Data_Sheet_1_The Intestinal Effect of Atorvastatin: Akkermansia muciniphila and Barrier Function.docx

Studies have shown that the cholesterol-lowering medicine statins alter the gut microbiome, induce chronic metabolic inflammation, and disrupt glycemic homeostasis. In this study, we aimed to investigate whether effects of atorvastatin (Ator) on gut microbiome and metabolic inflammation could be causally correlated. Mice at 8-week age were fed with high-fat diet (HFD) or HFD with Ator (HFD+Ator) for 16 weeks. 16S rRNA sequencing of stool and RNA sequencing of colon tissue were employed to analyze the intestinal alterations that could be induced by Ator. A human colon carcinoma cell line (Caco2) was used for in vitro experiments on barrier function. Compared to HFD, HFD+Ator induced more weight gain, impaired glucose tolerance, and led to gut microbiota dysbiosis, such as suppressing Akkermansia muciniphila in mice. The expressions of tight junction (TJ) proteins were attenuated in the colon, and the serum LPS-binding-protein (LBP) level was elevated in HFD+Ator mice, so as to transcriptionally activate the intestinal nuclear factor-k-gene binding (NF-κB) signaling pathway. Consistently, Ator impaired the barrier function of Caco2, and treatment of supernatant of A. Muciniphila culture could decrease the intestinal permeability and recover the attenuated expression of TJ proteins induced by Ator. In conclusion, long-term use of Ator with HFD may alter gut microbiota, induce intestinal barrier dysfunction, and hence promote chronic inflammation that contributes to disrupted glycemic homeostasis.

已有研究表明，降胆固醇药物他汀类（statins）可改变肠道微生物组，诱发慢性代谢性炎症，并破坏血糖稳态。本研究旨在探究阿托伐他汀（atorvastatin, Ator）对肠道微生物组及代谢性炎症的影响是否存在因果关联。将8周龄小鼠分为两组，分别喂食高脂饮食（high-fat diet, HFD）以及添加阿托伐他汀的高脂饮食（HFD+Ator），造模周期为16周。通过粪便16S rRNA测序与结肠组织RNA测序，分析阿托伐他汀诱导的肠道异常变化。本研究使用人结肠癌细胞系（Caco2）开展屏障功能相关体外实验。与单纯高脂饮食组相比，添加阿托伐他汀的高脂饮食组小鼠体重增长更多、葡萄糖耐量受损，且出现肠道菌群失调——例如可抑制小鼠体内的嗜黏蛋白阿克曼氏菌（Akkermansia muciniphila）。结肠组织中紧密连接（tight junction, TJ）蛋白的表达水平被下调，同时高脂饮食加阿托伐他汀组小鼠的血清脂多糖结合蛋白（lipopolysaccharide-binding protein, LBP）水平升高，进而转录激活肠道核因子-κB（nuclear factor-k-gene binding, NF-κB）信号通路。体外实验结果一致显示，阿托伐他汀会损伤Caco2细胞的屏障功能；而嗜黏蛋白阿克曼氏菌培养上清液可降低肠道通透性，并恢复阿托伐他汀诱导的紧密连接蛋白表达下调。综上，长期联合高脂饮食使用阿托伐他汀，可能通过改变肠道菌群、诱发肠道屏障功能障碍，进而促进慢性炎症，最终导致血糖稳态失衡。