What Role do Microbiomes Play in Urinary Tract Infections?

09/04/2023 Comments Off

Gut and urinary bacteria
Vaginal microbiome
The urinary microbiome
Conclusions
Resources
Further reading

Urinary tract infections (UTIs) are bacterial infections of the urinary tract that cause painful urination.

They affect at least 150 million people annually, making them among the most common bacterial infections. They are treated with antibiotics, but at least 25% of women get a second infection within the next six months. And some people get recurrent UTIs.

Image Credit: Totalart/Shutterstock.com

Gut and urinary bacteria

Most UTIs are due to the organism called Escherichia coli (E. coli), which can cause urinary and intestinal disease.

One small study of gut, urinary, and blood samples from women with recurrent UTIs showed that both this group and the group that did not develop recurrent infections had UPEC in their gut. Moreover, these strains were occasionally found to have also reached the bladder.

The fact that uropathogenic E. coli (UPEC) strains were abundant in the gut of people with UTI and the known proximity of the female urethra to the anus due to its shorter size and situation in the vulva is thought to favor the migration and colonization of the urinary tract with UPEC.

This theory proposes that contamination of the area around the urethra with uropathogens from the gut predisposes to urethral colonization, followed by ascending bladder infection.

Again, breastfeeding has a protective role against UTI in infants, potentially demonstrating the importance of the gut microbiome in these infections.

Much evidence has also come from metagenomics to show the presence of a gut-urinary tract link, indicating an "intestinal bloom of uropathogens" before a UTI develops.

The microbes responsible for recurrent UTIs are resistant to antimicrobials. Again, post-kidney transplant patients showed a higher relative abundance of Faecalibacterium and Romboutsia taxa, in inverse relationship to Enterobacteriaceae in urine and a reduced UTI risk.

These findings indicate that the gut microbiome must remain healthy to prevent UTIs. Some research suggests that recurrent UTIs seem to be linked to dysregulation of the human microbiomes in an intricate network of relationships.

Recurrent UTIs are often triggered by antibiotic use, since these wipe out pathogens from the urinary tract but leave them behind in the gut. This allows the surviving bacteria to spread to the bladder again, causing another infection.

Individuals with repeated UTIs had a lower diversity of beneficial gut commensals, which makes it easier for pathogenic bacteria to overgrow. Among the most notable findings was the reduction in butyrate-producing bacteria, as this is a short-chain fatty acid (SCFA) with anti-inflammatory activity.

This could have helped healthy women to resist bladder infection because of their ability to clear the pathogens from their gut via immune mechanisms.

Repeated antibiotic courses disrupt the normal gut microbiome, reducing its diversity and ability to regulate the inflammatory cascade. Moreover, such patients typically show the presence of inflammation in the blood.

Antibiotics would not be the best response to urinary infections in this case. Beta-lactam antibiotics were shown to increase Enterococcus's abundance by 1% relative to other species. Probiotics, fecal microbiome transplants (FMT), and other methods to restore a healthy balance to the gut microbiome would be the right answer.

Vaginal microbiome

Along with the gut microbiome, that of the vagina is an important contributor to the health of the urinary microbiome. In keeping with this, scientists have shown that disruptions of the vaginal microbiome are potentially linked to colonization of the urinary tract with E. coli with recurrent UTIs.

In women of reproductive age, Lactobacillus forms the chief vaginal species in health, including L. crispatus, L. jensenii, L. gasseri, and L. iners. Their presence ensures an acidic vaginal environment, along with the presence of antimicrobials like hydrogen peroxide and bacteriocins.

Many women also have an abundance of other non-Lactobacilli organisms; however, these may replace or significantly reduce the number of Lactobacilli. This includes Gram-negative anaerobic microorganisms as well as Firmicutes and Actinobacteria. Such a state is considered a precursor of vaginal dysbiosis of bacterial vaginosis.

Interestingly, women with recurrent UTIs harbor E. coli in their vagina more often than healthy women, which is linked to lower levels of Lactobacilli in the vagina. L. crispatus and other species can inhibit E. coli growth. Bacterial vaginosis is thus a risk factor for E. coli colonization.

The ability of E. coli to successfully colonize the vaginal mucosa indicates the presence of a reservoir that allows the uropathogen to multiply before it ascends to colonize the urethra and cause ascending cystitis.

Apart from overt uropathogens, some vaginal bacteria briefly appear in the urinary tract. Still, before they are cleared, they upset the host-pathogen balance, disrupting the normal host-pathogen interactions and thus allowing for injury or altered immunologic responses. This is called "covert pathogenesis".

This could be how group B streptococci predispose to E. coli cystitis by helping the latter to survive in the bladder. Gardnerella vaginalis, a notorious and fastidious organism in bacterial vaginosis and in urinary and systemic infections, also triggers repeated UTIs by activating latent E. coli within bladder epithelial cells.

This effect is favored by the change in vaginal milieu during perimenopause when UTIs become more common.

The urinary microbiome

Urine is not naturally sterile, according to current scientific thought. Instead, both men and women have a healthy urinary microbiome.

The urinary microbiome is also key to UTI occurrence, as shown by the high prevalence of asymptomatic bacteriuria (ASB). In many cases, ASB is considered a protective barrier against recurrent UTIs.

The advanced techniques of current microbiology have helped identify hundreds of old and new bacterial species in the urine of healthy, asymptomatic people. These include Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes.

Some scientists say, "The majority of pathogenic bacteria are constituents of the commensal human urinary tract bacteria, and their pathogenicity occurs due to imbalance in their relative abundances." In fact, further findings seem to indicate that most urinary microbiota originate from the gut, such as Lactobacillus, Streptococcus, and the organisms linked to bacterial vaginosis like Gardnerella, Prevotella, and Bacteroides.

A lower diversity of the urinary microbiome is linked to a higher susceptibility to UTI when exposed to bacterial pathogens. Conversely, successful UTI treatment restores the urinary microbiome to normal. Urinary tract dysbiosis may thus precede the development of a UTI.

Understanding Urinary Tract Infections

Conclusions

New findings indicate the need to evolve alternative treatment strategies for UTIs. Better antimicrobials, vaccines, and correcting gut dysbiosis are areas under research. Probiotics are a potentially useful option to reduce the number of UTI episodes, as one study showed a favorable effect after administering several Lactobacillus species with cranberry extract.

Similarly, FMT may help prevent recurrent UTIs by restoring a healthy balance to the gut microbiome, eliminating antimicrobial-resistant bacteria, and establishing beneficial or commensal species instead.

Similar studies are required to understand the benefit that may be expected from the use of vaginal probiotics to prevent UTIs without the use of antibiotics. If such research is carried out, vaginal microbiome transplants in women with persistent bacterial vaginosis may be expected to restore healthy vaginal flora and prevent UTIs.

Resources

Bhandari, T. (2022). Recurrent UTIs Linked to Gut Microbiome, Chronic Inflammation. Retrieved from https://medicine.wustl.edu/news/recurrent-utis-linked-to-gut-microbiome-chronic-inflammation/. Accessed on August 18, 2022.
Mestrovic, T. et al. (2020). The Role of Gut, Vaginal, and Urinary Microbiome in Urinary Tract Infections: From Bench to Bedside. Diagnostics. http://dx.doi.org/10.3390/diagnostics11010007. https://www.researchgate.net/publication/347953094_The_Role_of_Gut_Vaginal_and_Urinary_Microbiome_in_Urinary_Tract_Infections_From_Bench_to_Bedside
Magruder, M. et al. (2019). Gut Uropathogen Abundance Is a Risk Factor for Development of Bacteriuria and Urinary Tract Infection. Nature Communications. https://doi.org/10.1038/s41467-019-13467-w. https://www.nature.com/articles/s41467-019-13467-w
Thanert, R. et al. (2019). Comparative Genomics of Antibiotic-Resistant Uropathogens Implicates Three Routes for Recurrence of Urinary Tract Infections. mBio. https://doi.org/10.1128/mBio.01977-19. https://journals.asm.org/doi/full/10.1128/mBio.01977-19
Lewis, A. L. et al. (2020). Roles of The Vagina and The Vaginal Microbiota in Urinary Tract Infection: Evidence from Clinical Correlations and Experimental Models. GMS Infectious Diseases. https://doi.org/10.3205%2Fid000046. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186798/
Gilbert, N. M. et al. (2017). Transient Microbiota Exposures Activate Dormant Escherichia Coli Infection in The Bladder and Drive Severe Outcomes of Recurrent Disease. PLOS Pathogens. https://doi.org/10.1371/journal.ppat.1006238. https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006238
Brubaker, L. et al. (2017). The female Urinary Microbiota, Urinary Health and Common Urinary Disorders. Annals of Translational Medicine. doi: 10.21037/atm.2016.11.62. https://atm.amegroups.com/article/view/13209/html
Kawalec, A. et al. (2022). Emerging Role of Microbiome in the Prevention of Urinary Tract Infections in Children. International Journal of Molecular Science. https://doi.org/10.3390%2Fijms23020870. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8775962/
Perez-Carrasco, V. et al. (2021). Urinary Microbiome: Yin and Yang of the Urinary Tract. Frontiers in Cellular and Infection Microbiology. https://doi.org/10.3389/fcimb.2021.617002. https://www.frontiersin.org/articles/10.3389/fcimb.2021.617002/full
De Seta, F. et al. (2022). The Vaginal Microbiome: III. The Vaginal Microbiome in Various Urogenital Disorders. Journal of Lower Genital Tract Disease. doi: 10.1097/LGT.0000000000000645. https://journals.lww.com/jlgtd/Fulltext/2022/01000/The_Vaginal_Microbiome__III__The_Vaginal.17.aspx

Gut and urinary bacteria

Vaginal microbiome

The urinary microbiome

Conclusions

Resources

Further reading

Dr. Liji Thomas