Urinary Tract Infections revisited: Microbial eco-evolutionary drivers and regulators

Urinary tract infections (UTIs) are very common in women, with high recurrence rates after antibiotic treatment. The microbes causing UTIs are more diverse than previously thought, especially in postmenopausal women, and antibiotic resistance is increasing. Combined with a lack of knowledge about the origins of UTIs, this compromises successful treatment. In this project we shift focus from the presence of specific microbes in UTI, to microbiome composition and microbial interactions within the microbiome, as a key driver of health and disease. Indeed, the urinary tract contains a resident community of microbes, and the composition of this microbiome may facilitate or protect against the development of UTIs. We hypothesize that UTI patients have a dysbiotic 'urobiome', in which microbial interactions facilitate UTI pathogenesis of uropathobionts. To investigate how and why an established urobiome goes "off balance" into a disease state, we will investigate the microbial interactions associated with UTIs in longitudinal clinical specimens from postmenopausal women with and without recurrent UTI (RUTI) and in reconstituted microbial communities. Our multi-disciplinary team of clinical microbiologists, infectious disease specialists, bioinformaticians, modelers, chemists, and eco-evolutionary biologists will combine in vivo measurements with in vitro reductionist bottom-up experiments to investigate 'who is there', 'who is doing what', and 'why'. (Meta)genomic sequencing, bioinformatic modeling , and metabolome measurements will give insight into the presence and absence of particular microbes, and their interactions in (a)symptomatic women. Urinary epithelial organoid experiments will unveil how specific microbial interactions lead to UTI. Lastly, evolutionary experiments and eco-evolutionary modeling will reveal why particular interactions lead to UTI. The relatively low complexity of the urobiome will give us the unique opportunity to disentangle these microbial eco-evolutionary drivers and regulators of UTI. We anticipate that the microbial interaction knowledge generated in this project can be translated to other more complex microbiomes.