Fisetin alleviates Salmonella typhimurium-induced colitis through the TLR2/TLR4-NF-κB pathway, regulating microbiota, and repressing intracellular bacterial proliferation by focal adhesion kinase

Abstract

Background: Salmonella typhimurium is a pathogen responsible for millions of cases of gastroenteritis in both humans and animals. This study aimed to evaluate the hypothesis that fisetin administration could mitigate colon damage and regulate the intestinal microbiota in mice treated with Salmonella typhimurium.

Methods: Six-week-old male mice were orally administered with or without 100 mg/kg fisetin and infected with Salmonella typhimurium.

Results: Fisetin administration ameliorated Salmonella typhimurium-induced colitis as shown by the decreased body weight loss, lowered disease activity index score, reduced colon shortening, inflammatory infiltration, and apoptosis. Meanwhile, Salmonella typhimurium exposure upregulated colonic Tnf-α, Il-6, Il-1β, Ifn-β, Ccl2, Ccl8 relative expression and MDA and H₂O₂ concentrations, whereas lowered Il-10, Nrf2, Nqo1, Coq10b, and Gss abundance, all of which were ameliorated by fisetin treatment. Moreover, fisetin recovered the occludin, zonula occludens-1, and zonula occludens-2 protein abundance in response to Salmonella typhimurium administration. Further investigation demonstrated that the protective role of fisetin was related to the inactivation of the TLR2/TLR4-NF-κB pathway, upregulation of Lactobacillus, and reduction of Salmonella abundance. Additionally, fisetin could limit the intracellular Salmonella typhimurium proliferation, which was likely to be attributed to the inhibition of focal adhesion kinase.

Conclusion: Together, our study elucidated the therapeutic potential of fisetin in ameliorating key aspects of colitis, including intestinal inflammation, oxidative stress, and barrier dysfunction, and these beneficial effects were mediated through the inactivation of the TLR2/TLR4-NF-κB pathway, the regulation of microbiota, and restricting the intracellular proliferation of Salmonella typhimurium by inhibiting focal adhesion kinase.

Keywords: Salmonella; Bacterial load; Fisetin; Inflammation; Intestinal tight junction.