PMID- 36575982 OWN - NLM STAT- MEDLINE DCOM- 20230123 LR - 20230226 IS - 1524-4571 (Electronic) IS - 0009-7330 (Linking) VI - 132 IP - 2 DP - 2023 Jan 20 TI - Flavonifractor plautii Protects Against Elevated Arterial Stiffness. PG - 167-181 LID - 10.1161/CIRCRESAHA.122.321975 [doi] AB - BACKGROUND: Dysbiosis of gut microbiota plays a pivotal role in vascular dysfunction and microbial diversity was reported to be inversely correlated with arterial stiffness. However, the causal role of gut microbiota in the progression of arterial stiffness and the specific species along with the molecular mechanisms underlying this change remain largely unknown. METHODS: Participants with elevated arterial stiffness and normal controls free of medication were matched for age and sex. The microbial composition and metabolic capacities between the 2 groups were compared with the integration of metagenomics and metabolomics. Subsequently, Ang II (angiotensin II)-induced and humanized mouse model were employed to evaluate the protective effect of Flavonifractor plautii (F plautii) and its main effector cis-aconitic acid. RESULTS: Human fecal metagenomic sequencing revealed a significantly high abundance and centrality of F plautii in normal controls, which was absent in the microbial community of subjects with elevated arterial stiffness. Moreover, blood pressure only mediated part of the effect of F plautii on lower arterial stiffness. The microbiome of normal controls exhibited an enhanced capacity for glycolysis and polysaccharide degradation, whereas, those of subjects with increased arterial stiffness were characterized by increased biosynthesis of fatty acids and aromatic amino acids. Integrative analysis with metabolomics profiling further suggested that increased cis-aconitic acid served as the main effector for the protective effect of F plautii against arterial stiffness. Replenishment with F plautii and cis-aconitic acid improved elastic fiber network and reversed increased pulse wave velocity through the suppression of MMP-2 (matrix metalloproteinase-2) and inhibition of MCP-1 (monocyte chemoattractant protein-1) and NF-kappaB (nuclear factor kappa-B) activation in both Ang II-induced and humanized model of arterial stiffness. CONCLUSIONS: Our translational study identifies a novel link between F plautii and arterial function and raises the possibility of sustaining vascular health by targeting gut microbiota. FAU - Luo, Shiyun AU - Luo S AD - Guangdong Provincial Key Laboratory of Food, Nutrition and Health, and Department of Nutrition (S.L., Y.Z., S.Z., L.L., B.Y., J.F., M.X.), School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, China. FAU - Zhao, Yawen AU - Zhao Y AD - Guangdong Provincial Key Laboratory of Food, Nutrition and Health, and Department of Nutrition (S.L., Y.Z., S.Z., L.L., B.Y., J.F., M.X.), School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, China. FAU - Zhu, Shanshan AU - Zhu S AD - Guangdong Provincial Key Laboratory of Food, Nutrition and Health, and Department of Nutrition (S.L., Y.Z., S.Z., L.L., B.Y., J.F., M.X.), School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, China. FAU - Liu, Ludi AU - Liu L AD - Guangdong Provincial Key Laboratory of Food, Nutrition and Health, and Department of Nutrition (S.L., Y.Z., S.Z., L.L., B.Y., J.F., M.X.), School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, China. AD - Department of Statistics and Epidemiology (L.L., B.Y.), School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, China. FAU - Cheng, Ken AU - Cheng K AD - XJTLU Wisdom Lake Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Suzhou, China (K.C., Y.H.). FAU - Ye, Bingqi AU - Ye B AD - Guangdong Provincial Key Laboratory of Food, Nutrition and Health, and Department of Nutrition (S.L., Y.Z., S.Z., L.L., B.Y., J.F., M.X.), School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, China. AD - Department of Statistics and Epidemiology (L.L., B.Y.), School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, China. FAU - Han, Yueyuan AU - Han Y AUID- ORCID: 0000-0001-9295-559X AD - XJTLU Wisdom Lake Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Suzhou, China (K.C., Y.H.). FAU - Fan, Jiahua AU - Fan J AUID- ORCID: 0000-0002-1629-3034 AD - Guangdong Provincial Key Laboratory of Food, Nutrition and Health, and Department of Nutrition (S.L., Y.Z., S.Z., L.L., B.Y., J.F., M.X.), School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, China. FAU - Xia, Min AU - Xia M AUID- ORCID: 0000-0001-5330-6466 AD - Guangdong Provincial Key Laboratory of Food, Nutrition and Health, and Department of Nutrition (S.L., Y.Z., S.Z., L.L., B.Y., J.F., M.X.), School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20221228 PL - United States TA - Circ Res JT - Circulation research JID - 0047103 RN - EC 3.4.24.24 (Matrix Metalloproteinase 2) RN - 93371T1BXP (Aconitic Acid) RN - Flavonifractor plautii SB - IM CIN - Circ Res. 2023 Jan 20;132(2):182-184. PMID: 36656969 MH - Animals MH - Mice MH - Humans MH - *Matrix Metalloproteinase 2 MH - *Vascular Stiffness/physiology MH - Pulse Wave Analysis MH - Aconitic Acid/pharmacology OTO - NOTNLM OT - elastic fiber OT - fatty acids OT - gut microbiota OT - vascular stiffness EDAT- 2022/12/29 06:00 MHDA- 2023/01/24 06:00 CRDT- 2022/12/28 05:02 PHST- 2022/12/29 06:00 [pubmed] PHST- 2023/01/24 06:00 [medline] PHST- 2022/12/28 05:02 [entrez] AID - 10.1161/CIRCRESAHA.122.321975 [doi] PST - ppublish SO - Circ Res. 2023 Jan 20;132(2):167-181. doi: 10.1161/CIRCRESAHA.122.321975. Epub 2022 Dec 28.