Gut microbiota‐derived butyric acid regulates calcific aortic valve disease pathogenesis by modulating GAPDH lactylation and butyrylation
Abstract 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 ne...
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Wiley
2025-08-01
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| Online Access: | https://doi.org/10.1002/imt2.70048 |
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| author | Chunli Wang Zongtao Liu Tingwen Zhou Jiaqin Wu Fan Feng Shunshun Wang Qingjia Chi Yongqiang Sha Shuai Zha Songren Shu Linghang Qu Qianqian Du Huiming Yu Li Yang Anna Malashicheva Nianguo Dong Fei Xie Guixue Wang Kang Xu |
| author_facet | Chunli Wang Zongtao Liu Tingwen Zhou Jiaqin Wu Fan Feng Shunshun Wang Qingjia Chi Yongqiang Sha Shuai Zha Songren Shu Linghang Qu Qianqian Du Huiming Yu Li Yang Anna Malashicheva Nianguo Dong Fei Xie Guixue Wang Kang Xu |
| author_sort | Chunli Wang |
| collection | DOAJ |
| description | Abstract 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 Faecalibacterium prausnitzii (F. prausnitzii) was significantly associated with increased calcification severity. Association analysis identified F. prausnitzii‐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 13C 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 F. prausnitzii 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. |
| format | Article |
| id | doaj-art-9941f6a6c47d4011abae8f8b2648c73d |
| institution | Kabale University |
| issn | 2770-596X |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | iMeta |
| spelling | doaj-art-9941f6a6c47d4011abae8f8b2648c73d2025-08-22T08:13:03ZengWileyiMeta2770-596X2025-08-0144n/an/a10.1002/imt2.70048Gut microbiota‐derived butyric acid regulates calcific aortic valve disease pathogenesis by modulating GAPDH lactylation and butyrylationChunli Wang0Zongtao Liu1Tingwen Zhou2Jiaqin Wu3Fan Feng4Shunshun Wang5Qingjia Chi6Yongqiang Sha7Shuai Zha8Songren Shu9Linghang Qu10Qianqian Du11Huiming Yu12Li Yang13Anna Malashicheva14Nianguo Dong15Fei Xie16Guixue Wang17Kang Xu18Hubei Shizhen Laboratory Wuhan ChinaDepartment of Cardiovascular Surgery, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan ChinaDepartment of Cardiovascular Surgery, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan ChinaHubei Shizhen Laboratory Wuhan ChinaHubei Shizhen Laboratory Wuhan ChinaSchool of Pharmacy Hubei University of Chinese Medicine Wuhan ChinaCollege of Electrical Engineering and Automation Anhui University Hefei ChinaCenter for Precision Medicine, School of Medicine and School of Biomedical Sciences Huaqiao University Xiamen ChinaHubei Shizhen Laboratory Wuhan ChinaFuwai Hospital, National Center for Cardiovascular Diseases Chinese Academy of Medical Sciences and Peking Union Medical College Beijing ChinaHubei Shizhen Laboratory Wuhan ChinaSchool of Pharmacy Hubei University of Chinese Medicine Wuhan ChinaSchool of Pharmacy Hubei University of Chinese Medicine Wuhan ChinaMinistry of Education Key Laboratory for Biorheological Science and Technology, National Local Joint Engineering Lab for Vascular Implants, College of Bioengineering Chongqing University Chongqing ChinaInstitute of Cytology Russian Academy of Science Petersburg RussiaDepartment of Cardiovascular Surgery, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan ChinaDepartment of Cardiovascular Surgery The First Affiliated Hospital of Zhengzhou University Zhengzhou ChinaMinistry of Education Key Laboratory for Biorheological Science and Technology, National Local Joint Engineering Lab for Vascular Implants, College of Bioengineering Chongqing University Chongqing ChinaHubei Shizhen Laboratory Wuhan ChinaAbstract 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 Faecalibacterium prausnitzii (F. prausnitzii) was significantly associated with increased calcification severity. Association analysis identified F. prausnitzii‐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 13C 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 F. prausnitzii 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.https://doi.org/10.1002/imt2.70048butyric acidbutyrylationcalcific aortic valve calcificationglycolysislactylation |
| spellingShingle | Chunli Wang Zongtao Liu Tingwen Zhou Jiaqin Wu Fan Feng Shunshun Wang Qingjia Chi Yongqiang Sha Shuai Zha Songren Shu Linghang Qu Qianqian Du Huiming Yu Li Yang Anna Malashicheva Nianguo Dong Fei Xie Guixue Wang Kang Xu Gut microbiota‐derived butyric acid regulates calcific aortic valve disease pathogenesis by modulating GAPDH lactylation and butyrylation iMeta butyric acid butyrylation calcific aortic valve calcification glycolysis lactylation |
| title | Gut microbiota‐derived butyric acid regulates calcific aortic valve disease pathogenesis by modulating GAPDH lactylation and butyrylation |
| title_full | Gut microbiota‐derived butyric acid regulates calcific aortic valve disease pathogenesis by modulating GAPDH lactylation and butyrylation |
| title_fullStr | Gut microbiota‐derived butyric acid regulates calcific aortic valve disease pathogenesis by modulating GAPDH lactylation and butyrylation |
| title_full_unstemmed | Gut microbiota‐derived butyric acid regulates calcific aortic valve disease pathogenesis by modulating GAPDH lactylation and butyrylation |
| title_short | Gut microbiota‐derived butyric acid regulates calcific aortic valve disease pathogenesis by modulating GAPDH lactylation and butyrylation |
| title_sort | gut microbiota derived butyric acid regulates calcific aortic valve disease pathogenesis by modulating gapdh lactylation and butyrylation |
| topic | butyric acid butyrylation calcific aortic valve calcification glycolysis lactylation |
| url | https://doi.org/10.1002/imt2.70048 |
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