Researchers at the Cleveland Clinic have discovered definitive proof that the kidney microbiome influences the formation of kidney stones—showing that the urinary tract is not sterile and low levels of bacteria are normal. The study, published in Nature Communications, identified certain bacteria that could either block or promote the formation of kidney stones. The study also showed the misuse of antibiotics in the hospital setting could promote or influence the makeup of the kidney microbiome, steering it toward stone-promoting bacteria.
For years, the urinary tract has been thought to be sterile, but growing evidence suggests otherwise.
“Urologic diseases like kidney stones impact 63% of the adult population and are getting worse,” said lead investigator Aaron Miller, PhD, head of the Urology Translational Research Laboratory at Cleveland Clinic. “The data consistently points towards bacteria. If we can’t get over the assumption of sterility, we can’t develop more effective treatments and preventative options.”
Miller, José Agudelo, MD, a Cleveland Clinic researcher and collaborator, and the research team used a multi-pronged approach to identify and characterize the bacteria within the kidneys, which revealed patterns of microbial influence on renal health.
Until recently, there was little to no direct evidence supporting the existence of a stable, active kidney microbiome. Previous studies had hinted at microbial populations in the urinary tract but failed to meet the three criteria for a true microbiome—stability, consistency and reproducibility, and metabolic activity. The new research showed that the bacteria present in the urinary tract met all three criteria and also showed that all bacteria living there weren’t only there in connection with a disease state.
The researchers sought to understand how these microbial communities might influence kidney stone formation, particularly in light of the growing concerns over antibiotic misuse in hospitals. Using a series of preclinical models and in vitro experiments, the team found that the kidney microbiome could either promote or inhibit kidney stone formation. Notably, they discovered that Escherichia coli (E. coli) bacteria, a known pathogen, can promote the formation of kidney stones, while Lactobacillus crispatus, a probiotic, can prevent stone development.
To test this, the researchers grew these bacteria in a chamber designed to mimic the movement of urine through the kidneys. When E. coli was grown in the chamber with calcium and oxalate, substances that form kidney stones, it promoted the growth of large, stone-like crystals. No stones formed in the chambers growing Lactobacillus in this way. But, when Lactobacillus and E. coli were grown together, the team observed the formation of very small crystal structures that were different from kidney stones indicating that Lactobacillus was blocking E. coli’s ability to create kidney stones.
Additional work showed the potential detrimental impact of antibiotics on the kidney microbiome. Long-term use of antibiotics reduced the presence of protective Lactobacillus and promoting the growth of stone-forming E. coli. This shift was particularly evident when mouse models were exposed to cefazolin, a common antibiotic used in surgical settings.
The investigators suggest that antibiotics can cause dysbiosis, where the normal microbial balance is disturbed, leading to an environment that promotes kidney stone formation. Dysbiosis was shown to trigger an inflammatory response and increase the presence of pro-lithogenic bacteria like E. coli.
This research firmly moves away from the common belief that the urinary tract is sterile and that the microbial populations found there influence the production of both pro- and anti-kidney stone molecules. Determining which bacteria these different influences could pave the way for the development of new diagnostics and therapeutics to identify the risk of kidney stone formation and methods to treat them.
Miller suggested that these new findings may only be scratching the surface of a better understanding of the kidney microbiome.
“If the kidney microbiome can influence kidney stones, it can likely influence other kidney diseases as well,” Miller concluded. “We are already looking at microbial signatures for other kidney diseases and have even submitted a grant to investigate how certain genetic variants influence the renal microbiome and kidney disease risk in different ethnicities.”
