The bidirectional Thymus-Gut Axis: redefining central tolerance in digestive autoimmunity

Digestive autoimmune diseases impose an escalating global burden, largely because current therapies predominantly target downstream inflammation rather than primordial defects in immune tolerance. The thymus establishes central tolerance through stringent T cell selection and thymus-derived regulatory T cell (tTreg) generation. This review proposes the Thymus-Gut Axis as a working conceptual framework for a dynamic, bidirectional communication network, departing from the traditional unidirectional thymocentric model, while explicitly acknowledging that much of the supporting evidence remains indirect, model-dependent, or derived from broader thymus-microbiota studies rather than from human digestive autoimmunity. We elucidate how thymic dysfunction-driven by defective negative selection, impaired tTreg generation, and AIRE/FEZF2-mediated antigen presentation defects-precipitates the escape of autoreactive clones that drive specific digestive autoimmunity. Conversely, we highlight the hypothetical retrograde signaling arm, wherein gut-derived microbial metabolites, inflammatory cytokines, and migratory dendritic cells have been shown, primarily in murine models, to modulate the thymic microenvironment. However, direct validation in human digestive autoimmunity is currently lacking, and the translational relevance of these findings remains uncertain. Furthermore, sex steroids and early-life microbiota critically program central tolerance, shaping sex-biased susceptibility and lifelong immune homeostasis. Translating these mechanistic insights, we evaluate thymectomy as a clinical model, emerging thymic rejuvenation strategies, and antigen-specific therapeutic Treg therapies. Ultimately, we emphasize the urgent need for human thymic profiling and longitudinal clinical studies integrating systemic thymic output biomarkers with mucosal immune phenotyping to bridge translational gaps and explore speculative but mechanistically rational therapeutic strategies.