# The gut microbiome in graft-versus-host disease: mechanisms of immune modulation and therapeutic approaches

## TL;DR

This review explores how gut microbes influence graft-versus-host disease and how modifying the microbiome could improve treatment outcomes.

## Contribution

The paper provides a comprehensive overview of the role of gut microbiota in GvHD and evaluates therapeutic strategies based on clinical studies.

## Key findings

- Gut microbiota significantly influences the initiation and progression of GvHD through innate and adaptive immune mechanisms.
- Over 40 clinical studies show that modifying the microbiome can improve GvHD outcomes using approaches like probiotics and fecal microbiota transplantation.
- Commensal microbes in the gut represent a vast and underexplored source of T-cell antigens that impact GvHD.

## Abstract

Graft-versus-host disease (GvHD) remains a major complication of allogeneic hematopoietic stem cell transplantation and occurs when T cells from the donor graft target recipient-derived antigen on host tissue. The involvement of the gastrointestinal (GI) tract drives morbidity and mortality—not coincidentally, the GI tract also harbors the most complex and abundant human microbial reservoir. In this review, we first revisit how the microbiota initiates, propagates, and protects against GvHD in the context of both innate and adaptive immunity. Historically, the impact of the microbiota on GvHD has been ascribed primarily to the activation of innate immunity, setting the stage for donor alloreactivity. Although established models of GvHD focus on donor–host genetic disparity as the principal driver of donor T-cell activation, commensal microbes in the GI tract, whose collective gene content exceeds that of the human genome by more than two orders of magnitude, constitutes an immense and poorly understood source of potential T-cell antigens. We next discuss the evolution of therapeutic approaches aimed at modifying the microbiota to improve GvHD outcomes, incorporating over 40 clinical studies spanning the last 40 years, from broad decontamination strategies to pre/probiotic approaches and targeted ecosystem replacement, including fecal microbiota transplantation.