Intestinal Enterococcus is a major risk factor for the development of acute Gvhd

ASH: 60th American Society of Hematology Annual Meeting & ExpositionCK Stein-Thoeringer, JU Peled, ALC Gomes, A Lazrak, MD Docampo, AE Slingerland, K Nichols, Y Shono, D Weber, AD Sung, D Hashimoto, J Cross, T Teshima, E Holler, NJ Chao, EG Pamer, MRM van den Brink | December 02, 2018

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Summary: In this study, researchers explored the hypothesis that Enterococcus can trigger the development of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT) in allo-HCT patients and in pre-clinical mouse transplant models. They concluded that an abundance of Enterococcus in the intestinal flora plays a role in the development of GVHD, and that the prevention of Enterococcus growth with a lactose-free diet may ameliorate GVHD.

Methods:

  • Researchers collected stool samples from 1,240 allo-HCT patients at four different transplant centers in the US, Germany, and Japan weekly during inpatient hospitalization.
  • They sequenced the V4-V5 region of the bacterial 16S rRNA genes from 6,718 samples at a central site on the Illumina platform.

Results:

  • In patients from the differing centers, researchers observed Enterococcus mono-domination (relative abundance > 30%) in post-transplant samples that ranged from 20% to 60%, which was primarily attributable to E. faecium and associated with a significantly increased risk for grade 2-4 acute GVHD.
  • In three different mouse models, they observed a transient bloom of E. faecalis around 7 days after transplant in allo-HCT recipients with GVHD (C57BL/6 -> 129SV model), which did not occur in allo-HCT recipients of a T-cell depleted allograft without GVHD.
  • To further investigate this Enterococcus bloom, researchers treated mice with an experimental E. faecalis-strain on days 4 to 6 after transplant; they found significantly increased lethal GVHD.
  • In addition, they observed that colonizing germ-free mice with a minimal gut flora also caused increased lethal GVHD when enterococci were added to the gnotobiotic flora.
  • The allo-HCT recipients with Enterococcus-containing flora had also increased serum IFNg levels.
  • In BMT mouse models, Enterococcus-dominated allo-HCT recipients with GVHD have significantly less cecal butyrate, a major short-chain fatty acid (SCFA); further, Enterococcus domination after allo-HCT ledto a decrease in fecal SCFAs in patients.
  • To test whether intestinal IgA may play protective role against this pathogen in mice, researchers found that 16S sequencing of flow sorted IgA-coated vs non-coated bacteria from fecal samples of allo-HCT patients and transplanted mice showed no specific IgA-coating pattern of enterococci both before or after transplant.
  • In mice, they found that a lactose-free diet significantly decreases the Enterococcus bloom after transplant in allo-T cell recipients and in first survival experiments attenuates lethal GVHD.

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