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<p>Vascular calcification (VC) is a major contributor to cardiovascular morbidity and mortality, yet effective therapies are lacking. Here, we show that alternate-day intermittent fasting (IF1:1) attenuates vitamin D-induced VC in mice, whereas a 5:2 regimen is ineffective. The protective effect of IF1:1 is gut microbiota-dependent, particularly through enrichment of <i>Akkermansia muciniphila</i> (<i>Akk</i>). Microbiota-derived extracellular vesicles (EVs) function as nano-scale mediators that bypass the spatiotemporal constraints of bacterial survival to facilitate long-distance communication with host cells, providing a crucial pathway for downstream mechanistic investigation. <i>Akk</i>-derived EVs (<i>Akk</i>-EVs) are internalized by vascular smooth muscle cells (VSMCs), suppressing osteogenic differentiation and calcification in vitro and in vivo. Proteomic analysis identified B2URF3 as a highly enriched functional protein in <i>Akk</i>-EVs and <i>Akk</i>, which interacts with Aldehyde Dehydrogenase 1 Family Member B1 (ALDH1B1) to inhibit VSMC osteogenic transdifferentiation. Clinically, reduced fecal <i>Akk</i> abundance and lower serum B2URF3 levels were observed in patients with coronary calcification. These findings define a gut-vascular axis by which IF1:1 mitigates VC and nominate <i>Akk</i>-EVs and B2URF3 as potential therapeutic targets and biomarkers.</p> Graphical abstract <p></p>

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A novel protein B2URF3 from Akkermansia muciniphila increased by intermittent fasting alleviates vascular calcification

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月7日

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  • Shi-Yu Zeng,
  • Jiang-Hua Liu,
  • Ying-Ying Xiang,
  • Zhao-Lin Zeng,
  • Zhi-Bo Zhao,
  • Jie zheng,
  • Yi-Fu Liu,
  • Zhi-Rou Lin,
  • Yi-Yi Wang,
  • Chun-Gu Hong,
  • Ling Jin,
  • Guo-Qiang Zhu,
  • Yi-Wei Liu,
  • Xin Wang,
  • Xiao-Xue Li,
  • Zhe Guan,
  • Zhen-Xing Wang,
  • Ting Sun,
  • Hui Xie,
  • Jiang-Hua Liu

摘要

Vascular calcification (VC) is a major contributor to cardiovascular morbidity and mortality, yet effective therapies are lacking. Here, we show that alternate-day intermittent fasting (IF1:1) attenuates vitamin D-induced VC in mice, whereas a 5:2 regimen is ineffective. The protective effect of IF1:1 is gut microbiota-dependent, particularly through enrichment of Akkermansia muciniphila (Akk). Microbiota-derived extracellular vesicles (EVs) function as nano-scale mediators that bypass the spatiotemporal constraints of bacterial survival to facilitate long-distance communication with host cells, providing a crucial pathway for downstream mechanistic investigation. Akk-derived EVs (Akk-EVs) are internalized by vascular smooth muscle cells (VSMCs), suppressing osteogenic differentiation and calcification in vitro and in vivo. Proteomic analysis identified B2URF3 as a highly enriched functional protein in Akk-EVs and Akk, which interacts with Aldehyde Dehydrogenase 1 Family Member B1 (ALDH1B1) to inhibit VSMC osteogenic transdifferentiation. Clinically, reduced fecal Akk abundance and lower serum B2URF3 levels were observed in patients with coronary calcification. These findings define a gut-vascular axis by which IF1:1 mitigates VC and nominate Akk-EVs and B2URF3 as potential therapeutic targets and biomarkers.

Graphical abstract