as a cellular integration hub for cooperative microbial signaling to modulate gut serotonin and motility
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.
Authors
- Jeong‐Heon Lee (ORCID: https://orcid.org/0000-0003-4007-9166)
- Laura H. Heitman (ORCID: https://orcid.org/0000-0002-1381-8464)
- Arthur Beyder (ORCID: https://orcid.org/0000-0002-9225-4854)
- Kristen Smith (ORCID: https://orcid.org/0000-0002-9330-4454)
- Arnaldo Mercado‐Perez (ORCID: https://orcid.org/0000-0001-8036-6771)
- Ruben A. Mars (ORCID: https://orcid.org/0000-0002-3917-9517)
- Kimberlee Kossick (ORCID: https://orcid.org/0000-0001-8120-7617)
- Lisa Till (ORCID: https://orcid.org/0000-0003-4943-3125)
- Tamás Ördög (ORCID: https://orcid.org/0000-0002-3940-7284)
- Rongfang Liu (ORCID: https://orcid.org/0000-0003-0136-8811)
- Daan van der Es (ORCID: https://orcid.org/0000-0003-3662-8177)
- Shreya S. Bellampalli (ORCID: https://orcid.org/0000-0003-3969-1155)
- Vaidhvi Singh (ORCID: https://orcid.org/0000-0002-9395-326X)
- Preedajit Wongkrasant (ORCID: https://orcid.org/0000-0002-9855-1454)
- Purna Kashyap (ORCID: https://orcid.org/0000-0002-2851-2388)
- Tijs Louwies (ORCID: https://orcid.org/0000-0003-4860-6100)
- Brian S. Edwards (ORCID: https://orcid.org/0000-0002-8382-4755)
- Alejandro Stark (ORCID: https://orcid.org/0000-0003-0625-5605)
- Y. S. Prakash (ORCID: https://orcid.org/0000-0002-2968-224X)
- Gianrico Farrugia (ORCID: https://orcid.org/0000-0003-3473-5235)
- Julia L. E. Willett (ORCID: https://orcid.org/0000-0002-0524-8289)
- Chun‐Jun Guo (ORCID: https://orcid.org/0000-0002-7227-4591)
- Yang Xiao (ORCID: https://orcid.org/0009-0007-8534-1734)
- Constanza Alcaino
- Aditya V. Bhagwate
- Dennis Tienter
- Krishna R. Kalari
- Eugene W. Krueger
- Yash Gupta
- Kaitlyn R. Hawkins
- Brooke R. Druliner
- Michael A. Thompson (ORCID: https://orcid.org/0009-0002-2295-9207)
- Prabhjot K. Sekhon
Institutions
- Pennsylvania State University (US)
- Cornell University (US)
- WinnMed (US)
- Center for Digestive and Liver Diseases (US)
- Wellcome/MRC Institute of Metabolic Science (GB)
- Mayo Clinic in Arizona (US)
- Centre for Human Drug Research (NL)
- University of Minnesota Medical Center (US)
- Epigenomics (Germany) (DE)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2026-08-24
- DOI
- https://doi.org/10.1073/pnas.2533336123
- Primary Topic
- Gastrointestinal motility and disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00