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Enterococcus Induces MHC-II Expression by the Intestinal Epithelium During Murine Graft-versus-host Disease

Researchers at City of Hope and Memorial Sloan Kettering Cancer Center, with collaborators from the University of Chicago, Fred Hutchinson Cancer Center, and Mayo Clinic, have found that intestinal Enterococcus can worsen graft-versus-host disease by inducing MHC class II expression on intestinal epithelial cells, potentially amplifying local antigen presentation and T cell–driven inflammation. Published in Blood in December 2025, the study links Enterococcus outgrowth to higher GVHD mortality in mice and identifies a specific host-microbe interaction where E. faecalis is sufficient to trigger epithelial MHC-II induction in the colon. The main message is that Enterococcus is not just a biomarker of severe GVHD but can actively drive a pathogenic epithelial immune program that contributes to lethal disease. 

Acute GVHD remains a leading cause of nonrelapse mortality after allogeneic hematopoietic cell transplantation, and multiple clinical studies have associated gut microbiome disruption and Enterococcus domination with poor outcomes. However, the mechanism connecting Enterococcus to intestinal injury has been unclear. To address this, the authors used an MHC-disparate murine GVHD model and gnotobiotic mice to isolate the effect of defined microbes on epithelial immune signaling. They measured MHC-II expression on colonic epithelial cells, tested whether monocolonization with E. faecalis was sufficient to reproduce this phenotype, and compared this to other Enterococcus species and a commensal anaerobe consortium. They also profiled immune activation in the colonic lamina propria to identify the inflammatory signals driving epithelial MHC-II induction and evaluated whether restoring colonization resistance against Enterococcus could improve outcomes after transplant. 

Endogenous Enterococcus outgrowth during GVHD was associated with both increased mortality and increased MHC-II expression by colonic epithelial cells. In gnotobiotic mice, monocolonization with E. faecalis alone induced colonic epithelial MHC-II, whereas select other Enterococcus species and a four-member anaerobic commensal consortium including Blautia producta did not. E. faecalis colonization also increased inflammatory responses in colonic lamina propria CD4 T cells and NK cells, identified as key interferon-gamma sources that can drive MHC-II expression in nonprofessional antigen-presenting cells such as epithelium. Therapeutically, introducing a lantibiotic-producing B. producta strain within a commensal consortium after transplant prevented Enterococcus domination and improved GVHD survival. These findings are important because they define a mechanistic Enterococcus–epithelium–MHC-II axis that can be targeted to prevent severe GVHD, supporting rational microbiome-based interventions rather than nonspecific antimicrobial approaches. 

Reference: 

Nguyen C, Funes J, Ghale R, et al. Enterococcus induces MHC-II expression by the intestinal epithelium during murine graft-versus-host disease. Blood. Published online December 29, 2025. http://doi.org/10.1182/blood.2024028248