Gardnerella piotii enhances uropathogenic Escherichia coli infection through a succinate-GPR91-uroplakin axis

Uropathogenic Escherichia coli (UPEC) is the principal causative agent of urinary tract infections (UTIs); however, urine samples from patients with recurrent cystitis frequently harbor diverse coexisting bacterial taxa. How such polymicrobial urobiota can functionally modulate bladder susceptibility to UPEC infection remains unclear.

We integrated 16S rRNA-based microbiota profiling of a recurrent cystitis cohort with mechanistic in vitro and in vivo models to assess host-microbe interactions within the urinary tract. We identified Gardnerella piotii as a microbial modifier that enhances the infectivity of UPEC without inducing overt epithelial damage or inflammation. Exposure to G. piotii increased UPEC burden in the bladder and in bladder epithelial cells by promoting early bacterial adhesion. Mechanistically, G. piotii actively produced succinate, which acted as a host-active metabolite to selectively upregulate uroplakin expression through signaling via the succinate receptor GPR91. Genetic ablation of GPR91 abolished succinate- and G. piotii-induced uroplakin upregulation and UPEC adhesion, establishing that this epithelial signaling axis is necessary for infection sensitization. Importantly, the heightened UPEC susceptibility induced by G. piotii could be partially mitigated; introduction of the beneficial commensal Lactobacillus crispatus or exposure to lactate partially reduced UPEC burden in vivo, highlighting the functional plasticity of the bladder microenvironment.

These findings unravel a metabolite-driven mechanism by which members of the urinary microbiota modulate host epithelial programs to influence UPEC infection. By identifying a succinate-GPR91-uroplakin signaling axis that links polymicrobial community structure to epithelial susceptibility, our study reframes recurrent cystitis as a dynamic ecological process shaped by microbial existence and metabolic signaling rather than by an individual pathogen. Video Abstract.