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.

The efficacy of drugs used to treat urinary incontinence may be dependent on the urinary tract microbiome

A very common issue among older women is urinary urgency incontinence (UUI), often referred to as an overactive or uncontrollable bladder. This is characterized by the sudden, intense need to urinate, followed by the loss of bladder control. Treatment for this problem includes solifenacin, an anticholinergic medication. Sequencing of urine bacteria has shown that UUI-affected women have different bacterial compositions than do non-UUI-affected women. This has prompted researchers at Loyola University Chicago to examine the relationship between solifenacin use and the microbiome of UUI patients. The hopes of this study was to begin understanding UUI-patients’ microbiome, in hopes of one day determining whether treatment of the microbiome would be at all beneficial to UUI patients.

Two groups of women were participants in this study: 74 UUI-affected women and 60 controls. The average age of the UUI-affected women group was 61.5 years, while that of the control group was 49 years. Urine samples were collected via transurethreal catheter. At baseline, similar amounts of bacterial DNA were detected in urine samples of both study groups; however, UUI-affected women had more cultivatable bacteria and significantly more bacterial diversity.

After testing symptom improvement following certain dosages of solifenacin, the researchers were able to conclude that certain microbiota characteristics are associated with treatment. It seems as though bacterial diversity could be used to predict treatment response, as women with higher microbial diversity responded better to treatment. It is important to remember that certain bacteria could be associated with bladder health, so the aim is not to eliminate bacteria altogether, but to identify whether bacteria could be targeted as a means of improving symptoms. The results of this study are exciting in that not only are we discovering more about the microbiome, but it could be used to treat yet another malady.

Bacteria may be responsible for chronic prostatitis

Editors note: Two of our blog posts on aging and the microbiome were recently shared with the website Gut Microbiota for Health. Our readers should take a look!

Link to post.

Some people suffer from an enigmatic diagnosis known as urologic chronic pelvic pain syndrome (UCPPS), also known as non-bacterial chronic prostatitis.  UCPPS’s symptoms are rather similar to urinary tract infections (UTI’s), with a conspicuous lack of a bacterial cause.  In order to diagnose UCPPS doctors must do a bacterial culture of the urine, and if no bacteria grow then the UCPPS diagnosis may be given.  While many believe that this disease may be caused by stress or hormone imbalances, a team of researchers from across the U.S. and Canada investigated if there was a bacterial cause.  As we know, much of the microbiome is unculturable, and can only be identified through genome sequencing.  These researchers hypothesized that bacteria are the true cause of UCPPS, and that UCPPS is similar to UTI, only the bacteria are unculturable, and so basic hospital screens for the bacteria fail to identify them.  The scientists recently published the results of their study in The Journal of Urology.

The researchers did genome analyses on 110 urine samples from male patients suffering from UCPPS and 115 urine samples from normal males with no UCPPS diagnosis.  The results showed that both the groups had approximately 75 bacteria in their urine, all of which would unlikely have cultured in normal hospital assays.  When they compared the types of bacteria between the groups they noticed that Burkholderia cenocepacia was highly abundant in patients with UCPPS but not the control group.  Interestingly, this species had been previously identified as a possible urologic pathogen.

The study had a number of limitations, and the authors admit as much.  For example, it is unclear there sampling procedures would adequately identify any bacteria causing biofilms, and they limited the study to bacteria so fungi and viruses went untested.  Still, it is compelling evidence for a bacterial cause to a disease that had previously been thought to not have a bacterial origin.  These findings really speak to what prominent microbiome scientist, and member of the AMI’s scientific advisory board, Rob Knight recently said in an interview with NPR:  “When you consider the number of diseases where, just over the last five years, it went from being crazy to think the microbes were involved to now being crazy to think the microbes aren't involved, it's amazing how rapidly the evidence has been accumulating.”