Intestinal Blautia Is Associated with Reduced Death from Graft-versus-Host Disease

Abstract

The relationship between intestinal microbiota composition and acute graft-versus-host disease (GVHD) after allogeneic blood/marrow transplantation (allo-BMT) is not well understood. Intestinal bacteria have long been thought to contribute to GVHD pathophysiology, but recent animal studies in nontransplant settings have found that anti-inflammatory effects are mediated by certain subpopulations of intestinal commensals. Hypothesizing that a more nuanced relationship may exist between the intestinal bacteria and GVHD, we evaluated the fecal bacterial composition of 64 patients 12 days after BMT. We found that increased bacterial diversity was associated with reduced GVHD-related mortality. Furthermore, harboring increased amounts of bacteria belonging to the genus Blautia was associated with reduced GVHD lethality in this cohort and was confirmed in another independent cohort of 51 patients from the same institution. Blautia abundance was also associated with improved overall survival. We evaluated the abundance of Blautia with respect to clinical factors and found that loss of Blautia was associated with treatment with antibiotics that inhibit anaerobic bacteria and receiving total parenteral nutrition for longer durations. We conclude that increased abundance of commensal bacteria belonging to the Blautia genus is associated with reduced lethal GVHD and improved overall survival.

Keywords: Graft-versus-host disease; Intestinal bacteria.

Figure 1

Changes in the intestinal flora are associated with differences in GVHD-related mortality. A) Bacterial diversity was quantified using the inverse Simpson index following composition analysis of stool samples from Cohort 1 performed by 16S gene sequencing. Patients were stratified by the median diversity index value and analyzed for cumulative incidence of GVHD-related mortality. B) Associations of bacterial genera with GVHD-related mortality outcomes were quantified by LEfSe analysis. Position along the vertical axis indicates statistical significance. C) Patients from Cohorts 1 and 2 were stratified by median Blautia abundance (0.05% in both) and analyzed for incidence of GVHD-related mortality.

Figure 2

A) Association of Blautia abundance and outcomes after allo BMT. Patients from the two flora cohorts were combined and stratified by Blautia abundance below or above 0.05%, and evaluated for the indicated outcomes; similar results were seen for each individual cohort (not shown). B) Blautia abundance (left), survival, and cause of death (right) are indicated for individual patients from two cohorts combined, ranked by Blauita abundance.

Figure 3

Association of Blautia abundance with clinical acute GVHD. A) Patients were stratified by Blautia abundance below or above 0.05%, and evaluated for development of the indicated severity grades of acute GVHD, as well as acute GVHD that required systemic therapy with corticosteroids. B) Patients were evaluated for development of acute GVHD in typical target organs.

Figure 4

Identifying potential determinants of Blautia abundance in allo BMT patients. A) Left: Blautia abundances in all available stool samples from both flora cohorts. An abundance trend was constructed using moving average filtering (solid blue line; 95% confidence intervals shown in gray). Middle and Right: Serial fecal sample composition analysis from two representative patients. Vertical bars indicate composition of fecal microbiota by the indicated taxa. Horizontal bars indicate antibiotic and TPN exposures. Flora composition and time courses of antibiotic and TPN exposure for all patients are shown in Figure S2. Abbreviations: intravenous (IV), oral (PO), piperacillin-tazobactam (pip-tazo), trimethoprim-sulfamethoxazole (tmp-smx), total parenteral nutrition (TPN). B) Patients were subsetted by exposure to antibiotics with anaerobic coverage prior to sample collection, and duration of TPN therapy, and Blautia abundance was evaluated. Horizontal bars indicate median Blautia abundance. C) A subset of patients who were not exposed to antibiotics with anaerobic coverage prior to sample collection were further subsetted by duration of TPN therapy and evaluated for Blautia abundance in a stool sample prior to day 12 and from day 12.