Luteolin ameliorates Escherichia coli-induced intestinal injury by modulating gut microbiota, metabolites and the TLR4/MyD88/NF-kB signaling pathway

Luteolin, a naturally occurring flavonoid abundantly found in various fruits and vegetables, possesses anti-inflammatory and antioxidant properties. Its biological activities, including modulating immune responses and alleviating oxidative stress, make it a promising therapeutic candidate for inflammatory diseases. However, the precise role of this compound in mitigating Escherichia coli induced ( E. coli -induced) intestinal inflammation remains largely unexplored. More specifically, the mechanistic underpinnings by which it preserves intestinal mucosal barrier integrity, fine-tunes the activation dynamics of key mediators in intestinal inflammatory signaling cascades, and orchestrates the intricate crosstalk between intestinal microbiota homeostasis and host immune responses remain poorly elucidated. In this study, a total of 144 three-week-old specific pathogen-free (SPF) chickens were randomly divided into groups. An E. coli -induced enteritis model was subsequently established in these animals. Luteolin was administered at varying doses through the feed for a period of one week. The potential protective effects of luteolin against E. coli -induced intestinal damage were investigated from multiple aspects, including intestinal barriers function, gut microbiota composition, and differential metabolites profiles. Luteolin alleviated intestinal damage, enhanced survival rate and weight gain in chicken ( P <0.05) and improved antioxidant capacity by reducing oxidative stress ( P <0.05). It repaired intestinal barrier injury by upregulating the mRNA levels of tight junction proteins, and reduced intestinal inflammation by inhibiting the activation of the Toll-like receptor 4 nuclear (TLR4)/Myeloid Differentiation Primary Response Protein 88 (MyD88)/factor-κB (NF-κB) signaling pathway ( P <0.05). In addition, luteolin reversed E. coli -induced gut microbiota dysbiosis, increasing the abundance of beneficial microorganisms such as Lachnospiraceae-Clostridium and Butyricimonas. Metabolomics analysis further revealed that luteolin partially corrected E. coli -induced metabolic disorders by modulating nucleotide metabolism (IMP, P <0.05), amino acid biosynthesis(arginine ornithine and lysine, P <0.05), and glutathione metabolism (S - lactoyl glutathione, P <0.05). Notably, a significant association was observed between gut microbiota and metabolic products ( P <0.05). In summary, luteolin alleviates E. coli -induced enteritis in chickens via a multi-target mode of action that entails preserving gut microbiota homeostasis, restoring intestinal metabolic signatures, and suppressing the TLR4/MyD88/NF-κB signaling cascade, which offers new perspectives for avian disease management and highlights its prospects as a safe antibiotic substitute.