基于肠道菌群为靶点的白藜芦醇调控TMAO代谢转化及抗动脉粥样硬化作用研究

Resveratrol (RSV) as an important polyphenolic phytochemicals has significant anti-atherosclerosis (AS) effect, but the mechanism has not been thouroughly elucidated.The pathogenesis of AS is complex, the latest study found that trimethylamine oxide (trimethylamine-N-oxide, TMAO), which is the generation of lecithin from animal foods through intestinal flora metabolism and liver transformation, is closely related to AS. And TMAO has become the most important independent risk factor for AS. Moreover, studies suggest that intestinal flora plays a key role in TMAO transformation and TMAO-induced AS. Based on the latest mechanism of AS pathogenesis, the current study therefore focouses on the intestinal flora and begins with the two essencial steps of TMAO generation including intestinal flora-dependent production of trimethylamine (TMA) which is the precursor of TMAO and hepatocyte-dependent TMA transformation, as well as the regulation of "gut flora-T-β-MCA-FXR-FMO3" signaling pathway. Via ApoE-/- knockout mice model, sterile animal model and metagenomic sequencing technology, we found that RSV can affect the gut flora and inhibit the bacteria-mediated conversion of lecithin, subsequent the decrease of TMAO production, thereby reducing the risk of AS. Our study will provide a new perspective for the mechanism of RSV's anti-AS effect and the prevention of AS through dietary approaches, indicating an important scientific significance and practical value.

白藜芦醇（RSV）作为重要的多酚类植物化学物，具有抗动脉粥样硬化（AS）的作用，但机制尚未阐明。AS发生机制复杂，最新研究发现，肠道菌群依赖的卵磷脂代谢及相关代谢产物氧化三甲胺（TMAO）与动物性食物（红肉）诱发AS的发生密切相关，TMAO已成为重要的AS独立危险因子。研究提示，肠道菌群在TMAO代谢转化及诱发AS中起关键作用。本课题基于这一最新的AS发生机制，以肠道菌群为中心，从TMAO产生的两个关键环节，即肠道菌群依赖的TMAO前体物三甲胺（TMA）生成和肝细胞依赖的TMA代谢转化入手，围绕"肠道菌群-T-β-MCA-FXR-FMO3"信号通路代谢调节，利用基因敲除、无菌动物模型、宏基因组测序等技术，发现RSV可通过影响肠道菌群及其介导的卵磷脂代谢转化、抑制TMAO生成，进而降低AS发生风险。项目将为RSV抗AS机制研究及从膳食营养途径预防AS提供新的视角，具有重要科学意义和实用价值。

白藜芦醇（RSV）作为重要的多酚类植物化学物，其潜在的抗动脉粥样硬化（AS）作用已引起人们的广泛关注，但其作用机制尚不明确。AS发病机制复杂，最新的研究发现，动物性食物中的卵磷脂经肠道菌群代谢和肝脏活化后生成的氧化三甲胺（trimethylamine-N-oxide, TMAO）与AS发生密切相关，TMAO已成为最重要的AS独立危险因子之一。本课题以肠道菌群为靶点，从肠道菌群依赖的TMAO生成及胆汁酸代谢两个关键环节入手，以C57BL/6J和ApoE-/-小鼠为研究对象，利用肠道菌群研究的主要技术方法（16SrRNA高通量测序、qPCR、细菌培养）和分子营养学技术方法（免疫印迹、qPCR、LC/MS）等，首次发现RSV能够通过改变肠道菌群结构减少TMAO的生成；同时，通过影响肠道菌群结构，抑制肠肝FXR/FGF15轴，促进肝脏胆汁酸的合成，进而实现其抗AS的作用。此外，采用多种抑制剂、激动剂、RNAi等技术并结合SIRT3-/-小鼠，证实了SIRT3-NLRP3炎性小体通路在TMAO诱导内皮炎性损伤中的重要作用。本研究结果为RSV的临床应用提供了新的科学试验依据，也为AS膳食营养防治提供了新的策略和指导。