Researchers at the UC Davis School of Medicine have revealed how an imbalanced gut microbiome escalates the production of metabolic byproducts by certain gut bacteria. This imbalance leads to a feedback loop that worsens chronic kidney disease (CKD) in mice. Scientists have identified an investigational drug that can break the destructive cycle. The findings were published in Science.
The team showed that kidney dysfunction increased nitrate levels in the colon. Nitrates are supercharged Escherichia coli’s (E. coli) production of indole, an organic compound that is converted into a harmful waste product – indoxyl sulfate – that further damages the kidneys.
Blocking the production of a single enzyme in the gut – inducible nitric oxide synthase (iNOS) – was able to stop this destructive cycle.
“Previous research has shown that chronic kidney disease is associated with an increased abundance of enterobacteria in feces,” said Jee-Yon Lee, first author of the study and a project scientist in the Department of Medical Microbiology and Immunology.
Enterobacteriaceae is a large family of bacteria that includes both harmless and pathogenic species.
“This study identifies host-derived nitrate as a switch that transforms commensal gut bacteria E. coli to indole producers capable of accelerating chronic kidney disease,” Lee said.
CKD affects about 1 in 7 adults in the US
Chronic kidney disease, which is a gradual loss of kidney function, affects about 1 in 7 adults in the US, or about 35.5 million Americans. About 1 in 3 people with diabetes and 1 in 5 people with high blood pressure have kidney disease. Globally, approximately 788 million people are estimated to have CKD in 2023.
For people with kidney failure, dialysis is a life-saving procedure that removes waste and extra fluid from the blood. But indoxyl sulfate cannot be removed by dialysis because it binds to serum albumin, a common protein in the blood. Higher serum levels of indoxyl sulfate are associated with more severe chronic kidney disease.
“By identifying the driver responsible for the increase of Enterobacteriaceae in CKD and demonstrating the importance of these bacteria for indole production and disease progression, our research points to iNOS as a potential target for intervention strategies,” said Andreas Bäumler, Distinguished Professor in the Department of Medical Microbiology and Immunology and senior author of the paper.
Methods and possible treatment
The researchers looked at specific strains of it E. coli in mice. They also looked at stool samples from people with and without CKD. In mice, they found:
- Renal dysfunction induced increased transcription Nos2 (the gene responsible for making iNOS) in the lining of the colon.
- Increased iNOS led to an increase in nitric oxide, which reacted with oxygen radicals to form nitrate.
- Increased nitrate levels are fed coli development, leading to higher production of indoxyl sulfate, a kidney toxin, creating the harmful feedback loop.
In addition to the mouse findings, the researchers found that stool samples from people with CKD showed the same effect seen in mice. Although stool samples from people with kidney disease showed higher levels E. coliindole production increased only when nitrate was added, compared to healthy controls.
To determine whether reducing iNOS levels could improve outcomes in the mice, the researchers tested aminoguanidine, an investigational drug known to inhibit iNOS. Mice given aminoguanidine showed reduced mucosal nitrate, reduced indoxyl sulfate, and improved kidney outcomes.
Limitations and next steps
Although the results are promising for finding a mechanism to reduce indole sulfate—and potentially improve the progression of kidney disease—the researchers note several limitations.
Although human gut bacteria mirror the nitrate-dependent indole surge in mice, more studies will be needed to confirm the results in humans. Clinical trials are also needed to test whether iNOS inhibitors, or other agonists or inhibitors, could safely reduce indoxyl sulfate and improve outcomes in people with CKD.
And finally, they note that the gut ecosystem is complex. E. coli is not the only indole-producing gut bacterium, and long-term suppression of nitrate pathways may have unknown trade-offs.
“This study shows that changing the gut environment—not just the microbes themselves—can have profound effects on disease progression,” Bäumler said. “Targeting host pathways that modulate microbial metabolism may represent a new way to intervene in chronic kidney disease.”
