Identification of Intestinal Commensal Bacteria Protective Against GVHD in Mice and Humans (2014)

For patients with hematologic malignancies such as leukemias, lymphomas and other related cancers, allogeneic blood/marrow transplantation (allo BMT) is a critically important therapy that can produce cures when chemotherapy alone cannot. More than 25,000 patients undergo allo BMT world-wide each year. A major risk of allo BMT continues to be graft-versus-host disease (GVHD), which results from the donor immune system recognizing the transplant recipient's organs as foreign, leading to life-threatening inflammation. Developing strategies that reduce GVHD but leave global immune function intact should produce a major benefit for patients. One promising approach that we have developed is targeting the complex community of microbes that reside within our intestinal tracts, collectively termed the intestinal microbiota. While a relationship between the microbiota and GVHD has been suspected for many years, it remains imperfectly understood. Gut decontamination with antibiotics is practiced at some but not all centers, and there is no consensus regarding ideal choice of antibiotic coverage. Here we present results demonstrating that the abundance of bacteria belonging to the genus Blautia, a commensal commonly found in the intestinal tract of humans, predicts for protection from life-threatening GVHD in allo BMT patients (Figure 1). Furthermore, in murine models, introducing a species of Blautia of murine origin reduces GVHD severity (Figure 2A). It appears to do so by inducing regulatory T cells with generation of short-chain fatty acid metabolic byproducts (Figures 2B and 2C). Additional studies characterizing the natural history of Blautia abundance in allo BMT recipients demonstrate that the vast majority of patients begin with abundant amounts of endogenous Blautia, but many lose their Blautia in a dramatic fashion during the transplantation process (Figure 3A). Interestingly, loss of Blautia correlates strongly with reductions in oral nutritional intake in both humans and mice (Figures 3B and 3C). Thus development of nutritional intervention strategies to support Blautia abundance following allo BMT could potentially mitigate GVHD. In murine models we have found that these nutritional approaches can successfully prevent loss of Blautia as well as reduce severity GVHD. Our results have identified the microbiota as a potent therapeutic target that can be recruited to significantly reduce GVHD. Approaches to potentially translate these findings include investigating the safety of introduction of Blautia to allo BMT recipients, or alternatively developing nutritional strategies to support endogenous Blautia during the transplantation process.Figure 2Administration of Blautia to mice mitigates GVHD severity. A) B6 mice were treated orally with a 2 day course of vancomycin, a 2 day course of ampicillin, then inoculated 5 and 7 days later with Blautia or Enterococcus of murine origin, and then 2 weeks later irradiated and transplanted with B10.BR bone marrow and T cells. Presented is overall survival, combined results from 2 experiments. B) Mice were treated as in A. Flow cytometric evaluation of T cell populations, results of a single experiment, mice harvested on BMT day 14 n=4/group. C) Mice were treated with antibiotics and bacteria as in A but without BMT, and stool was evaluated for short chain fatty acid content by HPLC two weeks after bacterial introduction.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 3Reduced nutritional intake appears to drive loss of Blautia in allo BMT recipients, A) Ninety-four allo BMT patients were evaluated weekly for changes in the intestinal microbiota during transplant hospitalization. Blautia abundance is depicted by a solid black line with 95% confidence bands shown in gray constructed using moving average filtering. B) Daily nutritional and microbiota analysis was collected in 5 allo BMT patients during transplant hospitalization, and abundance of Blautia analyzed for stool samples stratified by kCal consumption. C) Stool abundance of Clostridials (the order to which Blautia belongs) was assayed in mice before and after one week of 25% reduction m food consumption.View Large Image Figure ViewerDownload Hi-res image Download (PPT)