Citrus-Derived Exosome-like Nanoparticles Attenuate High-Fat Diet-Aggravated Colitis by Gut Microbiota-Metabolites Modulation

High-fat diet (HFD) is a recognized risk factor that exacerbates intestinal inflammation and complicates colitis pathology, posing challenges for treatment. This study evaluated citrus-derived exosome-like nanoparticles (CELNs) as a dietary intervention. Results demonstrated that CELNs effectively ameliorated HFD-aggravated colitis, improving the disease activity, colon length, and immune organ index. Mechanistically, CELNs restored gut barrier integrity (upregulating occludin and ZO-1), suppressed oxidative stress and pro-inflammatory signaling, and rebuilt microbial dysbiosis (enriching <i>Faecalibaculum</i> and <i>Bacteroides</i>). Furthermore, CELNs normalized critical metabolic pathways by increasing short-chain fatty acid production, reshaping bile acid profiles (increasing chenodeoxycholic acid and deoxycholic acid content), promoting anti-inflammatory indole derivatives (especially indole acrylic acid), and modulating branched-chain amino acid metabolism. This study highlights CELNs as a potent dietary intervention strategy that rectifies dysbiosis and subsequent metabolic disorders, strengthening the intestinal barrier, and suppressing inflammation. Therefore, CELNs represent a promising novel strategy for treating complex metabolic-inflammatory gut diseases.