Gut-microbiota metabolites could be associated with renal failure

It’s becoming increasingly recognized that dysbiosis in the gut microbiome can result in the development of sickness or disease.  Understanding these implications, researchers have also turned to studying biomarkers and indicators that can better predict this outcome and disease onset.  A novel and easily detectable biomarker could serve as an indicator of dysbiosis and facilitate therapeutic development.   Renal function decline is a disorder that can eventually lead to chronic kidney disease (CKD )and impacts many people worldwide.  A conglomerate team of researchers investigated whether metabolites produced from bacterial fermentation could serve as early indicators of renal function decline, and whether or not disruption to taxonomic units are detectible in this stage of the disease. 

The researchers measured circulating metabolites in 4439 individual healthy patients with minimal renal function decline.  Estimated glomerular filtration rate (eGFR) was measured as an indicator for reduced renal function, and the onset of CKD was defined by the kidney losing half of its filtration capacity.  It was found that indoxyl-sulfate, p-cresyl-sulfate, and phenylacetylglutamine –metabolic products of gut microbiota fermentation of tyrosine and tryptophan – were associated with reduction in eGFR, suggesting that these markers could be indicators of early renal function decline.  The researchers were also able to correlate these metabolite levels with changes to in intestinal flora.  16S sequencing revealed that 3 operational taxonomic units were correlated with indoxyl-sulfate, 52 with phenylacetylglutamine, and 1 with p-cresyl sulfate. 

Specific changes within the gut microbiome could indicate disease onset, and these changes could perhaps be monitored by circulating metabolic products.  Following metabolic activity could allow clinicians to treat disease early in its progression, and this principle could theoretically apply to a variety of host diseases, not just kidney failure.  Metabolic products of the microbiome could serve as a useful tool that can lead to novel therapy development.  

Microbiome metabolite, TMAO, associated with increased risk of chronic kidney disease and atherosclerosis

Our microbiome is responsible for producing many of the molecules and metabolites that end up in our bloodstream.  Here, these molecules can serve many important therapeutic functions, like in the case of short chained fatty acids (SCFAs).  However, some of these metabolites are beginning to be linked to various diseases.  The best known example of this is microbiome mediated production of trimethylamine-(N)-oxide (TMAO).  TMAO is produced by the microbiome from molecules called carnitine and choline, which come from foods like red meat and eggs.  A lot of literature is now being published that is establishing a connection between TMAO and atherosclerosis, and more recently between TMAO and chronic kidney disease (CKD).  In a new study published last week in the Journal of the American Society of Nephrology, researchers from the University of Kansas assessed the connection between each of these things, TMAO, atherosclerosis, and CKD.

The researchers hypothesized that patients with chronic kidney disease would show increased levels of atherosclerosis because circulating TMAO cannot be cleared from the blood by their injured kidneys.  They measured the degree of CKD and plasma TMAO levels in over 100 patients and confirmed their hypothesis: they noticed a direct relationship between severity of their CKD and circulating TMAO levels.  In addition, the researchers noticed that those people who received kidney transplants had improved TMAO levels, showing that the relationship between CKD and TMAO was most likely due to loss of kidney function.  Finally, the researchers measured biomarkers for atherosclerosis in these patients and correlated the amount of TMAO with the amount of atherosclerosis, even showing that the long term survival of these patients was related to the amount of circulating TMAO levels.

This paper is one of the first to make a connection between circulating TMAO levels and kidney function, which itself is related to atherosclerosis and mortality.  The microbiome is ultimately responsible for the creation of TMAO in the blood, by breaking down things like meats, eggs, and nuts.  It appears that a dietary shift, or a modulation of the microbiome that decreases its ability to perform this transformation should be considered for patients with CKD who are at risk for atherosclerosis.

Gut bacteria may prevent kidney injury

Scientists have found that short chain fatty acids (SCFAs), a product of gut bacteria, may protect the kidneys from acute kidney injury (AKI), a condition with high mortality rates that can also lead to other very serious kidney diseases. AKI is often caused by something called ischemia reperfusion injury, an injury resulting from a loss of oxygen to the tissue (ischemia) and a rush of blood back to the site (reperfusion). This instigates a cascade of events resulting in several immune cell populations accumulating at the site of the injury, causing inflammation and kidney damage.

Because AKI is a result of inflammation and because SCFAs are known to have anti-inflammatory effects, scientists in Brazil hypothesized that treatment with SCFAs could ameliorate kidney function. The results published in the Journal of the American Society of Nephrology were the first to show the protective role of SCFAs in kidney ischemia reperfusion injury (IRI). They found that when the three main SCFAs (acetate, propionate, and butyrate) were administered to mice undergoing this IRI injury, they protected the kidney from undergoing AKI.  As suspected, the SCFAs prevented an autoimmune response which resulted in less inflammation and apoptosis (cell death).

Acetate was the SCFA that was most protective to the kidney, so in another experiment the scientists administered acetate-producing bacteria to the mice.  Bifidobacterium adolescentis and Bifidobacterium longum were administered separately and each did produce acetate, as evidenced by increased acetate levels in the mice's feces. They found that these mice were protected from kidney IRI and therefore the bacteria were effective. They did note, though,  that it is unlikely the bacteria colonized the gut, so further investigation is needed.  

This study provides another example of probiotics preventing conditions that may have resulted in serious injury and even death. The bacteria in this study are already used in probiotics to treat other diseases, and so repurposing them for kidney disease should be possible.  The study also describes the anti-inflammatory effects of SCFAs, which we have written extensively about in this blog.