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.