Pharmacological inhibition of toll-like receptor 4 with TLR4-IN-C34 modulates the intestinal flora homeostasis and the MyD88/NF-κB axis in ulcerative colitis

Toll-like receptor 4, a highly conserved protein of innate immunity, is responsible for the regulation and maintenance of homeostasis. It has been implicated in the progression of ulcerative colitis (UC) by interacting with its downstream pathway myeloid differentiation factor 88 (MyD88) and nuclear factor kappa B (NF-κB). This study aimed to evaluate the effect of a specific inhibitor of toll-like receptor 4, TLR4-IN-C34 on gut microbiota to elucidate its mechanism in UC mice. Dextran sulfate sodium significantly induced weight loss, diarrhea and rectal bleeding, and colonic damage in mice, which occurred concomitant with dysbiosis of intestinal flora. Intestinal dysbiosis were partially ameliorated by TLR4-IN-C34. Meanwhile, a reduction in inflammatory cell infiltration, enhanced antioxidant activity in colon tissues, and reconstruction of intestinal barrier were observed in mice administrated with TLR4-IN-C34. MyD88 and NF-κB were significantly reduced after TLR4-IN-C34 treatment. MyD88-/- mice were found with improved dysbiosis of intestinal flora, which was mitigated by overexpression of NF-κB. Collectively, our results suggest that TLR4-IN-C34 alleviates UC in mice by blocking the MyD88/NF-κB pathway to improve intestinal flora dysbiosis, inflammatory infiltration, oxidative stress and intestinal barrier function.