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<p>Gut microbiota has been implicated in atherosclerosis and plaque destabilization. However, the relationship between microbiota composition and plaque vulnerability remains incompletely understood. This study tested whether fecal microbiota from patients with acute coronary syndrome (ACS) versus chronic coronary syndrome (CCS) differentially associates with atherosclerotic plaque phenotype in a fecal microbiota transplantation (FMT) model. Female ApoE⁻/⁻ mice underwent antibiotic-mediated microbiota depletion followed by repeated FMT from ACS (<i>n</i> = 9) or CCS (<i>n</i> = 11) donors. Mice were fed a standard diet or a 1% choline-enriched diet for 12 weeks. Atherosclerosis burden and plaque vulnerability were assessed by Oil Red O morphometry (necrotic core area, fibrous cap thickness, cap-to-core ratio) and immunostaining (including MMP2). Serum trimethylamine N-oxide (TMAO) levels were quantified by UPLC–MS/MS, and fecal microbiota composition was analyzed by 16&#xa0;S rRNA gene sequencing at study end. Choline supplementation increased circulating TMAO levels in all experimental groups. However, TMAO concentrations did not differ between ACS- and CCS-FMT recipient mice and did not correlate with lesion size or plaque vulnerability parameters. Despite comparable TMAO levels, choline-fed ACS-FMT recipient mice developed a more vulnerable plaque phenotype than CCS-FMT recipients, characterized by larger necrotic cores, thinner fibrous caps, a reduced cap-to-core ratio, increased intraplaque MMP2 expression, and elevated pro-inflammatory cytokines and chemokines. In addition, 16&#xa0;S rRNA gene sequencing identified distinct microbial taxa associated with plaque vulnerability–related features. In this ApoE⁻/⁻ FMT model, donor coronary syndrome status is associated with differential plaque vulnerability features and distinct gut microbiota signatures, independently of circulating TMAO levels.</p>

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Human gut microbiota from acute coronary syndrome patients promotes plaque vulnerability in a mouse model of atherosclerosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月7日

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  • Riccardo Nieri,
  • Anna Severino,
  • Eleonora Foglio,
  • Flavio De Maio,
  • Daniele Santoni,
  • Maria Luisa Savo Sardaro,
  • Giovanni Fancello,
  • Luca Masucci,
  • Alessia D’Aiello,
  • Sofia Morini,
  • Dalila Tarquini,
  • Jacopo Gervasoni,
  • Lavinia Santucci,
  • Omar Leoni,
  • Caterina Mammi,
  • Daniela Pedicino,
  • Antonella Mangoni,
  • Katherine Ryan Amato,
  • Matteo Antonio Russo,
  • Filippo Crea,
  • Giovanna Liuzzo,
  • Federica Limana

摘要

Gut microbiota has been implicated in atherosclerosis and plaque destabilization. However, the relationship between microbiota composition and plaque vulnerability remains incompletely understood. This study tested whether fecal microbiota from patients with acute coronary syndrome (ACS) versus chronic coronary syndrome (CCS) differentially associates with atherosclerotic plaque phenotype in a fecal microbiota transplantation (FMT) model. Female ApoE⁻/⁻ mice underwent antibiotic-mediated microbiota depletion followed by repeated FMT from ACS (n = 9) or CCS (n = 11) donors. Mice were fed a standard diet or a 1% choline-enriched diet for 12 weeks. Atherosclerosis burden and plaque vulnerability were assessed by Oil Red O morphometry (necrotic core area, fibrous cap thickness, cap-to-core ratio) and immunostaining (including MMP2). Serum trimethylamine N-oxide (TMAO) levels were quantified by UPLC–MS/MS, and fecal microbiota composition was analyzed by 16 S rRNA gene sequencing at study end. Choline supplementation increased circulating TMAO levels in all experimental groups. However, TMAO concentrations did not differ between ACS- and CCS-FMT recipient mice and did not correlate with lesion size or plaque vulnerability parameters. Despite comparable TMAO levels, choline-fed ACS-FMT recipient mice developed a more vulnerable plaque phenotype than CCS-FMT recipients, characterized by larger necrotic cores, thinner fibrous caps, a reduced cap-to-core ratio, increased intraplaque MMP2 expression, and elevated pro-inflammatory cytokines and chemokines. In addition, 16 S rRNA gene sequencing identified distinct microbial taxa associated with plaque vulnerability–related features. In this ApoE⁻/⁻ FMT model, donor coronary syndrome status is associated with differential plaque vulnerability features and distinct gut microbiota signatures, independently of circulating TMAO levels.