飲食天然物對於食源性糖化終產物加劇高脂高果糖飲食誘導之代謝紊亂的改善效果

Abstract

食源性糖化終產物 (dietary advanced glycation end products, dAGEs) 主要存在於高溫加工食品中，因此西方飲食為 dAGEs 最主要之來源。近年來，西方飲食日益盛行，其特點為富含高油脂和添加糖的過度加工食品。動物研究結果顯示，飼料經高溫加熱產生之 dAGEs 會加劇高脂高糖飲食誘導之代謝紊亂，且 dAGEs 進入體內與其受體 receptor for advanced glycation end products (RAGE) 作用，會導致糖尿病、血脂異常與其它慢性代謝疾病，同時也會影響腸道菌相及其代謝物。植化素已被證實有益於調節宿主之腸道菌相，且體外研究發現植化素具有抑制 dAGEs 作用之潛力，然而植化素在生物體內改善 dAGEs 造成之代謝紊亂的功效仍未知。因此，本研究藉由高溫加熱飼料合併高脂和高果糖飲食模擬西化飲食中多重因子對健康之交互影響，並介入富含植化素之多重植物萃取物樣品 supersterol (SS)，藉此闡明 dAGEs 是否會加劇高脂高果糖飲食誘導之代謝紊亂及其潛在機制，同時評估 SS 對 dAGEs 影響之改善作用及其對腸道微生物組成與代謝紊亂間的影響。實驗結果顯示，高溫烘烤會大幅增加飼料中 dAGEs 含量。dAGEs 可能藉由降低脂聯素濃度和增加葡萄糖耐受不良，而導致胰島素濃度降低，並可觀察到脂肪組織異常增加脂解作用。同時，dAGEs 進入小鼠體內可能透過與 RAGE 作用來減少下游蛋白質 glucose transporter 2 (GLUT2) 表現，進而降低肝臟的葡萄糖吸收，影響葡萄糖耐受性。腸道菌相分析結果顯示 Muribaculaceae 及 Clostridium 分別與葡萄糖耐受不良呈負相關及正相關，而 dAGEs 降低 Muribaculaceae 並增加 Clostridium 之相對豐度，且顯著增加胺基酸從頭合成代謝路徑。SS 介入可改善高溫加熱合併高脂及高果糖飲食誘導小鼠之葡萄糖耐受不良及異常脂解。就血糖調控機制而言，SS 具有改善肝臟 GLUT2 蛋白質表現之趨勢，進而可能促進肝臟對血糖之調節，以改善葡萄糖耐受不良。此外 SS 能夠調節小鼠因 dAGEs 而改變之腸道菌相組成及胺基酸從頭合成代謝路徑。顯示 SS 可能透過調節腸道菌相組成及胺基酸代謝物生成，以改善 dAGEs 導致之血糖代謝紊亂。

Dietary advanced glycation end products (dAGEs) are mainly found in high-temperature processed foods. Therefore, Western diets are considered the main sources of dAGEs. In recent years, the Western diet has grown in popularity and is characterized by highly processed foods high in fat and added sugar. Animal studies have shown that dAGEs can exacerbate metabolic disorders resulting from a diet high in fat and sugar. Moreover, after dAGEs enter circulation, they would interact with receptor for advanced glycation end products (RAGE), leading to diabetes, dyslipidemia, and other chronic metabolic disorders. Meanwhile, the composition of the gut microbiota and their metabolites are profoundly influenced by dAGEs. Phytochemicals have been proven to be beneficial in modulating the gut microbiota of the host. Notably, in vitro studies have highlighted that several phytochemicals possess the potential to alleviate the harmful effects of dAGEs. However, their impact in vivo and their effects on the gut microbiota and its metabolites have yet to be explored. Therefore, this study aimed to elucidate if dAGEs would accelerate the metabolism disorders caused by high-fat and high-fructose diet and the potential mechanisms involved. Furthermore, to investigate the effects of supersterol (SS), a multi-plant extract containing various phytochemicals, on the detrimental consequences of dAGEs and its implications for the correlation between gut microbiota compositions and metabolism disorders. C57BL/6 mice were fed a dAGEs-enriched high-fat and high-fructose diet to mimic the modern Western diet. The findings revealed that the amount of dAGEs in the diet significantly increased after high-heat baking. dAGEs reduced adiponectin concentrations and increased glucose intolerance, thereby reducing insulin concentrations. Interestingly, dAGEs abnormally increased lipolysis in adipose tissue. Furthermore, dAGEs would enter the circulation and reduce the expression of the glucose transporter 2 (GLUT2) by interacting with RAGE, therefore reducing the glucose uptake by the liver and resulting in glucose tolerance. The results of gut microbiota analysis showed that Muribaculaceae and Clostridium were respectively negatively and positively correlated with glucose intolerance. dAGEs decreased the relative abundance of Muribaculaceae and increased that of Clostridium. Notably, dAGEs significantly increased the amino acid biosynthesis pathway. The intervention of SS can attenuate glucose intolerance and abnormal lipolysis in mice induced by a dAGEs-enriched high-fat and high-fructose diet. In terms of the glucose metabolism regulation mechanism, SS tends to improve the expression of GLUT2 protein in the liver, which may promote the regulation of glucose metabolism in the liver to alleviate glucose intolerance. In addition, SS can regulate the gut microbiota composition and amino acid biosynthesis pathway induced by a dAGEs-enriched diet. In conclusion, SS may improve the glucose metabolism disorder caused by dAGEs by regulating the composition of gut microbiota and the production of amino acid metabolites.