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

Worby, Colin J. and Schreiber, Henry L., IV and Straub, Timothy J. and van Dijk, Lucas R. and Bronson, Ryan A. and Olson, Benjamin S. and Pinkner, Jerome S. and Obernuefemann, Chloe L. P. and Muñoz, Vanessa L. and Paharik, Alexandra E. and Azimzadeh, Philippe N. and Walker, Bruce J. and Desjardins, Christopher A. and Chou, Wen-Chi and Bergeron, Karla and Chapman, Sinéad B. and Klim, Aleksandra and Manson, Abigail L. and Hannan, Thomas J. and Hooton, Thomas M. and Kau, Andrew L. and Lai, H. Henry and Dodson, Karen W. and Hultgren, Scott J. and Earl, Ashlee M. (2022) Longitudinal multi-omics analyses link gut microbiome dysbiosis with recurrent urinary tract infections in women. Nature Microbiology, 7 (5). pp. 630-639. ISSN 2058-5276. doi:10.1038/s41564-022-01107-x. https://resolver.caltech.edu/CaltechAUTHORS:20220509-812784000

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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 rUTI, from whom we collected urine, blood and monthly faecal samples for metagenomic and transcriptomic interrogation. During the study 24 UTIs were reported, with 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 with 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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1038/s41564-022-01107-xDOIArticle
https://rdcu.be/cNci4PublisherFree ReadCube access
https://www.ncbi.nlm.nih.gov/bioproject/?term=PRJNA400628Related ItemData
ORCID:
AuthorORCID
Worby, Colin J.0000-0002-9132-7249
Schreiber, Henry L., IV0000-0002-4501-9886
Straub, Timothy J.0000-0001-5009-0778
van Dijk, Lucas R.0000-0002-7565-5859
Olson, Benjamin S.0000-0002-5440-1315
Pinkner, Jerome S.0000-0002-7389-7440
Paharik, Alexandra E.0000-0003-4743-0406
Azimzadeh, Philippe N.0000-0001-8172-5051
Desjardins, Christopher A.0000-0002-3160-4734
Chou, Wen-Chi0000-0001-8408-3533
Chapman, Sinéad B.0000-0002-9454-2737
Manson, Abigail L.0000-0002-3800-0714
Hannan, Thomas J.0000-0003-0498-8231
Hooton, Thomas M.0000-0001-5810-6543
Kau, Andrew L.0000-0002-9386-3766
Lai, H. Henry0000-0003-2691-994X
Dodson, Karen W.0000-0001-7421-9660
Hultgren, Scott J.0000-0001-8785-564X
Earl, Ashlee M.0000-0001-7857-9145
Additional Information:© 2022 Nature Publishing Group. Received 14 September 2021; Accepted 18 March 2022; Published 02 May 2022. 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 no. U19AI110818 to the Broad Institute, from the National Institutes of Health Mucosal Immunology Studies Team consortium under grant no. U01AI095542 to Washington University and the National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Department of Health and Human Services, under Grant Number R01DK121822 to the Broad Institute and Washington University. B.S.O. was supported by grants from the National Institutes of Health, USA (nos. T32GM007067 and T32GM139774). A.L.K. was supported by grants from the National Institutes of Health, Department of Health, USA (no. R01AI165915) and the Doris Duke Charitable Foundation. This work was also supported by funds from the Center for Women’s Infectious Disease Research at Washington University School of Medicine. We thank members of the Broad’s Bacterial Genomics group and H. Vlamakis for helpful conversations. We thank B. 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: Metagenomic sequence data are available from the Sequence Read Archive under Bioproject PRJNA400628. PBMC RNA-seq data are available from the database of Genotypes and Phenotypes (dbGaP) under project no. phs002728. Questionnaire data and output files from MetaPhlan2, Humann2 and StrainGE are available from github.com/cworby/UMB-study. Source data are provided with this paper. Code availability: Custom R scripts used to analyse outputs are available from github.com/cworby/UMB-study. Contributions: Study design was undertaken by H.L.S., K.W.D., S.J.H. and A.M.E. Study coordination was carried out by H.L.S., K.B., S.B.C. and A.K. Experiments were performed by H.L.S., J.S.P., C.L.P.O., V.L.M. and A.E.P. Data analysis was undertaken by C.J.W., H.L.S., T.J.S., L.R.v.D., R.A.B., B.S.O., B.J.H., C.A.D. and W.-C.C. Consultation and supervision of analyses were the responsibility of B.J.W., A.L.M., T.J.H., T.M.H., A.L.K., H.H.L., K.W.D., S.J.H. and A.M.E. C.J.W., A.L.M., K.W.D., S.J.H. and A.M.E. prepared the original draft. Review and approval of the final manuscript was provided by all authors. The authors declare no competing interests. Peer review information: Nature Microbiology thanks John Lee, Alice McHardy and Mark Schembri for their contribution to the peer review of this work.
Funders:
Funding AgencyGrant Number
NIHU19AI110818
NIHU01AI095542
NIHR01DK121822
NIH Predoctoral FellowshipT32GM007067
NIH Predoctoral FellowshipT32GM139774
NIHR01AI165915
Doris Duke Charitable FoundationUNSPECIFIED
Washington UniversityUNSPECIFIED
Subject Keywords:Bacterial genomics; Bacterial infection; Microbiome
Issue or Number:5
DOI:10.1038/s41564-022-01107-x
Record Number:CaltechAUTHORS:20220509-812784000
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20220509-812784000
Official Citation:Worby, C.J., Schreiber, H.L., Straub, T.J. et al. Longitudinal multi-omics analyses link gut microbiome dysbiosis with recurrent urinary tract infections in women. Nat Microbiol 7, 630–639 (2022). https://doi.org/10.1038/s41564-022-01107-x
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:114654
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:09 May 2022 20:34
Last Modified:09 May 2022 20:34

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