Gut-bladder axis syndrome associated with recurrent UTIs in humans

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.

Establishing the role of the gut microbiota in susceptibility to recurrent urinary tract infections

“…Whether UPEC gut presence alters the immune system’s response to eventual bladder exposure remains an open question. Our recent work revealed a significant depletion of butyrate producers in women with rUTI history regardless of immediate UTI status as well as tentative evidence for differential immune markers at healthy time points compared with a healthy cohort ( 11 ). While considerable work is needed to further explore these dynamics, we propose that the gut-bladder axis may be an as yet overlooked, but relevant, driver of rUTI susceptibility.…”

“…While current evidence remains limited due to the lack of appropriate cohort studies, recent work has shown that children with UTIs ( 9 ) and kidney transplant patients with bacteriuria ( 10 ) have differential microbiome structures compared with respective control cohorts, suggesting a link between the resident microbiota and uropathogen gut colonization and/or transmission to the bladder. Furthermore, our recent longitudinal cohort study identified reduced microbial diversity and lower levels of butyrate-producing bacteria in the guts of women with rUTI history compared with healthy controls ( 11 ). Antibiotic treatment of UTIs is certainly a confounder in such studies due to the resulting perturbations of the gut microbiota associated with repeated exposure.…”

How Advanced Is Our Understanding of the Role of Intestinal Barrier Dysfunction in the Pathogenesis of Recurrent Urinary Tract Infections

“…It should be noted, that all the examined patients had increased levels of sIg A and myeloperoxidase activity in coprofiltrates, which suggested enteric inflammation, while only 20% had clinical symptoms of gut dysbiosis. These data have been recently confirmed in a year-long study by Worby et al in which the authors showed strong similarities between gut dysbiosis in RUTIs and inflammatory bowel disease characterized by depleted levels of butyrate-producing bacteria and diminished microbial richness (Worby et al, 2021). Moreover, the authors found a higher plasma marker of intestinal inflammation, eotaxin-1, in women with RUTIs compared to healthy controls, suggesting low-level enteric inflammation (Worby et al, 2021).…”

“…These data have been recently confirmed in a year-long study by Worby et al in which the authors showed strong similarities between gut dysbiosis in RUTIs and inflammatory bowel disease characterized by depleted levels of butyrate-producing bacteria and diminished microbial richness ( Worby et al, 2021 ). Moreover, the authors found a higher plasma marker of intestinal inflammation, eotaxin-1, in women with RUTIs compared to healthy controls, suggesting low-level enteric inflammation ( Worby et al, 2021 ). The presence of such subclinical enteric inflammation in patients with RUTIs indicates the formation of a vicious circle.…”

The Urinary Microbiome; Axis Crosstalk and Short-Chain Fatty Acid

“…Although the intestinal and bladder dynamics of Escherichia coli were similar between cohorts, the rUTI strain that colonized the intestine was not cleared for a long time by antibiotic treatment. They concluded that a distinct immune response to bacterial invasion of the bladder is potentially mediated by the gut microbiome [ 76 ]. This is evidence for the gut–bladder axis.…”