Longitudinal multi-omics analyses link gut microbiome dysbiosis with recurrent urinary tract infections in women

Abstract

Recurrent urinary tract infections (rUTIs) are a major health burden worldwide, with history of infection being a significant risk factor. While the gut is a known reservoir for uropathogenic bacteria, the role of the microbiota in rUTI remains unclear. We conducted a year-long study of women with (n=15) and without (n=16) history of rUTIs, from whom we collected urine, blood and monthly fecal samples for metagenomic and transcriptomic interrogation. During the study, 24 UTIs were reported, and additional samples collected during and after infection. The gut microbiome of individuals with a history of rUTI was significantly depleted in microbial richness and butyrate-producing bacteria compared to controls, reminiscent of other inflammatory conditions. However, Escherichia coli gut and bladder populations were comparable between cohorts in both relative abundance and phylogroup. Transcriptional analysis of peripheral blood mononuclear cells revealed expression profiles indicative of differential systemic immunity between cohorts. Altogether, these results suggest that rUTI susceptibility is in part mediated through the gut-bladder axis, comprising gut dysbiosis and differential immune response to bacterial bladder colonization, manifesting in symptoms.

An Iterative Approach Guides Discovery of the FabI Inhibitor Fabimycin, a Late-Stage Antibiotic Candidate with In Vivo Efficacy against Drug-Resistant Gram-Negative Infections

“…32 In this vein, the activity of fabimycin against UTIs is very promising, given how antibiotic treatment of UTIs is known to trigger Clostridioides diff icile infection 49 and the recently described "gut−bladder axis" in recurrent UTIs. 50,51 Similar to fusidic acid and some other antibiotics, 52,53 the advancement of this class of FabI inhibitors has been complicated by the uniquely poor stability of these compounds in mouse plasma. Given the promising activity of fabimycin in mouse infection models and encouraging data that fabimycin is dramatically more stable in rat and human plasma, it is reasonable to believe that fabimycin efficacy may improve as it is used to treat infections in higher organisms.…”

“…While this includes some pathogenic bacteria, such as P. aeruginosa , it also includes many commensal bacteria, suggesting that a suitable FabI inhibitor could be less damaging to the gut microbiome than the typical broad-spectrum antibiotic . In this vein, the activity of fabimycin against UTIs is very promising, given how antibiotic treatment of UTIs is known to trigger Clostridioides difficile infection and the recently described “gut–bladder axis” in recurrent UTIs. , …”

Integrative Multi-Omics Analysis for the Determination of Non-Muscle Invasive vs. Muscle Invasive Bladder Cancer: A Pilot Study

“…Though few studies have investigated the relationships between gut and bladder, recent studies have indicated a “gut–bladder axis” linking those two distal organs [ 19 , 20 ], where gut microbiota may play a pivotal role. With the emergence of accumulative evidence, gut microbiome has been reported to be associated with cancer occurrence and development; however, the spectrum of direct and indirect interactions between the gut microbiota and the bladder cancer remains largely unknown.…”

Strong pathogen competition in neonatal gut colonisation

“…Another recent study investigated the polymicrobial nature of recurrent urinary tract infections (rUTIs) and found that E. coli populations in the gut and the bladder were comparable between women with and without a history of rUTI in both relative abundance and phylogroup [37]. However, a deeper lineage level analysis, such as the one performed here, combined with screening of genetic determinants of persistent bladder colonisation from the metagenome assemblies could provide a more refined characterisation of the possible population differences between gut and the bladder.…”