抗生素诱导的肠道微生物菌群紊乱通过减少短链脂肪酸乙酸盐促进血管钙化。
Antibiotic-induced gut microbiota disruption promotes vascular calcification by reducing short-chain fatty acid acetate.
机构信息
Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
The Second Affiliated Hospital, Department of Urology, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
出版信息
Mol Med. 2024 Aug 24;30(1):130. doi: 10.1186/s10020-024-00900-0.
BACKGROUND
Vascular calcification is a common vascular lesion associated with high morbidity and mortality from cardiovascular events. Antibiotics can disrupt the gut microbiota (GM) and have been shown to exacerbate or attenuate several human diseases. However, whether antibiotic-induced GM disruption affects vascular calcification remains unclear.
METHODS
Antibiotic cocktail (ABX) treatment was utilized to test the potential effects of antibiotics on vascular calcification. The effects of antibiotics on GM and serum short-chain fatty acids (SCFAs) in vascular calcification mice were analyzed using 16 S rRNA gene sequencing and targeted metabolomics, respectively. Further, the effects of acetate, propionate and butyrate on vascular calcification were evaluated. Finally, the potential mechanism by which acetate inhibits osteogenic transformation of VSMCs was explored by proteomics.
RESULTS
ABX and vancomycin exacerbated vascular calcification. 16 S rRNA gene sequencing and targeted metabolomics analyses showed that ABX and vancomycin treatments resulted in decreased abundance of Bacteroidetes in the fecal microbiota of the mice and decreased serum levels of SCFAs. In addition, supplementation with acetate was found to reduce calcium salt deposition in the aorta of mice and inhibit osteogenic transformation in VSMCs. Finally, using proteomics, we found that the inhibition of osteogenic transformation of VSMCs by acetate may be related to glutathione metabolism and ubiquitin-mediated proteolysis. After adding the glutathione inhibitor Buthionine sulfoximine (BSO) and the ubiquitination inhibitor MG132, we found that the inhibitory effect of acetate on VSMC osteogenic differentiation was weakened by the intervention of BSO, but MG132 had no effect.
CONCLUSION
ABX exacerbates vascular calcification, possibly by depleting the abundance of Bacteroidetes and SCFAs in the intestine. Supplementation with acetate has the potential to alleviate vascular calcification, which may be an important target for future treatment of vascular calcification.
背景
血管钙化是一种常见的血管病变，与心血管事件导致的高发病率和死亡率有关。抗生素可以破坏肠道微生物群（GM），并已被证明可加重或减轻几种人类疾病。然而，抗生素诱导的 GM 破坏是否会影响血管钙化仍不清楚。
方法
使用抗生素鸡尾酒（ABX）处理来测试抗生素对血管钙化的潜在影响。通过 16S rRNA 基因测序和靶向代谢组学分别分析抗生素对血管钙化小鼠 GM 和血清短链脂肪酸（SCFA）的影响。此外，评估了乙酸盐、丙酸盐和丁酸盐对血管钙化的影响。最后，通过蛋白质组学探索了乙酸盐抑制血管平滑肌细胞成骨转化的潜在机制。
结果
ABX 和万古霉素加剧了血管钙化。16S rRNA 基因测序和靶向代谢组学分析表明，ABX 和万古霉素处理导致小鼠粪便微生物群中拟杆菌门的丰度降低，血清 SCFA 水平降低。此外，补充乙酸盐可减少小鼠主动脉钙盐沉积，并抑制 VSMC 的成骨转化。最后，通过蛋白质组学发现，乙酸盐抑制 VSMC 成骨转化可能与谷胱甘肽代谢和泛素介导的蛋白水解有关。在用谷胱甘肽抑制剂 Buthionine sulfoximine (BSO) 和泛素化抑制剂 MG132 进行干预后，我们发现 BSO 的干预削弱了乙酸盐对 VSMC 成骨分化的抑制作用，但 MG132 没有影响。
结论
ABX 可加剧血管钙化，可能是通过耗尽肠道中拟杆菌门和 SCFA 的丰度。补充乙酸盐有可能缓解血管钙化，这可能是未来治疗血管钙化的一个重要靶点。
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