Odoribacter splanchnicus rescues aging-related intestinal P-glycoprotein damage via GDP-L-fucose secretion
- Cheng Cui
- Lu Fang
- 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
2025-11-27
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.