Link between gut microbiota, clinical outcomes generalizable among allogeneic HSCT recipients
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Patterns of microbiota disruption, marked by loss of intestinal diversity and single taxa domination, appeared similar among a cohort of patients undergoing allogeneic hematopoietic stem cell transplantation across various centers and geographic areas, according to findings published in The New England Journal of Medicine.
In addition, significant progressive loss of intestinal flora diversity appeared associated with increased risk for graft-versus-host disease.
“A lot of associations have been observed between features of the gut microbiome and clinical outcomes for transplant patients, but most of these have been small, single-center studies,” Jonathan U. Peled, MD, PhD, assistant attending at the adult bone marrow transplant service in the department of medicine at Memorial Sloan Kettering Cancer Center, told Healio. “Clinical practices vary greatly across transplant centers, particularly with respect to diet and antibiotics, which are two critical determinants of microbiome composition. This raised the question of whether the associations individual centers have found between the microbiota and clinical outcomes of transplant patients are generalizable.”
For the multicenter study, Peled and colleagues used 16S ribosomal RNA gene sequencing to profile microbiota composition of 8,767 fecal samples obtained from 1,362 patients undergoing allogeneic HSCT at four international transplant centers: Duke University in Durham, North Carolina, Memorial Sloan Kettering Cancer Center in New York, and university hospitals in Regensburg, Germany, and Sapporo, Japan. They used Cox proportional hazards analysis to assess association between microbiota diversity and mortality.
Baseline samples showed evidence of microbiome disruption before transplantation, according to the researchers. In addition, lower intestinal diversity before transplantation appeared associated with poor survival.
Investigators used the median diversity value (2.64) among patients at Memorial Sloan Kettering Cancer Center to stratify cohorts into higher-diversity (> 2.64) and lower-diversity (< 2.64) groups.
Cohort one included patients treated at Memorial Sloan Kettering Cancer Center and cohort two included patients treated across the other three centers.
Researchers reported a loss of diversity among patients at all four centers during the transplantation period.
In cohort one, they observed 104 deaths among 354 patients in the higher-diversity subgroup compared with 136 deaths among 350 patients in the lower-diversity subgroup (HR = 0.75; 95% CI, 0.58-0.96). The association of higher intestinal microbiota diversity and lower risk for death remained even after adjusting for age, intensity of conditioning regimen, graft source and hematopoietic cell transplantation-comorbidity index (adjusted HR [aHR] = 0.71; 95% CI, 0.55-0.92), as well as in an analysis where diversity was considered a continuous variable (aHR = 0.5; 95% CI, 0.31-0.8).
In cohort two, there were 18 deaths among 87 patients in the higher-diversity subgroup and 35 deaths among 92 patients in the lower-diversity subgroup (aHR = 0.49; 95% CI, 0.27-0.9).
Results of subgroup analyses of cohort one showed an association between lower intestinal diversity and a higher risk for transplant-associated death, as well as death attributable to GVHD.
“Our research underscores a reason to be judicious in our use of various drugs, especially antibiotics, as well as oral nutrition in [patients undergoing] bone marrow transplant,” Peled told Healio. “The data highlight two specific times relative to transplantation around which clinical trials could be designed to prevent or remediate microbiota injury — both pretransplant and following engraftment.”
Future trials should test treatment strategies such as fecal microbiota transplantation, rationally designed probiotics and other approaches, Peled added.
“The next steps are in complementary directions,” he said. “The first is to design clinical trials to prevent or remediate microbiota injury in transplant patients. The second is to use animal models of GVHD to understand the mechanism by which the microbiome influences alloreactivity. A third is to develop biomarkers that can inform clinicians about the health of a patient’s microbiota in real time.” – by Jennifer Southall
For more information:
Jonathan U. Peled, MD, PhD, can be reached at Memorial Sloan Kettering Cancer Center, 1275 York Ave., Box 111, New York, NY 10065; email: peledj@mskcc.org.
Disclosures: Peled reports research funding from Seres Therapeutics. Please see the study for all other authors’ relevant financial disclosures.
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