Butyrate in the epigenetic regulation of regulatory T cells: linking the microbiome–immune axis to gastrointestinal acute graft-versus-host disease

Gastrointestinal acute graft-versus-host disease (GI-aGVHD) is an immune-microbiome condition that arises from gut microbiome (GM) dysbiosis and dysregulation of peripheral immune tolerance, primarily mediated by regulatory T (Treg) cells. Butyrate plays a crucial role in bridging the two systems. Numerous studies provide proof of concept for butyrate’s roles in Treg cell development, frequency, functional state, and stability, mediated either directly through interaction with Treg cells or indirectly by regulating intestinal or other immune cells. This hypothesis review highlights the butyrate-Treg axis as a gut-specific tolerance mediator, focusing on epigenetic mechanisms, especially histone deacetylase (HDAC) inhibitory effects, current clinical and preclinical evidence, and strategies to optimize this axis for clinical application. Finally, person-specific butyrate profiles may potentially inform the development of future personalized and precision Treg therapeutic interventions in GI-aGVHD management. Gut microbiome (GM) dysbiosis is a key trigger for the onset of gastrointestinal acute graft-versus-host disease (GI-aGVHD). Regulatory T (Treg) cells are the central orchestrators of immune tolerance, which is compromised in GI-aGVHD. Butyrate, as an immunomodulatory microbiome-derived metabolite, constitutes a bridge between the microbiome and the immune system. Butyrate triggers Treg cells' development and functional enhancement through an inhibitory effect on histone deacetylase (HDAC). First, Gut-specific tolerance is connected to microbiome diversity. Second, changes in microbiome diversity alter levels of microbiome-derived immunomodulatory metabolites (IMMs), especially butyrate. Third, butyrate changes vary by individual. Fourth, personalized variability determines immune tolerance after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Finally, focusing on the microbiome-immune axis may be a precise and effective strategy in the GI-aGVHD context. Utilizing Treg cell-based immunotherapy potentially prevents GI-aGVHD Butyrate supplementation is associated with optimal outcomes in allo-HSCT patients Better immune tolerance accompanied by better GI-aGVHD management How can we optimize the butyrate-Treg axis for GI-aGVHD management? How does this immunometabolism pathway link to precision and personalized medicine?