Editors' ChoiceHost-Microbe Interactions

ssRNA stimulates Piezo1 and serotonin synthesis

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Science Signaling  08 Sep 2020:
Vol. 13, Issue 648, eabe6352
DOI: 10.1126/scisignal.abe6352

The gut produces serotonin upon activation of the Ca2+ channel Piezo1 by microbiome-derived ssRNA.

Enterochromaffin cells in the intestine produce most of the peripheral serotonin (5-HT), which suppresses bone formation, promotes gut peristalsis, and exacerbates bowel inflammation. Sugisawa et al. found that activation of the Ca2+ channel Piezo1 by microbiome-produced single-stranded RNA (ssRNA) triggered 5-HT production by enterochromaffin cells (see also Matute et al.). Mice with a gut-specific ablation of Piezo1 (Villin-Piezo1flox/flox) had less 5-HT in the gut due to decreased expression of Thp1, which encodes a rate-limiting enzyme for serotonin production in enterochromaffin cells. Villin-Piezo1flox/flox mice had greater bone mass due to increased osteoblast numbers and activity, impaired gut peristalsis, and resistance to chemically induced colitis, effects that were reversed by 5-HT injection. Stretching of RIN14B chromaffin cells induced the production of 5-HT independently of Piezo1, indicating that mechanical activation of Piezo1 did not promote 5-HT secretion. Antibiotic-induced microbiome depletion decreased serum 5-HT concentrations only in wild-type mice and did not reverse the increased bone mass or impaired gut peristalsis of Villin-Piezo1flox/flox mice. HEK293T cells expressing Piezo1 produced Ca2+ currents when exposed to RNA extracted from mouse feces, an effect abolished by RNase A treatment, or when exposed to ssRNA40, a ssRNA oligonucleotide. ssRNA40 induced Ca2+ responses and 5-HT secretion in primary intestinal epithelium from wild-type mice, but not in that from Villin-Piezo1flox/flox mice. Colonic infusion of RNase A into aged wild-type mice reduced serum 5-HT concentrations and fecal RNA and increased bone mass. Thus, the gut produces 5-HT in response to activation of Piezo1 by ssRNA from the microbiome.

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