yoda-1 and Colitis

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.

Topics: Adaptor Proteins, Vesicular Transport; Animals; Bone and Bones; Calcium; Colitis; Colon; Feces; Female; Gastrointestinal Motility; HEK293 Cells; Humans; Immunohistochemistry; Intestinal Mucosa; Ion Channels; Ligands; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microbiota; Myeloid Differentiation Factor 88; Osteoclasts; Pyrazines; Ribonuclease, Pancreatic; RNA; Serotonin; Thiadiazoles