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Microbiome Composition Predicts Clinical Outcome Among Stem Cell Transplant Patients

NEW YORK – The makeup of patients' microbiomes can predict their clinical outcomes when undergoing stem cell transplants.

Allogeneic hematopoietic stem cell transplants are common among patients with blood cancers, and while they may cure the disease, such transplants can also lead to complications such as graft-versus-host disease and infections. Previous research has suggested there are links between the gut microbiome and such adverse outcomes, but those studies were largely limited to single centers.

An international team of researchers collected more than 8,700 fecal samples from patients undergoing allogeneic hematopoietic stem cell transplants at four different centers in three countries to analyze their microbial composition. As they reported in the New England Journal of Medicine Wednesday, researchers led by Memorial Sloan-Kettering Cancer Center's Marcel van den Brink found that the pattern of microbiome disruption was similar across the centers and that decreased microbial diversity was associated with a higher risk of death.

"This study defines opportunities for rational interventions to restore integrity to the intestinal microbiota, such as with fecal microbiota replacement or other strategies, which could also be evaluated in clinical settings beyond allogeneic hematopoietic-cell transplantation," van den Brink and his colleagues wrote in their paper.

The researchers prospectively collected a median four stool samples from 1,362 patients at Sloan-Kettering, Duke University Medical Center, University Hospital Regensburg in Germany, and Hokkaido University Hospital in Japan undergoing allogeneic hematopoietic stem cell transplants. Most patients were being treated for acute leukemia, though others had myeloma or aplastic anemia.

Using 16S ribosomal RNA gene sequencing, they characterized patients' gut microbiomes before and after transplantation. Patients at all four centers exhibited a loss of microbial diversity during the transplant time frame.

When they divided patients from MSKCC into high and low diversity groups, the researchers noticed that higher gut microbiome diversity was associated with a lower risk of death, including transplant-related death. This association held even after they accounted for patients' age, how intense patients' pre-transplant conditioning regime was, and graft source. Similarly, higher gut microbiome diversity was associated with a lower risk of death among patients from the three other medical centers combined.

Lower-diversity microbiomes were often marked by an overabundance of certain bacteria. In particular, there was an enrichment of Enterococcus, Klebsiella, Escherichia, Staphylococcus, and Streptococcus among these samples. The researchers noted that higher levels of Enterococcus has previously been linked to an increased risk of vancomycin-resistant enterococcal bacteremia and graft-versus-host disease. 

But even before undergoing the transplant, patients had less diverse gut microbiomes than healthy individuals. The initial 600 fecal samples the researchers collected from patients at all four centers had less diversity than samples from healthy volunteers, indicating that the patients arrive for treatment with microbiomes that already differed from those of healthy individuals. 

This, the researchers noted, suggests there are two time points — before transplantation and during engraftment — when interventions to prevent or mitigate microbiome changes could possibly be tried.

Based on their findings, the researchers also developed a microbiome diversity risk score. They developed this score using the MSKCC cohort and validated it in the combined cohort of the other centers. Patients with a high score in the second cohort had a nearly 40 percent increased risk of death.

"The similarities we observed in patterns of microbiota injury and their associations with clinical outcomes highlight the important interactions that occur between microbial communities and their hosts," the researchers wrote.