Uropathogenic Dysbiosis Pattern is Associated With Urethral Fibrosis

Purpose: Cellular mechanisms of stricture progression after repeated transurethral interventions are unclear. We hypothesize that urethral injury and mechanical stretch cause tears on the urethral epithelial cell lining leading to leaking epithelium and urine extravasation. Urinary bacteria traverse the epithelial lining and may promote fibrogenesis through inflammation due to microbial activity. Our objective was to perform a case-control study of the urobiome from patients with urethral stricture disease or healthy controls using 16S rRNA and shotgun metagenomic sequencing profiling to elucidate the clinical relevance of the urobiome in urinary stricture progression. Materials and Methods: First catch urine samples from patients and healthy volunteers were collected and pelleted urine was used for DNA extraction, followed by high throughput 16S rRNA and shotgun metagenomic sequencing. Sequencing data were used to determine microbial taxa and functions associated with urethral stricture disease. Results: Sequencing results revealed that the lower urinary tract urobiome was significantly different between urethral stricture disease cases and healthy controls. In particular, taxonomic and metabolic profiles point toward anaerobic biofilm formation by antibiotic-resistant species of Klebsiella, which is a known uropathogen. Importantly, no patients in the study exhibited signs or symptoms of clinical infection. Conclusions: Our findings suggest a role for biofilm formation by uropathogens such as Klebsiella spp. in developing an inflammatory environment and consequent fibrosis progression. Future studies will elucidate specific mechanisms of Klebsiella- induced fibrosis. Our data suggest that targeting specific bacteria or biofilm formation may be beneficial for urethral stricture disease detection and prevention of progression.