Transforming growth factor β-activated kinase 1 as a central integrator of immune-microbiota crosstalk in colitis (Review).

Colitis, particularly ulcerative colitis, involves the convergence of epithelial barrier disruption, innate immune activation and microbiota dysbiosis. Transforming growth factor β-activated kinase 1 (TAK1; also known as MAP3K7) is positioned at this interface because it integrates signals downstream of tumor necrosis factor (TNF) receptors, Toll-like receptors and interleukin (IL)-1 receptors, and activates nuclear factor-κB and mitogen-activated protein kinase pathways, which control cytokine production, epithelial survival and tissue repair. Current evidence supports a cell type- and disease stage-specific model for TAK1 rather than a uniform pro-inflammatory role. In intestinal epithelial cells, TAK1 preserves barrier integrity by limiting TNF receptor 1 (TNFR1)-proximal death signaling mediated by TNFR1-associated death domain protein and receptor-interacting serine/threonine-protein kinase 1, and by supporting repair. In myeloid cells, TAK1 can amplify inflammatory pathways through modulation of the signaling gain of the TAK1/TAK1-binding protein signalosome, ubiquitin modification and scaffold-dependent pathway coupling. Evidence from dendritic cells and adaptive immune circuits further indicates that TAK1 outputs can restrain IL-23 production, promote IL-27/type 1 regulatory T cell-associated barrier protection and maintain immune regulatory capacity. These divergent functions create a therapeutic paradox: Global TAK1 inhibition may suppress inflammatory amplification but may also compromise epithelial survival and barrier maintenance. Future studies should prioritize cell-type-specific TAK1 activity profiling, identifying biomarkers that distinguish inflammatory amplification from repair-competent states, and investigating output-based or compartment-targeted strategies that modulate pathogenic TAK1 signaling while preserving epithelial protection.