Beyond the Gut: How the Thymus Reshapes the Immune Landscape of Inflammatory Bowel Disease.

Abstract

Inflammatory bowel disease (IBD) comprises a group of chronic inflammatory disorders of the gastrointestinal tract driven by immune dysregulation. In recent years, increasing attention has been directed toward the role of the thymus in the pathogenesis of IBD. However, a comprehensive and systematic review on this topic remains lacking. This article focuses on the immunoregulatory function of the thymus in IBD, emphasizing its pivotal role in maintaining intestinal immune homeostasis through the development and function of regulatory T cells (Tregs). We systematically review the mechanisms by which the thymic microenvironment, transcription factors, signaling pathways, and intercellular interactions regulate Treg homeostasis. Additionally, we propose the concept of the "gut-thymus axis," elucidating how intestinal microbiota dysbiosis can impair thymic structure and function-primarily via TLR signaling pathways-thereby reducing Treg output, establishing a pro-inflammatory positive feedback loop, and exacerbating IBD progression. We further note that although thymus-targeted therapeutic strategies have been extensively explored-including thymectomy, ex vivo expansion and in vivo induction of Tregs, molecular targeting of signaling pathways, and thymic microenvironment remodeling-the translational maturity of these strategies varies considerably. In summary, thymic dysfunction may contribute to the pathogenesis of IBD by disrupting Treg-mediated central immune tolerance; nevertheless, its core pathogenic role in human IBD requires further clinical validation. Future research leveraging emerging technologies such as single-cell omics and organoid models may further elucidate gut-thymus crosstalk mechanisms and offer theoretical foundations and therapeutic targets for precision immunotherapy in IBD.