Chicory Sesquiterpene Lactones Trained Faeces-derived Extracellular Vesicles Alleviated Ulcerative Colitis by Modulating Gut Microbiota and Bile Acids Metabolism

<p class="0000" style="margin-top: 6.0pt;"><span lang="EN-US">The gut microbiota communicates with the host via extracellular vesicles (EVs), offering a promising therapeutic target for ulcerative colitis (UC). This study investigates the therapeutic potential of sesquiterpene lactones (SL) from chicory and the EVs derived from the faeces of SL-treated mice (SL-trained FEVs) in a dextran sulfate sodium (DSS)-induced UC model. Oral administration of SL significantly ameliorated colitis symptoms, reduced intestinal inflammation, preserved intestinal barrier integrity by maintaining tight junction proteins, and attenuated colonic tissue damage. These protective effects were mechanistically linked to the attenuation of gut microbiota dysbiosis and the restoration of bile acid metabolism homeostasis. Notably, gavage of SL-trained FEVs recapitulated the therapeutic benefits of direct SL treatment, demonstrating the critical role of microbiota-derived EVs in mediating SL's effects. Profiling revealed that SL treatment enriched specific microRNAs (e.g., miR-26a-5p, miR-200b-3p, and miR-194-5p) within these FEVs. Both SL and SL-trained FEVs induced comparable and significant shifts in the gut microbiota composition, notably modulating the relative abundance of genera including <em>Odoribacter</em>, <em>Oscillibacter</em>, <em>Escherichia-Shigella</em>, <em>g-Clostridia_UCG-014_unclassified</em>, and phyla such as p-Actinobacteriota and p-Patescibacteria. Concomitantly, both interventions significantly altered key bile acid profiles, affecting levels of taurocholic acid (TCA), lithocholic acid (LCA), nor-deoxycholic acid (NorDCA), and taurochenodeoxycholic acid (TCDCA). In conclusion, our findings highlight SL and SL-trained FEVs as promising agents for UC treatment, acting through the coordinated modulation of the gut microbiota-bile acid axis, and propose FEVs as a novel, targeted delivery system for microbiota-based therapeutics.</span>