Feed

The comorbidity of overactive bladder (OAB) and irritable bowel syndrome (IBS) presents a major clinical challenge, with the underlying neural and microbial mechanisms of the gut-bladder axis poorly understood. Here we aimed to delineate the complete causal pathway from a specific gut microorganism to bladder dysfunction and validate it as a therapeutic target. We combined analysis of human OAB-IBS cohorts with a postinflammatory mouse model, integrating retrograde neuronal tracing, multiomics (16S rDNA and metabolomics), fecal microbiota transplantation, urodynamics, dorsal root ganglion (DRG) electrophysiology and pharmacological and/or surgical interventions. We first confirmed a direct anatomical link, identifying dichotomized DRG neurons co-innervating the colon and bladder. Patients with OAB-IBS and mice exhibited a shared gut dysbiosis characterized by Akkermansia muciniphila enrichment. This comorbidity occurred in the absence of local bladder inflammation or urinary colonization with A. muciniphila, confirming a functional, noninfectious mechanism. Fecal microbiota transplantation of A. muciniphila or patient microbiota causally exacerbated visceral hypersensitivity, the OAB phenotype and DRG hyperexcitability. Mechanistically, A. muciniphila enrichment shunted host tryptophan metabolism toward the serotonin (5-HT) pathway. The resulting excess 5-HT acted on specifically upregulated colonic 5-HT_3a receptors to drive neuronal sensitization. Crucially, pharmacological blockade of the colonic 5-HT_3a receptor or surgical severing of the mesenteric nerves reversed the bladder dysfunction and visceral hypersensitivity. Our findings delineate a novel pathway wherein A. muciniphila drives functional gut-bladder comorbidity by promoting a gut-derived serotonergic signal that sensitizes shared afferent neurons, establishing the gut-specific 5-HT_3a receptor as a key, druggable therapeutic target.