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<p>The mechanisms underlying the continuum from asymptomatic intracranial atherosclerotic stenosis (aICAS) to symptomatic intracranial large-artery atherosclerotic ischemic stroke (iLAA-IS) remain unclear. We investigated the gut microbiota-metabolite axis in this transition to identify predictive biomarkers and clarify key functional pathways. In a case-control study (63 iLAA-IS cases; 56 aICAS controls), fecal shotgun metagenomics and untargeted plasma metabolomics were profiled. Using machine learning with 10-fold nested cross-validation, we identified five robust biomarkers associated with the transition: <i>Alistipes putredinis</i> (risk-associated) and four protective features (<i>Segatella copri</i>, Gln-Gly, Methionine Sulfoxide, and N6-Acetyl-L-Lysine). Integrated models incorporating these markers significantly improved predictive performance relative to conventional risk factors (e.g., mean AUC of Gln-Gly: 0.9104 vs. 0.7188). Mechanistic analyses revealed a <i>Segatella copri</i>-centered metabolic dysregulation: its depletion coincided with a broad loss of anabolic pathways (BCAA biosynthesis, folate-SAM-methionine metabolism, and tRNA charging), which were positively linked to amino acid-related metabolites. In contrast, the pathways of <i>Alistipes putredinis</i> showed no such coupling. These findings suggest that the aICAS-to-iLAA-IS transition is characterized by chronic metabolic dysregulation, involving a <i>Segatella copri</i>-centered microbiota-metabolite axis. This multi-omic signature offers novel insights into stroke pathogenesis and potential targets for prevention.</p>

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A Segatella Copri-centered Gut Microbiota-mediated Metabolic Dysregulation Associated with Transition from Asymptomatic to Symptomatic Intracranial Atherosclerosis

  • 期刊论文

  • 发表日期：

    2026年3月28日

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  • Manqi Zheng,
  • Xiao Yang,
  • Ruobing Tian,
  • Xue Xia,
  • Qin Xu,
  • Ying Hui,
  • Shuohua Chen,
  • Yan Liu,
  • Anxin Wang

摘要

The mechanisms underlying the continuum from asymptomatic intracranial atherosclerotic stenosis (aICAS) to symptomatic intracranial large-artery atherosclerotic ischemic stroke (iLAA-IS) remain unclear. We investigated the gut microbiota-metabolite axis in this transition to identify predictive biomarkers and clarify key functional pathways. In a case-control study (63 iLAA-IS cases; 56 aICAS controls), fecal shotgun metagenomics and untargeted plasma metabolomics were profiled. Using machine learning with 10-fold nested cross-validation, we identified five robust biomarkers associated with the transition: Alistipes putredinis (risk-associated) and four protective features (Segatella copri, Gln-Gly, Methionine Sulfoxide, and N6-Acetyl-L-Lysine). Integrated models incorporating these markers significantly improved predictive performance relative to conventional risk factors (e.g., mean AUC of Gln-Gly: 0.9104 vs. 0.7188). Mechanistic analyses revealed a Segatella copri-centered metabolic dysregulation: its depletion coincided with a broad loss of anabolic pathways (BCAA biosynthesis, folate-SAM-methionine metabolism, and tRNA charging), which were positively linked to amino acid-related metabolites. In contrast, the pathways of Alistipes putredinis showed no such coupling. These findings suggest that the aICAS-to-iLAA-IS transition is characterized by chronic metabolic dysregulation, involving a Segatella copri-centered microbiota-metabolite axis. This multi-omic signature offers novel insights into stroke pathogenesis and potential targets for prevention.