Researchers at the University of California, Davis School of Medicine have shown how an imbalance in the gut microbiome increases the production of metabolic byproducts by certain gut bacteria. This imbalance triggers a feedback loop that exacerbates chronic kidney disease (CKD) in mice. Scientists have identified an experimental drug that has the potential to break the destructive cycle. The survey results are science.
The research team showed that kidney damage increases nitrate levels in the colon. nitrate turbocharged “Escherichia coli”s (Escherichia coli) Production of indole. The organic compounds convert into the harmful waste product indoxyl sulfate, further damaging the kidneys.
By blocking the production of a single enzyme in the intestine, inducible nitric oxide synthase (iNOS), we were able to stop this destructive cycle.
“Previous studies have shown that chronic kidney disease is associated with an increased abundance of Enterobacteriaceae in feces,” said Jiyong Lee, lead author of the study and project scientist in the Department of Medical Microbiology and Immunology.
Enterobacteriaceae is a large bacterial family that includes both harmless and pathogenic species.
“This study identified nitrates from the host as a switch that changes common gut bacteria to: Escherichia coli It affects indole-producing substances that can accelerate chronic kidney disease,” Lee said.
Approximately 1 in 7 adults in the United States has CKD.
Chronic kidney disease, a gradual loss of kidney function, affects about 1 in 7 U.S. adults, or an estimated 35.5 million Americans. Approximately 1 in 3 people with diabetes and 1 in 5 people with high blood pressure have kidney disease. It is estimated that approximately 788 million people worldwide will have CKD in 2023.
For people with kidney failure, hemodialysis is a life-saving procedure that removes waste and excess fluid from the blood. However, indoxyl sulfate cannot be removed by dialysis because it binds to serum albumin, a common protein in the blood. Higher serum indoxyl sulfate levels are associated with more severe chronic kidney disease.
“By identifying the cause of the increase in Enterobacteriaceae in chronic kidney disease and demonstrating the importance of these bacteria for indole production and disease progression, our study shows that iNOS is a potential target for intervention strategies,” said Andreas Baumler, Distinguished Professor in the Department of Medical Microbiology and Immunology and lead author of the paper.
Methods and possible treatments
Researchers tested specific strains. Escherichia coli with a mouse. They also tested fecal samples from CKD and non-CKD patients. With the mouse, I found the following:
- Kidney dysfunction increased the following transcripts: Nos2 (gene involved in the production of iNOS) Located in the mucosal layer of the colon.
- The increase in iNOS led to an increase in nitric oxide, which reacted with oxygen radicals to produce nitrates.
- Fueled by increased nitrate levels Escherichia coli growth, Production of the kidney toxin indoxyl sulfate increases, creating a harmful feedback loop.
In addition to their findings in mice, the researchers found that fecal samples from CKD patients also showed the same effects seen in mice. In fecal samples from kidney disease patients, higher levels of Escherichia colicompared to healthy controls, indole production increased only when nitrate was added.
To determine whether lowering iNOS levels could improve outcomes in mice, the researchers tested aminoguanidine, an investigational drug known to inhibit iNOS. Mice receiving aminoguanidine showed reduced nitrate mucus, reduced indoxyl sulfate, and improved renal outcomes.
Limitations and next steps
Although the results hold promise for discovering mechanisms to reduce indole sulfate and potentially ameliorate the progression of kidney disease, the researchers note several limitations.
Human gut bacteria mirrored the nitrate-dependent indole surge in mice, but further studies are needed to confirm the results in humans. Clinical trials are also needed to test whether iNOS inhibitors and other agonists and inhibitors can safely lower indoxyl sulfate and improve outcomes in CKD patients.
And finally, they point out that the gut ecosystem is complex. Escherichia coli Long-term inhibition of the nitrate pathway may involve unknown trade-offs, as indole is not the only gut bacteria that produce it.
“This study shows that changes in the gut environment, not just the microbes themselves, can have a significant impact on disease progression,” Baumler said. “Targeting host pathways that shape microbial metabolism may represent a new way to intervene in chronic kidney disease.”
sauce:
University of California Davis Health
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DOI: 10.1126/science.ady5217
