Chi Thi Nguyen, Jennifer Funes, Romina Ghale, Nathan Nam Minh Duong, Kristen Victor, Brianna Gipson, Zhenrun J. Zhang, Anqi Dai, Rita Li, Gabriel K. Armijo, Ashley S Huang, Miriam Martínez, Yuqing Chen, Daniel Mousa Ghazarian, Melissa D. Docampo, Khyatiben V. Pathak, Patrick Pirrotte, Kate A. Markey, Jonathan U. Peled, Jenny Paredes, Marina Burgos da Silva, Marcel R.M. van den Brink
ABSTRACT: Intestinal Enterococcus domination has been associated with an increased risk of mortality from acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT), a curative-intent treatment for patients with hematologic malignancies. In this study, we investigated 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 in the colon in an MHC-disparate mouse model of GVHD. Monocolonization of nontransplanted gnotobiotic mice with Enterococcus faecalis was sufficient to induce colonic MHC-II expression. Conversely, select species within the genus Enterococcus, as well as a consortium of 4 anaerobic commensal bacteria including Blautia producta, did not affect colonic MHC-II expression in gnotobiotic mice. In addition, E faecalis colonization induced inflammatory responses in CD4+ T cells and natural killer cells from the colonic lamina propria, the 2 main sources of interferon gamma production that drives MHC-II expression in nonprofessional 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 after transplantation 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.