Fisetin modulates the gut microbiota alongside biomarkers of senescence and inflammation in a DSS-induced murine model of colitis

非西汀 某种肠道细菌 阿克曼西亚 炎症 结肠炎 衰老 失调 肠道菌群 CXCL1型 免疫学 医学 药理学 生物 趋化因子 内科学 生物化学 抗氧化剂 乳酸菌 槲皮素 发酵
作者
Sarah Ashiqueali,Diptaraj Chaudhari,Xiang Zhu,Sarah Noureddine,Sarah Siddiqi,Driele N. Garcia,Aleksandra Gostyńska,Maciej Stawny,Błażej Rubiś,Bianka M. Zanini,Mishfak A. M. Mansoor,Augusto Schneider,Saleh A. Naser,Hariom Yadav,Michał M. Masternak
出处
期刊:GeroScience [Springer Nature]
卷期号:46 (3): 3085-3103 被引量:7
标识
DOI:10.1007/s11357-024-01060-z
摘要

Colitis, a subtype of inflammatory bowel disease (IBD), is a multifactorial disorder characterized by chronic inflammation of the colon. Among various experimental models used in the study of IBD, the chemical colitogenic dextran sulfate sodium (DSS) is most commonly employed to induce colitis in vivo. In the search for new therapeutic strategies, Fisetin, a flavonoid found in many fruits and vegetables, has recently garnered attention for its senolytic properties. Female mice were administered 2.5% DSS in sterile drinking water and were subsequently treated with Fisetin or vehicle by oral gavage. DSS significantly upregulated beta-galactosidase activity in colonic proteins, while Fisetin remarkably inhibited its activity to baseline levels. Particularly, qPCR revealed that the senescence and inflammation markers Vimentin and Ptgs2 were elevated by DSS exposure with Fisetin treatment inhibiting the expression of p53, Bcl2, Cxcl1, and Mcp1, indicating that the treatment reduced senescent cell burden in the DSS targeted intestine. Alongside, senescence and inflammation associated miRNAs miR-149-5p, miR-96-5p, miR-34a-5p, and miR-30e-5p were significantly inhibited by DSS exposure and restored by Fisetin treatment, revealing novel targets for the treatment of IBDs. Metagenomics was implemented to assess impacts on the microbiota, with DSS increasing the prevalence of bacteria in the phyla Bacteroidetes. Meanwhile, Fisetin restored gut health through increased abundance of Akkermansia muciniphila, which is negatively correlated with senescence and inflammation. Our study suggests that Fisetin mitigates DSS-induced colitis by targeting senescence and inflammation and restoring beneficial bacteria in the gut indicating its potential as a therapeutic intervention for IBDs.
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