(A) Effects of conditioning. Conditioning chemotherapy and radiation damage cells in the intestinal epithelium (including IECs, thereby compromising barrier function), intestinal stem cells (impairing epithelial regeneration), Paneth cells (decreasing the antimicrobial peptide [AMPs] production that maintains intestinal bacterial populations), and goblet cells (depleting the mucus barrier separating bacteria from epithelium and immune cells). Coincident with conditioning, patients undergoing HCT typically receive systemic broad-spectrum antibiotics intended to prevent bacterial infections during neutropenia; these also disrupt gut microbiota and reduce bacterial diversity. (B) GvHD pathogenesis. Intestinal dysbiosis arising from antibiotics, altered diet, and tissue damage in HCT recipients may deplete riboflavin metabolites and SCFAs (e.g., butyrate), impairing antiinflammatory MAIT cell activation and Treg stimulation, respectively. Depletion of butyrate, the primary energy source for repair-promoting IECs, may also contribute to epithelial defects, allowing ingress of proinflammatory bacteria and MAMPs. Pattern recognition receptors on immune cells like DCs recognize bacteria and MAMPs, eliciting Th1 and Th17 responses that enhance tissue damage. Reduced bacterial diversity may correlate with reduced bile acid metabolism and increased intestinal bile acids, affecting cell function and viability. Overgrowth of mucin-degrading bacteria (e.g., Akkermansia) in the absence of complex dietary carbohydrates may further deplete the mucus barrier, permitting direct bacterial contact with the epithelial surface, activating immune cells. The net effect constitutes a disruption in the gut barrier with inflammation that may trigger and sustain GvHD. (C) Absence of GvHD. Preservation of the gut microbiota, including bacteria with key metabolic properties (riboflavin metabolism, SCFA production), dampens inflammation via MAIT cells and Tregs. Bacterial butyrate production, normal bile acid metabolism, and the absence of mucin-degrading bacteria facilitate healing of the gut epithelium. An intact barrier discourages bacterial translocation and MAMPs in the mucosa, resulting in reduced inflammation and reduced alloantigen presentation to T cells.