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<p>Intestinal P-glycoprotein (P-gp/<i>ABCB1</i>) 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 <i>Odoribacter splanchnicus</i> (<i>O. splanchnicus</i>) as a key commensal species whose depletion impairs intestinal P-gp function. Mechanistically, <i>O. splanchnicus</i> 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 <i>ABCB1</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月27日

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  • 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

摘要

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.