Wang Chunli, Liu Zongtao, Zhou Tingwen, Wu Jiaqin, Feng Fan, Wang Shunshun, Chi Qingjia, Sha Yongqiang, Zha Shuai, Shu Songren, Qu Linghang, Du Qianqian, Yu Huiming, Yang Li, Malashicheva Anna, Dong Nianguo, Xie Fei, Wang Guixue, Xu Kang
Hubei Shizhen Laboratory Wuhan China.
School of Laboratory Medicine Hubei University of Chinese Medicine Wuhan China.
Imeta. 2025 May 19;4(4):e70048. doi: 10.1002/imt2.70048. eCollection 2025 Aug.
The involvement of gut microbiota in calcific aortic valve disease (CAVD) pathogenesis remains underexplored. Here, we provide evidence for a strong association between the gut microbiota and CAVD development. ApoE mice were stratified into easy- and difficult- to calcify groups using neural network and cluster analyses, and subsequent faecal transplantation and dirty cage sharing experiments demonstrated that the microbiota from difficult-to-calcify mice significantly ameliorated CAVD. 16S rRNA sequencing revealed that reduced abundance of () was significantly associated with increased calcification severity. Association analysis identified -derived butyric acid as a key anti-calcific metabolite. These findings were validated in a clinical cohort (25 CAVD patients vs. 25 controls), where serum butyric acid levels inversely correlated with disease severity. Functional experiments showed that butyric acid effectively hindered osteogenic differentiation in human aortic valve interstitial cells (hVICs) and attenuated CAVD progression in mice. Isotope labeling and C flux analyses confirmed that butyric acid produced in the intestine can reach heart tissue, where it reshapes glycolysis by specifically modifying GAPDH. Mechanistically, butyric acid-induced butyrylation (Kbu) at lysine 263 of GAPDH competitively inhibited lactylation (Kla) at the same site, thereby counteracting glycolysis-driven calcification. These findings uncover a novel mechanism through which and its metabolite butyric acid contribute to the preservation of valve function in CAVD, highlighting the gut microbiota-metabolite-glycolysis axis as a promising therapeutic target.
肠道微生物群在钙化性主动脉瓣疾病（CAVD）发病机制中的作用仍未得到充分研究。在此，我们提供证据表明肠道微生物群与CAVD发展之间存在密切关联。使用神经网络和聚类分析将载脂蛋白E（ApoE）小鼠分为易钙化组和难钙化组，随后的粪便移植和脏笼共享实验表明，来自难钙化小鼠的微生物群显著改善了CAVD。16S rRNA测序显示，（）丰度降低与钙化严重程度增加显著相关。关联分析确定源自（）的丁酸是一种关键的抗钙化代谢物。这些发现在一个临床队列（25例CAVD患者与25例对照）中得到验证，其中血清丁酸水平与疾病严重程度呈负相关。功能实验表明，丁酸有效地阻碍了人主动脉瓣间质细胞（hVICs）的成骨分化，并减轻了小鼠CAVD的进展。同位素标记和C通量分析证实，肠道中产生的丁酸可以到达心脏组织，在那里它通过特异性修饰甘油醛-3-磷酸脱氢酶（GAPDH）重塑糖酵解。从机制上讲，丁酸诱导的GAPDH赖氨酸263位点的丁酰化（Kbu）竞争性抑制了同一位点的乳酰化（Kla），从而抵消了糖酵解驱动的钙化。这些发现揭示了一种新机制，通过该机制（）及其代谢物丁酸有助于在CAVD中维持瓣膜功能，突出了肠道微生物群-代谢物-糖酵解轴作为一个有前景的治疗靶点。
