The cross talk of the microbiome and the intestinal immune system in acute GVHD. Under physiologic conditions, the intestinal epithelial cell (IEC) surface maintains an intact barrier that prevents bacterial translocation into host tissue. In addition, Paneth cells produce antimicrobial proteins (AMPs), such as α-defensins and regenerating islet-derived 3α (REG-3α), that further protect against pathogenic organisms and provide trophic signals to intestinal stem cells (ISC). Goblet cells secrete mucus that solidifies the barrier separating the microbiota and host tissues. In allo-SCT, a conditioning regimen often consisting of chemotherapy, with or without total body irradiation (TBI), interrupts the integrity of the intestinal barrier bacterial translocation into host tissue. This leads to neutrophil infiltration into the small intestine producing reactive oxygen species that further contribute to the barrier damage. Bacterial translocation also leads to monocyte activation that mediates T helper 17 cell (Th17) differentiation, which, in turn, leads to macrophage and neutrophil accumulation into the inflammatory sites, as well as dendritic cell (DC) activation that leads to alloreactive cytotoxic T-cell homing. Microbiota-derived short-chain fatty acids (SCFAs) serve as an energy source for IECs and play a protective role in GVHD by inducing regulatory T cells (Treg) that secrete the anti-inflammatory cytokines transforming growth factor-β (TGF-β) and interleukin-10 (IL-10), as well as group 3 innate lymphoid cells (ILC3) that secrete interleukin-22 (IL-22) and, again, mediate anti-inflammatory effects. Th1, T helper 1 cell; Th2, T helper 2 cell.