Chronic kidney disease and its effect on microbiome metabolism

Patient receiving dialysis

A substantial body of evidence points to the importance of renal filtration and the elimination of microbiome-derived metabolites.  Chronic kidney disease can lead to renal failure, which can have detrimental consequences for the elimination of microbiome metabolites.  Specifically, p­­-cresyl sulfate and indoxyl sulfate are cometabolites between human metabolism and microbiome fermentation.  Kidney failure or loss of renal function can lead to retention of these metabolites, and they can induce toxic harm by remaining in systemic circulation.  While there has been significant interest in this field, much is unknown regarding CKD’s influence on microbiota function and metabolism.  Researchers in Belgium sought to address this and identify what role CKD would have on the microbiota metabolism in the colon in patients on hemodialysis. 

The experimenters examined 20 patients on hemodialysis.  These fecal metabolites profiles of these patients were compared to 20 healthy controls using gas chromatography-mass spectrometry.  Initial observations revealed that healthy controls had a significantly higher number of volatile organic compounds (VOCs) – an indicator of microbiota metabolism - as compared to the patients on hemodialysis.  After adjusting the data for statistical confounders and discriminating VOCs between groups, the researchers determined that 81 individual VOCs were significantly different between hemodialysis patients and healthy controls.  Consistent with previous findings and known clinical conditions, both p-cresol and indole were significantly upregulated in hemodialysis patients.  A major confounder in this study is diet, as hemodialysis patients are on a very restricted diet, and as we know, dietary intake impacts microbiome composition and metabolism.  The researchers conducted the same analysis with the hemodialysis patients with household contacts who were on the same diets.  Interestingly, no significant difference in VOCs was observed between groups. 

The researchers demonstrated that CKD patients on hemodialysis experience an altered microbiota metabolism; however, dietary influence may be driving this effect rather than loss of renal function.  It was good to see the researchers included the household controls, as this evidence suggests renal function by itself may not have direct impacts on gut microbiota function.  Regardless, much of the CKD-microbiome research to this date has focused on the microbiome’s role in CKD or CKD-mediated downstream maladies.  It was interesting to see a study that took the opposite approach, as we know microbiome health is important for homeostatic mechanisms that maintain a healthy body.  

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.

The oral microbiome of periodontitis patients has distinct profiles dependent on disease severity

A few weeks ago we discussed periodontitis, a bacterial infection of the gums that leads to inflammation and deep pockets to develop in which harmful bacteria can colonize. Periodontitis develops in association with dramatic changes in the makeup of the oral microbiome. Smokers and diabetics are more frequently victims of the disease. The study we discussed previously was one performed by researchers in Istanbul, Turkey in which they tested whether a probiotic lozenge could improve the patients’ condition. In a different, more recently published study concerning periodontitis, researchers in Connecticut and Massachusetts looked not to change the oral microbiome of patients suffering from periodontitis, but to organize and identify the microbial characteristics of the disease.

In the study published in Plos One, seventeen subjects, 8 of whom were diabetic, with Chronic Kidney Disease (CKD) and seventeen subjects without CKD, 3 of whom were diabetic, were studied.  All 34 subjects suffered from periodontitis. Samples were taken from each participant, from the deepest pockets in two different areas of the mouth. DNA was then isolated and sequenced to identify microbial communities in each individual. After much statistical analysis, the researchers found that the microbial communities tended toward two clusters, A and B, with type B communities correlating with more severe periodontitis. Group A subjects had communities with greater health-associated bacteria and cluster B communities were dominated by Porphyromonas gingivalis and Tannerella forsythia. Additionally, the analysis showed that diabetes and CKD are not correlated with a certain periodontitis microbial makeup.

A set-back of this experiment is the low sample size, which makes for less meaningful statistical analysis. Greater sample sizes of each cluster could give stronger claim to the findings of this study. However, this study does begin to clarify the bacterial community characterization of healthy, unhealthy, and severely unhealthy oral microbiomes. In addition, the results from this study could be used to ask further questions about the disease, including questions such as: what environmental factors cause the difference in clusters A and B? Do inflammatory diseases such as CKD and diabetes have anything to do with the severity of inflammatory response of periodontitis? Further analysis may allow us to answer these tough questions.