Barbaloin from <em/> <em>Aloe vera</em> alleviates DSS-induced ulcerative colitis by modulating gut microbiota, serum metabolism and MAPK/NF-&amp;kappa;B signaling pathway

Ulcerative colitis (UC) is a multifactorial, chronic inflammatory bowel disease with complex pathogenesis, posing significant challenges for therapeutic intervention. Barbaloin, a bioactive compound derived primarily from <em>Aloe vera</em>, exhibits diverse pharmacological properties, including anti-inflammation, anticancer, and organ-protective effects. This study comprehensively evaluated the anti-colitis function of barbaloin through <em>in vivo</em> and <em>in vitro</em> models. In the DSS-induced mouse colitis model, the administration of barbaloin significantly ameliorated disease severity, as confirmed by the reduced clinical and pathological damage. Notably, barbaloin restored gut microbiota homeostasis and increased beneficial bacterial genera (<em>Akkermansia</em>, <em>Bacteroides</em>, and <em>Parabacteroides</em>), while inhibiting the pathogenic <em>Escherichia-Shigella</em>. Serum metabolomics revealed changes in key metabolites such as 9-hpode and PE-NMe2 (22:6/14:1), indicating their involvement in lipid metabolism. Network pharmacology discovered that MAPK and NF-κB signaling pathways were potential targets for the action of barbaloin, and molecular docking and dynamics simulation showed that they had stable binding interactions. <em>In vitro</em>, barbaloin suppressed LPS-induced inflammation in RAW264.7 macrophages by inhibiting MAPK/NF-κB activation. Collectively, these findings elucidate a dual mechanism whereby barbaloin ameliorates colitis through microbiota-metabolite reprogramming and suppression of pro-inflammatory signaling, which provides a foundation for its development as a novel UC therapeutic agent.