Deficiency of PSRC1 accelerates atherosclerosis by increasing TMAO production via manipulating gut microbiota and flavin monooxygenase 3

作者：Tiantian Luo, Zhigang Guo, Dan Liu, Zhongzhou Guo, Qiao Wu, Qinxian Li, Rongzhan Lin, Peier Chen, Caiwen Ou, Minsheng Chen · 发表于：Gut Microbes · 年份：2022 · DOI：10.1080/19490976.2022.2077602 · 被引用次数：58 · 研究领域：Gut microbiota and health、Epigenetics and DNA Methylation、IL-33, ST2, and ILC Pathways

Maladaptive inflammatory and immune responses are responsible for intestinal barrier integrity and function dysregulation. Proline/serine-rich coiled-coil protein 1 (PSRC1) critically contributes to the immune system, but direct data on the gut microbiota and the microbial metabolite trimethylamine N-oxide (TMAO) are lacking. Here, we investigated the impact of PSRC1 deletion on TMAO generation and atherosclerosis. We first found that PSRC1 deletion in apoE−/− mice accelerated atherosclerotic plaque formation, and then the gut microbiota and metabolites were detected using metagenomics and untargeted metabolomics. Our results showed that PSRC1 deficiency enriched trimethylamine (TMA)-producing bacteria and functional potential for TMA synthesis and accordingly enhanced plasma betaine and TMAO production. Furthermore, PSRC1 deficiency resulted in a proinflammatory colonic phenotype that was significantly associated with the dysregulated bacteria. Unexpectedly, hepatic RNA-seq indicated upregulated flavin monooxygenase 3 (FMO3) expression following PSRC1 knockout. Mechanistically, PSRC1 overexpression inhibited FMO3 expression in vitro, while an ERα inhibitor rescued the downregulation. Consistently, PSRC1-knockout mice exhibited higher plasma TMAO levels with a choline-supplemented diet, which was gut microbiota dependent, as evidenced by antibiotic treatment. To investigate the role of dysbiosis induced by PSRC1 deletion in atherogenesis, apoE−/− mice were transplanted with t...