A Golden Opportunity: Eliminating Dogma about the Bladder’s Microbiome
Forget what you’ve heard: Urine is *not* sterile.
The paper in Nature Communications is here: https://go.nature.com/2qL6F5d
Forget what you’ve heard: Urine is *not* sterile. This pervasive dogma has been showing up in pop culture, news, and of course in the doctor’s office for nearly 60 years, since Dr. Ed Kass1, developed a test to identify patients at risk for pyelonephritis. His test was very effective at this goal, but was inappropriately adopted for all urine culture applications. Clinical lab reports stated “no growth” for healthy patients, and the clinical understanding of this result morphed over the decades from “no infection” to “it must be sterile”. Thus, there are many women who are “culture negative” and yet suffer from urinary tract symptoms.
Fast forward to 2012: microbiome research is starting to boom and next gen sequencing technologies allow characterization of previously inaccessible areas. Urogynecologist Linda Brubaker and microbial geneticist Alan Wolfe team up to test if urine is actually sterile. The first hurdle was to determine if bacteria resided in the bladder, not the urethra or vaginal environment. Urine was collected by supra-pubic aspiration, thereby bypassing any vulvo-vaginal contamination. Sure enough, they found detectable bacterial DNA in the bladders of women2. They also showed that aspirated urine was similar to catheterized urine but different from voided urine. A later study confirmed that those bacterial sequences corresponded to live, cultivatable bacteria 3. Together, these results proved that the bladder contains a specific, discrete microbiome, separate from that of the gut and vagina.
Soon it was discovered that the bladder, like other microbiome sites, is measurably different in health and disease states and that certain organisms are associated with health while others are indicators of disease. However, because the bladder has been considered sterile for so long, there was a lack of reference organisms for study. With the exception of uropathogenic E. coli (UPEC), few organisms have been studied in the context of the bladder. This lack of bladder isolates limited our ability to move our research forward, so we set out to create our own collection.
When explaining this history at a conference, I met Trevor Lawley from the Wellcome Trust Genome Institute, who immediately grasped the importance of cultivation. The bladder culture collection presented in this paper is the result of our collaboration. With these isolates we can not only search their genomes for evidence of phages, we can cultivate them from the original isolates, allowing for characterization of novel phages 4. We have begun to study the ability of Aerococcus urinae to create biofilms and colonize the bladder of mice. We can even begin to understand the potential benefits of Lactobacillus strains on bladder epithelium. Making this culture collection available to the wider community will help definitively end 60 years of dogma and spur a new era of sophisticated bladder microbiome research.
1. Kass, E.H. Asymptomatic infections of the urinary tract. Trans Assoc Am Physicians 69, 56-64 (1956).
2. Wolfe, A.J. et al. Evidence of uncultivated bacteria in the adult female bladder. J Clin Microbiol 50, 1376-83 (2012).
3. Hilt, E.E. et al. Urine is not sterile: use of enhanced urine culture techniques to detect resident bacterial flora in the adult female bladder. J Clin Microbiol 52, 871-6 (2014).
4. Miller-Ensminger, T. et al. Bacteriophages of the Urinary Microbiome. J Bacteriol (2018).