Enterococcus induces MHC-II expression by the intestinal epithelium during murine graft-versus-host disease

Intestinal Enterococcus domination has been associated with an increased risk of mortality by acute graft-versus-host disease (GVHD) following allogeneic hematopoietic cell transplantation (allo-HCT), a curative-intent treatment for patients with hematologic malignancies. In this study, we investigate the interactions between Enterococcus and the intestinal epithelium as a mechanism to aggravate GVHD. We observed that endogenous intestinal Enterococcus outgrowth was associated with increased GVHD mortality and major histocompatibility complex class II (MHC-II) expression by intestinal epithelial cells (IECs) in the colon in an MHC-disparate mouse model of GVHD. Monocolonization of non-transplanted gnotobiotic mice with E. faecalis was sufficient to induce colonic MHC-II expression. Conversely, select species within the genus Enterococcus, as well as a consortium of four anaerobic commensal bacteria including Blautia producta, did not affect colonic MHC-II expression in gnotobiotic mice. In addition, E. faecalis colonization also induced inflammatory responses in CD4+ T cells and NK cells from the colonic lamina propria, the two main sources of interferon-gamma production that drives MHC-II expression in non-professional antigen-presenting cells. We further explored the potential therapeutic benefit of establishing colonization resistance against E. faecalis through administration of a lantibiotic-producing B. producta strain after allo-HCT. Colonization of transplanted mice with a consortium of commensal bacteria containing the lantibiotic-producing B. producta strain prevented intestinal Enterococcus domination post-transplant and improved GVHD survival. Our results demonstrate a potential mechanism by which Enterococcus aggravates GVHD through increased MHC-II expression in the intestinal epithelium. Targeting the Enterococcus-epithelium-MHC-II axis thus presents a therapeutic opportunity to prevent lethal GVHD.