Microbiome metabolite in urine predicts severity of graft versus host disease

Molecular structure of indoxyl-sulfate

People that suffer from blood cancers, such as acute myeloid leukemia, often times receive hematopoietic stem cell transplants (HSCT) as part of their therapy.  This procedure typically replaces the sick person’s white blood cells with those of a healthy donor.  While this is a life-saving procedure it does carry a type of transplant ‘rejection’ risk.  While in a normal organ transplant a person’s own white blood cells will attack the foreign organ, in this case the new, donor white blood cells begin attacking parts of the recipient’s body.  This is called graft versus host disease (GvHD), and can often times be fatal.  One of the primary areas that are attacked by the new blood cells is the gut microbiome.  This is not surprising because the ‘replacement’ immune system is not programmed to tolerate and accept the bacteria in the gut, because they are so different from the bacteria it was originally adapted for.  Therefore, GvHD, is often considered a microbiome disease, and there have even been studies to investigate whether matching microbiomes decreases risk for the disease. 

An important area of research is focused on detecting GvHD before it begins so that it can be treated early.  While normally GvHD is diagnosed by symptoms, it may be possible to use the microbiome itself for early detection of the disease.  A group out of Germany recently showed that by monitoring a specific metabolite produced in the gut, indoxyl sulfate, one could predict the severity of GvHD.  This molecule is only produced by bacteria, mostly in the gut, by breaking down the amino acid tryptophan.  Moreover, indoxyl sulfate is an important signaling molecule that is thought to modulate the gut epithelial function, and may cause inflammation.  They published the results of their study in the journal Blood last week. 

The scientists measured the indoxyl sulfate concentration in the urine of 131 individuals undergoing HSCT over the course of 28 days following the treatment.  After, the ranked the patients in terms of indoxyl sulfate level during the first ten days after transplant, and compared their outcomes.  Remarkably, the people that had the lowest levels of indoxyl sulfate had a statistically significant higher risk of dying of GvHD after 12 months.  Next, the scientists attempted to relate the gut microbiome composition of the patients with the indoxyl sulfate levels.  They realized higher diversity microbiomes were related to higher indoxyl sulfate levels, and healthier outcomes.  In addition, higher levels of Clostridia and lower levels of Bacilli led to higher indoxyl sulfate.

This study may go a long way in informing clinicians about GvHD risk in their patients.  Not only does it show that monitoring indoxyl sulfate may predict GvHD severity, but it also points to specific bacteria that may be important in controlling its levels.  HSCTs are a highly effective treatment for blood cancer, that often times have a higher efficacy/safety profile compared with traditional cancer therapies.  Understanding the microbiome’s role in GvHD, one of the most important risks of HSCT, will hopefully lead to improved therapies and better overall cancer outcomes.

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.