替米沙坦在动脉粥样硬化中对肠道菌群及其代谢产物TMAO的影响

目的：探讨替米沙坦在动脉粥样硬化中对肠道菌群及代谢产物氧化三甲胺（trimethylamine N-Oxide, TMAO）的影响。方法：将17只ApoE-/-小鼠随机分为两组：对照组（Control, CTL）（n=8）和替米沙坦（10 mg·kg-1·d-1，灌胃）治疗组（telmisartan, TLM）（n=9）。喂食高脂饮食12周，3%水合氯醛麻醉处死，从眶后窦处采集静脉血，用高效液相色谱-串联质谱法检测TMAO，油红“O”染色法测量主动脉根部斑块的面积，免疫组化法检测斑块内白细胞介素-6（IL-6）、单核细胞趋化蛋白1（MCP-1）和巨噬细胞表面因子（mac-3），留取结肠粪便进行肠道菌群16S-rRNA，V3-V4区测序。结果：与CTL组相比，TLM组的主动脉根部斑块面积明显减少，炎性因子IL-6、MCP-1和mac-3表达水平下降、血浆TMAO水平明显降低；肠道菌群功能差异分析提示两组小鼠在细胞转运及代谢、能量与转换、信号转导等方面具有统计学差异（P<0.05），丰度差异分析提示TLM组较CTL组产生TMAO的肠道菌群（Anaeroplasmataceae, Bacteroidaceae, Clostridiaceae, Lachnospiraceae, Ruminococcaceae, Proteus）明显减少。结论：替米沙坦减轻动脉粥样硬化的机制除与阻断血管紧张素II 1型受体（AT1R）有关外，还可能与改变肠道菌群组成使得TMAO血浆含量减少有关。

Effects of telmisartan on intestinal flora and its metabolite TMAO in atherosclerosis

AIM: To investigate the effect of telmisartan on intestinal flora and metabolite TMAO in atherosclerosis. METHODS: Seventeen ApoE-/-mice were randomly divided into two groups: a control group (n=8) and a telmisartan (10 mg/kg, intragastric administration) treatment group (n=9). All mice were fed a high-fat diet. After 12 weeks, the mice were sacrificed. Venous blood was collected from the retro-orbital sinus to detect TMAO using high-performance liquid phase chromatography-tandem mass spectrometry. The severity of atherosclerosis was determined by measuring the area of the plaque at the root of the aorta. The plaque stability was determined by analyzing the expression of interleukin-6 (IL-6), monocyte chemoattractant protein 1 (MCP-1) and macrophage infiltration in plaques and plaque morphology. Colonic fecal 16S- RNA V3-V4 region sequencing was used to analyze intestinal flora. RESULTS: Compared with the control group, the plaque area of the telmisartan treatment group decreased significantly, and the expression of IL-6, MCP-1, and infiltration macrophages also decreased significantly. Plasma TMAO levels were significantly lower in the telmisartan-treated group than in the control group. Meanwhile, the blood pressure and body weight of the mice treated with telmisartan were lower than those of the control group. Intestinal flora analysis showed that telmisartan significantly changed the composition of intestinal flora and reduced six bacteria known to produce TMAO, including Anaeroplasmataceae, Bacteroidaceae, Clostridiaceae, Lachnospiraceae, Ruminococcaceae, and Proteus. CONCLUSION: In addition to blocking AT1R, telmisartan may reduce TMAO plasma content by changing intestinal flora composition.