Cheng Cui, Fang Lü, Lei Li, Xuan Lai, Ruitao Zhang, Qi Zhang, Rong Miao, Gaofei Hu, Miao Zhang, Jie En Valerie Sia, Jingcheng Chen, Haodi Chai, Xinyi Wu, Zijin Lin, Fan Zhang, Haiyan Li, Lemin Zheng, Dongyang Liu
Intestinal P-glycoprotein (P-gp/ABCB1) is a key barrier limiting xenobiotic absorption, yet its functional decline with aging is poorly understood. Here, we show that gut microbiota dysbiosis contributes to age-associated P-gp deficiency. Integrated multi-omics analyses of human cohorts and murine models identify Odoribacter splanchnicus (O. splanchnicus) as a key commensal species whose depletion impairs intestinal P-gp function. Mechanistically, O. splanchnicus encodes GDP-mannose 4, 6-dehydratase (GMDS) and GDP-L-fucose synthase (TSTA3), enabling microbial biosynthesis of GDP-L-fucose. This metabolite directly promotes phosphorylation of the eukaryotic translation initiation factor 4E (eIF4E) and activates c-Jun-driven ABCB1 expression, thereby restoring xenobiotic efflux. These findings establish a microbiota-metabolite-transporter signaling axis that maintains intestinal detoxification, suggesting that targeting either microbes or metabolites could help prevent adverse drug reactions in older adults.