Journal
CELL
Volume 182, Issue 3, Pages 609-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2020.06.022
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Funding
- Takeda Science Foundation
- KAKENHI [JP16K15665, JP18H02970, JP19K22712]
- Translational Research Network Program from the Japan Agency for Medical Research and Development (AMED)
- Lotte Foundation
- Kowa Life Science Foundation
- Kanzawa Medical Research Foundation
- Akashi Medical Foundation
- Yakult Bioscience Research Foundation
- Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care
- Lydia O'Leary Memorial Pias Dermatological Foundation
- Canon Foundation
- Life Science Foundation
- Japan Dairy Association
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Gastrointestinal enterochromaffin cells regulate bone and gut homeostasis via serotonin (5-hydroxytryptamine [5-HT]) production. A recent report suggested that gut microbes regulate 5-HT levels; however, the precise underlying molecular mechanisms are unexplored. Here, we reveal that the cation channel Piezo1 in the gut acts as a sensor of single-stranded RNA (ssRNA) governing 5-HT production. Intestinal epithelium-specific deletion of mouse Piezo1 profoundly disturbed gut peristalsis, impeded experimental colitis, and suppressed serum 5-HT levels. Because of systemic 5-HT deficiency, conditional knockout of Piezo1 increased bone formation. Notably, fecal ssRNA was identified as a natural Piezo1 ligand, and ssRNA-stimulated 5-HT synthesis from the gut was evoked in a MyD88/TRIF-independent manner. Colonic infusion of RNase A suppressed gut motility and increased bone mass. These findings suggest gut ssRNA as a master determinant of systemic 5-HT levels, indicating the ssRNA-Piezo1 axis as a potential prophylactic target for treatment of bone and gut disorders.
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