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<p>Osteoarthritis (OA) is a heterogeneous whole-joint disorder in which mechanical loading, ageing, obesity, metabolic inflammation and tissue-cell stress interact. Increasing evidence links gut microbiota dysbiosis and cellular senescence to OA, but the strength of this evidence differs across model systems and clinical settings. This review therefore reframes the proposed gut microbiota-cellular senescence-OA axis as an evidence-graded ternary network rather than a single linear pathogenic pathway. Current data support several links: dysbiosis and increased intestinal permeability can promote lipopolysaccharide (LPS)-driven TLR4/NF-κB/NLRP3 activation; inflammatory and metabolic signals can induce senescence-associated secretory phenotype (SASP) programmes in chondrocytes, synoviocytes and subchondral bone cells; and senescent joint cells can amplify matrix degradation through MMP-13, ADAMTS-4 and ADAMTS-5. By contrast, the reverse pathway in which SASP factors directly remodel the intestinal barrier and microbiota in OA remains plausible but incompletely demonstrated. Microbiota-directed approaches, including diet, prebiotics, selected probiotics and fecal microbiota transplantation, and senescence-modulating approaches, including senomorphics and senolytics, should therefore be viewed mainly as preclinical or early translational strategies. We highlight obesity, high-fat diet and ionic or biomechanical stress as contextual modifiers of this network, and propose that longitudinal cohorts, mechanistic animal models and multi-omics validation are needed before precision intervention can be claimed.</p>

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A ternary network model of gut microbiota, cellular senescence and the pathogenesis of osteoarthritis and its intervention strategies

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月3日

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  • Zongyu Liu,
  • Qiong Gao,
  • Guodong Ma,
  • Zongyu Li,
  • Chunbiao Lou,
  • Mingliang Wang,
  • Jie Guo

摘要

Osteoarthritis (OA) is a heterogeneous whole-joint disorder in which mechanical loading, ageing, obesity, metabolic inflammation and tissue-cell stress interact. Increasing evidence links gut microbiota dysbiosis and cellular senescence to OA, but the strength of this evidence differs across model systems and clinical settings. This review therefore reframes the proposed gut microbiota-cellular senescence-OA axis as an evidence-graded ternary network rather than a single linear pathogenic pathway. Current data support several links: dysbiosis and increased intestinal permeability can promote lipopolysaccharide (LPS)-driven TLR4/NF-κB/NLRP3 activation; inflammatory and metabolic signals can induce senescence-associated secretory phenotype (SASP) programmes in chondrocytes, synoviocytes and subchondral bone cells; and senescent joint cells can amplify matrix degradation through MMP-13, ADAMTS-4 and ADAMTS-5. By contrast, the reverse pathway in which SASP factors directly remodel the intestinal barrier and microbiota in OA remains plausible but incompletely demonstrated. Microbiota-directed approaches, including diet, prebiotics, selected probiotics and fecal microbiota transplantation, and senescence-modulating approaches, including senomorphics and senolytics, should therefore be viewed mainly as preclinical or early translational strategies. We highlight obesity, high-fat diet and ionic or biomechanical stress as contextual modifiers of this network, and propose that longitudinal cohorts, mechanistic animal models and multi-omics validation are needed before precision intervention can be claimed.