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 () and Dongyang Liu ()
Additional contact information
Cheng Cui: Peking University Third Hospital, Drug Clinical Trial Center, Department of Pharmacy
Lu Fang: Peking University, The Institute of Cardiovascular Sciences, the Institute of Systems Biomedicine, School of Basic Medical Sciences, Health Science Center
Lei Li: Peking University, State Key Laboratory of Vascular Homeostasis and Remodeling, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides
Xuan Lai: Peking University Third Hospital, Geriatrics Department
Ruitao Zhang: Peking University, State Key Laboratory of Vascular Homeostasis and Remodeling, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides
Qi Zhang: Peking University, The Institute of Cardiovascular Sciences, the Institute of Systems Biomedicine, School of Basic Medical Sciences, Health Science Center
Rong Miao: Peking University, The Institute of Cardiovascular Sciences, the Institute of Systems Biomedicine, School of Basic Medical Sciences, Health Science Center
Gaofei Hu: Peking University, The Institute of Cardiovascular Sciences, the Institute of Systems Biomedicine, School of Basic Medical Sciences, Health Science Center
Miao Zhang: Peking University Third Hospital, Drug Clinical Trial Center, Department of Pharmacy
Jie En Valerie Sia: Peking University Third Hospital, Drug Clinical Trial Center, Department of Pharmacy
Jingcheng Chen: Peking University Third Hospital, Drug Clinical Trial Center, Department of Pharmacy
Haodi Chai: Peking University Third Hospital, Drug Clinical Trial Center, Department of Pharmacy
Xinyi Wu: Peking University Third Hospital, Drug Clinical Trial Center, Department of Pharmacy
Zijin Lin: Peking University Third Hospital, Drug Clinical Trial Center, Department of Pharmacy
Fan Zhang: Peking University Third Hospital, Geriatrics Department
Haiyan Li: Peking University, State Key Laboratory of Vascular Homeostasis and Remodeling, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides
Lemin Zheng: Peking University, The Institute of Cardiovascular Sciences, the Institute of Systems Biomedicine, School of Basic Medical Sciences, Health Science Center
Dongyang Liu: Peking University Third Hospital, Drug Clinical Trial Center, Department of Pharmacy

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-65692-1

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