Microbiota-dependent biotransformation of apiin drives butyrate-associated protection against colitis

Dietary glycosides represent an important class of microbiota-responsive food components with potential benefits for intestinal health, yet their biotransformation and functional mechanisms remain incompletely understood. Here, we investigated the protective effects of apiin (apigenin-7-O-apiosylglucoside), a naturally occurring flavone glycoside abundant in plant-based foods, against dextran sulfate sodium (DSS)-induced colitis. We demonstrate that apiin is resistant to host digestion but undergoes efficient microbial deglycosylation in the distal intestine, yielding the bioactive aglycone apigenin. Apiin administration was associated with alleviation of colitis severity, as evidenced by improved clinical and histopathological outcomes, reduced pro-inflammatory cytokine production (TNF-α, IL-1β, IL-6), and restoration of intestinal barrier integrity. Integrative multi-omics analyses revealed that apiin reshaped gut microbiota composition and function, leading to enhanced production of the short-chain fatty acid butyrate. This metabolic shift was associated with G protein-coupled receptors (GPR41 and GPR43) and PPARγ signaling, as well as NF-κB-driven inflammatory responses. Importantly, fecal microbiota transplantation recapitulated the protective effects of apiin, confirming a microbiota-dependent mechanism. Collectively, our findings identify apiin as a microbiota-dependent pro-flavonoid whose colonic biotransformation into apigenin and butyrate-associated signaling may contribute to its anti-inflammatory activity.