Microbiome metabolite in urine predicts severity of graft versus host disease

 Molecular structure of indoxyl-sulfate

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.

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