Intestinal Microbiota and Relapse After Hematopoietic-Cell Transplantation

Abstract

The major causes of mortality after allogeneic hematopoietic-cell transplantation (allo-HCT) are relapse, graft-versus-host disease (GVHD), and infection. We have reported previously that alterations in the intestinal flora are associated with GVHD, bacteremia, and reduced overall survival after allo-HCT. Because intestinal bacteria are potent modulators of systemic immune responses, including antitumor effects, we hypothesized that components of the intestinal flora could be associated with relapse after allo-HCT. MethodsThe intestinal microbiota of 541 patients admitted for allo-HCT was profiled by means of 16S ribosomal sequencing of prospectively collected stool samples. We examined the relationship between abundance of microbiota species or groups of related species and relapse/progression of disease during 2 years of follow-up time after allo-HCT by using cause-specific proportional hazards in a retrospective discovery-validation cohort study. ResultsHigher abundance of a bacterial group composed mostly of Eubacterium limosum in the validation set was associated with a decreased risk of relapse/progression of disease (hazard ratio [HR], 0.82 per 10-fold increase in abundance; 95% CI, 0.71 to 0.95; P = .009). When the patients were categorized according to presence or absence of this bacterial group, presence also was associated with less relapse/progression of disease (HR, 0.52; 95% CI, 0.31 to 0.87; P = .01). The 2-year cumulative incidences of relapse/progression among patients with and without this group of bacteria were 19.8% and 33.8%, respectively. These associations remained significant in multivariable models and were strongest among recipients of T-cell-replete allografts. ConclusionWe found associations between the abundance of a group of bacteria in the intestinal flora and relapse/progression of disease after allo-HCT. These might serve as potential biomarkers or therapeutic targets to prevent relapse and improve survival after allo-HCT.

Empiric antibiotic use in allogeneic hematopoietic cell transplantation: should we avoid anaerobe coverage?

“…40,41 Our retrospective observational analysis of 541 patients undergoing allo-HCT at a single center indicates high abundance of a cluster of bacteria dominated by the anaerobe Eubacterium limosum is correlated with less relapse after allo-HCT. 13 Taken together, these findings also support the deliberate choices of antibiotics that protect potentially beneficial anaerobes in allo-HCT patients.…”

“…5 Antibiotics, however, are able to damage the commensal gut microflora to various degrees, depending on the antibiotic class. 6,7 This becomes of increasing interest as recent studies with advanced DNA sequencing techniques of gutresident microorganisms begin to provide detailed relationships between the gut microbiota and clinical outcomes of allo-HCT, including overall survival (OS), 8 transplant-related mortality (TRM), 9 acute GVHD, [8][9][10][11][12] relapse, 13 and development of bacteremia. 14,15 Given the emerging evidence that the preserved diversity of gut microbiota is correlated with better clinical outcomes after allo-HCT, 8,9,12 concerns have been raised regarding the practice of GD for prophylaxis as well as the use of broadspectrum antibiotics for NF that target anaerobic bacteria of the gut (anaerobes).…”

Infection and GVHD

“…A most encouraging observation was the finding that colonization with certain groups of bacteria (Eubacteriaceae) like Enterobacterium limosum is associated with a decreased relapse rate [50]. The antileukemic mechanism is not well understood.…”

“…There are several encouraging new ways to prevent and to treat GVHD including modification of the gut microbiome [30,49,82]; it is now time to select donors according to their immune repertoire and their genetic background for T cell activation. Possibly this can be combined with an anti-leukemic effect based on anti-microbial activity [50,62] and HLA class II DP histocompatibility [83]. The immune repertoire may be primed by prior infections as they may be primed by prior transfusions and pregnancies, but activation may be decisive that is induced by the actual microbiome and determined genetically by the donor and the host.…”

The role of gut microbiota in forming a response to immunotherapy of malignant neoplasms: problem state

“…Во многих работах на мышиных моделях была опре-делена ключевая роль микробиоты кишечника в ответе опухоли на химиотерапию и иммунотерапию check-point-ингибиторами (ингибиторами иммунных «точек контро-ля» или регуляторными молекулами ключевых этапов иммунного ответа) [25,[34][35][36][37][38], что было связано с опухоле специфическими Т-клеточными ответами и нако-плением Т-клеток CD8 + [37,[39][40][41]. Также в некоторых исследованиях было показано, что механизм данного взаимодействия опосредован дендритными клетками, увеличивающими прайминг и накопление CD8+ Т-лимфо-цитов в микроокружении опухоли [37,42].…”