Gut-bladder axis syndrome associated with recurrent UTIs in humans

Creators: Worby, Colin J.; Schreiber, Henry L., IV; Straub, Timothy J.; van Dijk, Lucas R.; Bronson, Ryan A.; Olson, Benjamin; Pinkner, Jerome S.; Obernuefemann, Chloe L. P.; Muñoz, Vanessa L.; Paharik, Alexandra E.; Walker, Bruce J.; Desjardins, Christopher A.; Chou, Wen-Chi; Bergeron, Karla; Chapman, Sinéad B.; Klim, Aleksandra; Manson, Abigail L.; Hannan, Thomas J.; Hooton, Thomas M.; Kau, Andrew L.; Lai, H. Henry; Dodson, Karen W.; Hultgren, Scott J.; Earl, Ashlee M.

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 and without history of rUTIs, from whom we collected urine, blood and monthly fecal samples for multi-omic interrogation. The rUTI gut microbiome was significantly depleted in microbial richness and butyrate-producing bacteria compared to controls, reminiscent of other inflammatory conditions, though Escherichia coli gut and bladder dynamics were comparable between cohorts. Blood samples revealed signals of differential systemic immunity, leading us to hypothesize that rUTI susceptibility is in part mediated through a syndrome involving the gut-bladder axis, comprising gut dysbiosis and differential immune response to bacterial bladder colonization, manifesting in symptoms. This work highlights the potential for microbiome therapeutics to prevent and treat rUTIs.

Additional Information

The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license. This version posted November 16, 2021. This project has been funded in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Grant Number U19AI110818 to the Broad Institute. We would like to acknowledge members of the Broad's Bacterial Genomics group and Hera Vlamakis for helpful conversations. We thank Brian Haas for assistance with PBMC RNA-Seq analysis as well as the Multi-Omics Core and Genomics Platform at the Broad Institute for sample processing and data generation. Data Availability: Sequence data are available from the Sequence Read Archive under Bioproject PRJNA400628. Author contributions: Study design - HLS, KWD, SJH, AME; Study coordination - HLS, KB, SBC, AK; Experiments performed - HLS, JSP, CLPO, VLM, AEP; Data analysis - CJW, HLS, TJS, LRvD, RAB, BO, BJH, CAD, WCC; Consultation and supervision of analyses - BJW, ALM, TJH, TMH, ALK, HHL, KWD, SJH, AME; Prepared the original draft - CJW, ALM, KWD, SJH, AME; Review and approval of the final manuscript was provided by all authors. The authors declare no competing interests. Data availability: Sequence data are available from the Sequence Read Archive under Bioproject PRJNA400628. Author Declarations: I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes. The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was conducted with the approval and under the supervision of the Institutional Review Board of Washington University School of Medicine in St. Louis, MO I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes. I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes. I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes.

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