Naringenin Alleviates 5-Fluorouracil-Induced Intestinal Mucositis via Modulating the Gut Microbiota, Bile Acid Metabolism, and PPAR Signaling Pathway

Naringenin (Nar), a dihydroflavonoid compound present in citrus fruits, exhibited protective effects on digestive diseases. This study explored its effects on 5-fluorouracil-induced intestinal mucositis (IM) in mice by multiomics analysis. Nar mitigated weight loss, diarrhea, inflammatory response, and intestinal barrier damage of IM mice largely via gut microecology-dependent mechanism. 16S rRNA sequencing revealed that Nar regulated intestinal flora related to inflammation and bile acid metabolism, including <i>Parabacteroides</i>, Actinobacteria, Muribaculaceae, <i>Ruminiclostridium</i>, <i>Clostridium</i>, and Proteobacteria. Targeted bile acid metabolomics indicated that Nar regulated abnormal secondary bile acids (hyodeoxycholic acid, deoxycholic acid, and isochenodeoxycholic acid). Furthermore, transcriptomic and Western blot analysis manifested that Nar upregulated the expression levels of peroxisome proliferator-activated receptor γ, stearoyl CoA desaturase 1, and phosphoenolpyruvate carboxykinase 1, which manifested its action mechanism related to the activation of the PPAR signaling pathway. These findings demonstrated the multipathway-mediated anti-IM effects of Nar, which indicate its promising potential as an adjunctive treatment strategy for chemotherapy-induced intestinal toxicity in cancer patients.