ObjectiveThis paper aims to explore the effects and mechanisms of TAK-242, a specific inhibitor of Toll-like receptor 4 (TLR4), on the intestinal mucosal barrier in mice with ulcerative colitis (UC).MethodsA total of 30 C57BL/6 mice were randomly divided into a normal group (Normal group), a model group (Model group), a low-dose TAK-242 group (TAK-242-L group), a high-dose TAK-242 group (TAK-242-H group), and a 5-aminosalicylic acid group (5-ASA group). The Normal group was fed with normal feed. The Model group was given a 5% sodium dextran sulfate (DSS) solution as drinking water for modeling. The TAK-242-L and TAK-242-H groups were given TAK-242 intervention (3 mg/kg, 10 mg/kg) at the same time of modeling, and intraperitoneally injected once every day. The 5-ASA group was given 5-ASA (500 mg/kg) orally once a day during modeling. Each group was treated continuously for 7 days, and the changes in body mass and disease activity index (DAI) score were observed. After euthanizing the mice on the 8th day, the colon length was measured. H-E staining was used to observe the pathological changes of colon mucosa. ELISA was used to detect the expression levels of TNF-α, IL-1β, and IL-6 in various colon tissues. Western blotting was used to detect the expression levels of tight junction proteins Claudin-1 and ZO-1 in colon tissue, as well as the expression levels of TLR4, MyD88, and NF-κB p65 proteins related to the TLR4 signaling pathway.ResultsCompared with the Normal group, the Model group shows a significantly increase in DAI score, a marked shortening colon length, a significant increase in histological injury score, and significantly elevated expression levels of TNF-α, IL-1β, and IL-6 in colon tissue. Additionally, the expression levels of Claudin-1 and ZO-1 proteins in colon tissue are significantly decreased, while the expression levels of TLR4, MyD88, and NF-κB p65 proteins are significantly increased (P<0.05). Compared with the Model group, the TAK-242-H and 5-ASA groups show significantly reduced DAI scores, increased colon lengths, decreased histological injury scores, and significantly lowered expression levels of TNF-α, IL-1β, and IL-6 in colon tissue. Moreover, the expression levels of Claudin-1 and ZO-1 proteins in colon tissue are significantly increased, whereas the expression levels of TLR4, MyD88, and NF-κB p65 proteins are significantly reduced (P<0.05).ConclusionThe TLR4 inhibitor TAK-242 can alleviate intestinal inflammation and improve intestinal mucosal barrier function in UC by targeting the TLR4/MyD88/NF-κB signaling pathway.