Gut Bacterium Fusobacterium varium Drives Gut Pain and Motility Problems by Boosting the Piezo2 Sensor

Irritable bowel syndrome is the most common disorder of gut-brain interaction. It causes chronic abdominal pain and altered bowel habits, and the gut microbiota is increasingly seen as a driver. Piezo2 is a mechanosensitive ion channel that senses stretch and pressure in the gut. It helps trigger serotonin (5-HT) release from enterochromaffin cells. Whether gut microbes regulate Piezo2, and whether that explains the visceral hypersensitivity and altered motility of IBS, was unknown. A related channel, Piezo1, is already known to respond to microbial signals.

The team enrolled 55 patients with diarrhea-predominant IBS (Rome III criteria) and 19 healthy controls. Participants completed symptom and quality-of-life questionnaires, a rectal barostat test of visceral sensitivity, colonoscopy with sigmoid mucosal biopsy, and stool collection for 16S rRNA sequencing. In mice (268 male C57BL/6J in total), the gut microbiota was depleted with an antibiotic cocktail to create pseudo-germ-free animals. These mice then received pooled stool from five matched IBS-D donors or five healthy donors. Co-housing experiments tested whether the microbiota spreads between animals. Piezo2 was knocked down in the colon (intraperitoneal AAV9 shRNA) or in the dorsal root ganglia (intrathecal AAV9 shRNA). Mice were also gavaged with Akkermansia muciniphila or Fusobacterium varium (2 × 10^9 CFU every other day for two weeks). Cecal untargeted metabolomics and molecular docking were used to explore mechanisms.

In patients, the ratio of Piezo2-positive to 5-HT-positive cells in the colon was lower in IBS-D. It correlated positively with visceral sensation and with gut dysbiosis. Mice that received IBS-D microbiota developed colonic dysmotility and visceral hypersensitivity, along with higher Piezo2 protein in the colon and dorsal root ganglia. Knocking down Piezo2 in either location reduced both abnormalities. 16S sequencing showed distinct microbiota composition between groups. Among the single strains tested, F. varium induced dysmotility and hypersensitivity, and colon or dorsal root ganglion Piezo2 knockdown alleviated these effects. A. muciniphila did not. F. varium also raised Piezo2 protein and increased indole-3-acetic acid and indole-3-acrylic acid, tryptophan-related metabolites that docking predicted to bind Piezo2.

Taken together, the work suggests that gut microbes can tune Piezo2 signaling and thereby contribute to IBS-like symptoms. F. varium emerges as a candidate pathogenic species, and Piezo2 or its microbial metabolite ligands as possible therapeutic targets.

Several caveats apply. The causal evidence comes from mice with antibiotic-depleted microbiota. Human data are correlational and based on modest sample sizes. The binding of the indole metabolites to Piezo2 is only a computational prediction. The human finding of a lower Piezo2+/5-HT+ cell ratio sits alongside higher Piezo2 protein in mice, so the two measures need careful reconciliation. The text available to me ended partway through the methods, so detailed statistics and effect sizes were not reviewed.