Odoribacter splanchnicus rescues aging-related intestinal P-glycoprotein damage via GDP-L-fucose secretion PMID: 41309616

ADC Targets in Oncology

2026-04-10

Odoribacter splanchnicus rescues aging-related intestinal P-glycoprotein damage via GDP-L-fucose secretion

Nat Commun. 2025 Nov 27;16(1):10665. doi: 10.1038/s41467-025-65692-1.

Cheng Cui ^# ¹ ² , Lu Fang ^# ³ ⁴ ⁵ , Lei Li ^# ⁴ ⁶ ⁷ , Xuan Lai ⁸ , Ruitao Zhang ⁴ ⁶ ⁷ , Qi Zhang ³ ⁴ , Rong Miao ³ ⁴ , Gaofei Hu ³ ⁴ , Miao Zhang ¹ ² , Jie En Valerie Sia ¹ ² , Jingcheng Chen ¹ ² , Haodi Chai ¹ ² , Xinyi Wu ¹ ² , Zijin Lin ¹ ² , Fan Zhang ⁸ , Haiyan Li ⁴ ⁶ ⁷ , Lemin Zheng ⁹ ¹⁰ ¹¹ , Dongyang Liu ¹² ¹³ ¹⁴ ¹⁵

Affiliations

1. Drug Clinical Trial Center, Department of Pharmacy, Peking University Third Hospital, Beijing, China.
2. Center of Clinical Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China.
3. The Institute of Cardiovascular Sciences, the Institute of Systems Biomedicine, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China.
4. State Key Laboratory of Vascular Homeostasis and Remodeling, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing, China.
5. Research Center for Cardiopulmonary Rehabilitation, University of Health and Rehabilitation Sciences Qingdao Hospital (Qingdao Municipal Hospital), School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, China.
6. Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University Third Hospital, Beijing, China.
7. Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China.
8. Geriatrics Department, Peking University Third Hospital, Beijing, China.
9. The Institute of Cardiovascular Sciences, the Institute of Systems Biomedicine, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China. [email protected].
10. State Key Laboratory of Vascular Homeostasis and Remodeling, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing, China. [email protected].
11. Beijing Tiantan Hospital, China National Clinical Research Center for Neurological Diseases, Advanced Innovation Center for Human Brain Protection, The Capital Medical University, Beijing, China. [email protected].
12. Drug Clinical Trial Center, Department of Pharmacy, Peking University Third Hospital, Beijing, China. [email protected].
13. Center of Clinical Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China. [email protected].
14. State Key Laboratory of Vascular Homeostasis and Remodeling, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing, China. [email protected].
15. Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University Third Hospital, Beijing, China. [email protected].
# Contributed equally.

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.