探討膳食化合物降低TMAO生成及減緩血管發炎之功效

The effects of dietary phenolic compounds on reducing trimethylamine-N-oxide formation and decreasing vascular inflammation in L-carnitine feeding mice

陳佩妤(Pei-Yu Chen)

指導教授 ： 潘敏雄

國立臺灣大學/生物資源暨農學院/食品科技研究所/碩士(2019年)

https://doi.org/10.6342/NTU201900322

摘要

據統計，心血管疾病為全球人口最常見的的發病原因，並且是全世界十大死因的第一名。動脈粥狀硬化是造成心血管疾病的主要原因，已被視為工業化國家的公共衛生問題。 近年來，氧化三甲胺 (trimethylamine-N-oxide, TMAO)被認為會導致動脈粥狀硬化，並與心血管疾病有很強的相關性。TMAO是由膳食中的肉鹼(carnitine)經由腸道菌代謝成三甲胺 (trimethylamine, TMA)，隨後再經宿主的肝臟酵素flavin monooxygenases (FMOs)氧化成TMAO。本研究的目的是想探討多酚類化合物 (pterostilbene, oolong tea extract and PMFs)對於TMAO生成及減緩血管發炎之效果。結果顯示，相較於控制組，單獨給予1.3 %肉鹼飲用水的組別顯著性的增加了血漿中TMAO的含量；而給予多酚類化合物的小鼠，則可以降低肉鹼所引起的血漿中TMAO上升的現象。此外，相較於單獨給予肉鹼的組別，給予多酚類化合物的小鼠，其肝臟酵素FMO3的mRNA表現量都有顯著性的下降。採集動脈進行血管發炎因子 (TNF-α, VCAM-1 and E-selectin) mRNA表現量測定，結果顯示給予本篇使用的多酚類化合物之小鼠可以減緩血管的發炎。相較於單獨給予肉鹼的組別，PMFs顯著地降低了VCAM-1 mRNA表現量，而給予pterostilbene以及烏龍茶萃取物的組別則顯著性降低了TNF-α, VCAM-1和E-selectin mRNA表現量。經腸道菌分析結果顯示，三種多酚類化合物的給予都增加了類桿菌屬的相對豐富。而給予烏龍茶萃取物的組別，則可增加乳桿菌屬的相對豐富。艾克曼菌 (Akkermansia)則是在給予polymethoxyflavones的組別有觀察到增加的現象。綜合以上結果，此三種多酚類化合物可以經由調節腸道菌相以及降低肝臟酵素FMO3而達到減緩血管發炎的作用。

關鍵字

動脈粥狀硬化 ； 氧化三甲胺 (TMAO) ； 肉鹼 ； 腸道菌 ； 膳食化合物

並列摘要

Cardiovascular disease (CVD) has become a ubiquitous cause of morbidity and a leading contributor to mortality in most countries. Atherosclerosis, a major component of CVD, has properly been considered a public health problem of industrialized countries. Trimethylamine-N-oxide (TMAO) was recently discovered as a proatherogenic species which is generated from dietary carnitine through gut microbiota-dependent pathway. Carnitine, a dietary quaternary amine, has been identified to specifically metabolize to trimethylamine (TMA) by gut microbiota and subsequently oxidize to TMAO by host hepatic enzymes, flavin monooxygenases (FMOs). The objective of this study aims to investigate the effects of dietary phenolic compounds (pterostilbene, oolong tea extract and polymethoxyflavones mixture) on reducing TMAO formation and on reversing vascular inflammation in carnitine-feeding mice. Our studies used LC-MS/MS to detect plasma TMAO and the results showed that mice treated with 1.3% carnitine in drinking water significantly (p < 0.05) increased the plasma levels of TMAO compared to control group; and these three phenolic compounds can reverse it. Meanwhile, these dietary phenolic compounds significantly (p < 0.05) decreased hepatic FMO3 mRNA levels compared to carnitine only group. Additionally, these dietary compounds decreased mRNA levels of vascular inflammatory markers (TNF-α, VCAM-1 and E-selectin). We analyzed the taxonomic compositions of the microbiota using 16S rRNA gene sequencing of DNA extracted from the cecal samples. It has been found that these three dietary compounds can modulate the growth of certain gut microbiota in vivo. Genus-level analysis showed that these three dietary phenolic compounds induced an increase in the relative abundances of Bacteroides. Oolong tea extract-treated group up-regulated Lactobacillus genus, compared to carnitine only group. Administration of polymethoxyflavones mixture increased Akkermansia in mice. In conclusion, pterostilbene, oolong tea extract and polymethoxyflavones have protective effects against carnitine feeding-induced vascular inflammation by gut microbiota remodeling and decreased TMAO levels through hepatic FMO3 mRNA reduction.

並列關鍵字

Atherosclerosis ； Trimethylamine-N-oxide (TMAO) ； Carnitine ； Gut microbiota ； Flavin monooxygenases (FMOs) ； Dietary phenolic compounds

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