Guangdong Provincial Engineering Technology Research Center for Molecular Diagnosis and Innovative Drugs Translation of Cardiopulmonary Vascular Diseases, University Joint Laboratory of Guangdong Province and Macao Region on Molecular Targets and Intervention of Cardiovascular Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, China; Laboratory of Cardiovascular Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, China.
Laboratory of Vascular Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, China.
Phytomedicine. 2024 Jul;129:155621. doi: 10.1016/j.phymed.2024.155621. Epub 2024 Apr 10.
The metabolites produced from choline contribute to atherosclerosis (AS) pathogenesis, and the gut microbiota is redundantly essential for this process. Indole-3-carbinol (I3C), found in cruciferous vegetables such as broccoli, cabbage, cauliflower and brussels sprouts, helps prevent hyperlipidemia, maintain the gut microbiota balance, and decrease the production of trimethylamine-N-oxide (TMAO) from choline in the diet.
The objective of this research was to investigate the impact of I3C on choline-induced AS and to further elucidate the underlying mechanism involved.
AS models of high-choline-induced ApoE mice and TMAO-promoted foamy macrophages were established to observe the effect of I3C on the formation of atherosclerotic plaques and foam cells and changes in AS-related indicators (including blood biochemical indicators, TMA, TMAO, SRA, and SRB1), and integrated analyses of the microbiome and metabolome were used to reveal the mechanism of action of I3C.
We found that I3C inhibited high-choline-induced atheroma formation (50-100 mg/kg/d, in vivo) and slightly improved the lipid profile (15 mg/kg/d, in vivo). Moreover, I3C suppressed lipid influx at a concentration of 40 µmol/L in vitro, enhanced the diversity of the gut microbiota and the abundance of the phylum Verrucomicrobia, and consequently modified the gut microbial metabolites at a dosage of 50 mg/kg/d in the mice. Associative analyses based on microbiome and metabolomics revealed that 1-methyladenosine was a key modulator of the protective effect of I3C against AS in high-choline-induced ApoE mice.
These findings demonstrate for the first time that I3C ameliorates AS progression through remodeling of the gut microbiome and metabolomics, which paves the way for the possible therapeutic use of this vegetable-derived natural compound and may reduce the clinical severity of AS-related cardiovascular diseases.
胆碱产生的代谢物有助于动脉粥样硬化（AS）的发病机制，而肠道微生物群对于这一过程至关重要。吲哚-3-甲醇（I3C）存在于西兰花、白菜、菜花和抱子甘蓝等十字花科蔬菜中，有助于预防高血脂、维持肠道微生物群平衡，并减少饮食中胆碱产生的三甲胺-N-氧化物（TMAO）。
本研究旨在探讨 I3C 对胆碱诱导的 AS 的影响，并进一步阐明其潜在机制。
建立高胆碱诱导 ApoE 小鼠和 TMAO 促进泡沫巨噬细胞的 AS 模型，观察 I3C 对动脉粥样硬化斑块和泡沫细胞形成的影响，以及 AS 相关指标（包括血液生化指标、TMA、TMAO、SRA 和 SRB1）的变化，采用微生物组和代谢组学综合分析揭示 I3C 的作用机制。
我们发现 I3C 抑制高胆碱诱导的动脉粥样硬化形成（50-100mg/kg/d，体内），并略微改善血脂谱（15mg/kg/d，体内）。此外，I3C 在体外以 40µmol/L 的浓度抑制脂质内流，增强肠道微生物群的多样性和厚壁菌门的丰度，进而在 50mg/kg/d 的剂量下改变小鼠的肠道微生物代谢物。基于微生物组和代谢组学的关联分析表明，1-甲基腺苷是 I3C 抑制高胆碱诱导 ApoE 小鼠 AS 进展的保护作用的关键调节剂。
这些发现首次表明，I3C 通过重塑肠道微生物组和代谢组学来改善 AS 进展，为这种植物源天然化合物的可能治疗用途铺平了道路，并可能降低与 AS 相关的心血管疾病的临床严重程度。
