Bidirectional Interactions

ABSTRACT: Chronic graft-versus-host disease (cGVHD) of the skin represents a complex immunopathologic process triggered by donor-derived immune cells following allogeneic hematopoietic stem cell transplantation (HSCT). While traditionally understood through the lens of alloimmune activation and fibrotic remodeling, emerging evidence highlights the role of microbial dysbiosis-particularly in the skin microbiome-as both a contributor to and a consequence of disease progression. This review explores the evolving understanding of the microbiome-immune interface in cutaneous GVHD, focusing on how shifts in microbial composition, such as the loss of Staphylococcus epidermidis and the overgrowth of S. aureus, may impair barrier function, promote local immune activation, and potentiate systemic inflammation. Disruption of commensal-derived signals leads to reduced antimicrobial peptide production, diminished regulatory T cell activity, and proinflammatory T cell polarization, all of which contribute to immune-mediated skin damage. A self-reinforcing cycle of barrier dysfunction and microbial imbalance emerges, suggesting new avenues for intervention. We discuss microbiome-targeted therapies including donor-derived skin allografting as potential strategies to restore microbial equilibrium and mitigate inflammation. Additionally, we highlight the diagnostic potential of skin microbiome profiling as a biomarker for disease activity and treatment response. Understanding the bidirectional interactions between the microbiome and immune system may offer novel therapeutic and prognostic tools for managing cutaneous cGVHD.