Odoribacter splanchnicus rescues aging-related intestinal P-glycoprotein damage via GDP-L-fucose secretion
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.
Authors
- Fan Zhang (ORCID: https://orcid.org/0000-0002-0186-3137)
- Xuan Lai
- Xinyi Wu
- Zijin Lin (ORCID: https://orcid.org/0000-0002-6706-5410)
- Qi Zhang (ORCID: https://orcid.org/0000-0002-4746-3542)
- Jie En Valerie Sia (ORCID: https://orcid.org/0000-0001-8342-7277)
- Haiyan Li (ORCID: https://orcid.org/0000-0002-8286-2813)
- Miao Zhang (ORCID: https://orcid.org/0000-0002-3242-5957)
- Lei Li (ORCID: https://orcid.org/0000-0001-5478-5681)
- Rong Miao (ORCID: https://orcid.org/0000-0002-9603-8905)
- Dongyang Liu (ORCID: https://orcid.org/0000-0002-0608-8192)
- Jingcheng Chen (ORCID: https://orcid.org/0000-0002-1199-9599)
- Cheng Cui (ORCID: https://orcid.org/0000-0001-6446-0127)
- Lemin Zheng (ORCID: https://orcid.org/0000-0003-4473-6936)
- Ruitao Zhang (ORCID: https://orcid.org/0009-0005-2982-362X)
- Fang Lü (ORCID: https://orcid.org/0000-0001-6112-7214)
- Huifang Chai
Institutions
- Qingdao University (CN)
- Capital Medical University (CN)
- Peking University (CN)
- National Clinical Research Center for Digestive Diseases (CN)
- Affiliated Hospital of Qingdao University (CN)
- Qingdao Municipal Hospital (CN)
- Peking University Third Hospital (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-27
- DOI
- https://doi.org/10.1038/s41467-025-65692-1
- Citations
- 1
- Primary Topic
- Drug Transport and Resistance Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 1.05
Funders
- Bill and Melinda Gates Foundation
- National Natural Science Foundation of China
- National High-tech Research and Development Program