Researchers at UC Davis School of Medicine reported on Mar. 19 that an imbalance in the gut microbiome can worsen chronic kidney disease (CKD) in mice by increasing harmful metabolic byproducts. The findings, published in Science, also point to a potential drug target that could interrupt this damaging cycle.
The study is significant because CKD affects about one in seven adults in the United States, or roughly 35.5 million people. Understanding how gut bacteria contribute to the progression of CKD could lead to new treatment strategies for millions of patients worldwide.
The research team found that kidney impairment raises nitrate levels in the colon, which then boosts Escherichia coli's production of indole. Indole is converted into indoxyl sulfate, a waste product that further damages kidneys. Blocking the enzyme inducible nitric oxide synthase (iNOS) in the gut was shown to stop this destructive process.
"Previous research has shown that chronic kidney disease is linked to an elevated fecal abundance of Enterobacteriaceae," said Jee-Yon Lee, first author and project scientist at UC Davis. Lee added, "This study identifies nitrate from the host as a switch that turns common gut bacteria like E. coli into indole producers capable of accelerating chronic kidney disease."
Senior author Andreas Bäumler said, "By identifying the driver responsible for an increase of Enterobacteriaceae during chronic kidney disease, and by demonstrating the importance of these bacteria for indole production and disease progression, our research points to iNOS as a potential target for intervention strategies." The researchers tested aminoguanidine, an investigational drug known to inhibit iNOS, and found it reduced mucous nitrate and indoxyl sulfate while improving kidney outcomes in mice.
While promising, the researchers caution that more studies are needed to confirm these results in humans and determine if iNOS inhibitors can safely lower indoxyl sulfate levels and improve outcomes for people with CKD. They also note that E. coli is not the only bacterium involved and long-term suppression of nitrate pathways may have unknown effects.
"This study shows that altering the gut environment - not just the microbes themselves - can have profound effects on disease progression," Bäumler said. "Targeting host pathways that shape microbial metabolism may represent a new way to intervene in chronic kidney disease."
