馬利乳酸桿菌APS1對高脂飼糧誘導肥胖與非酒精性脂肪肝疾病動物模式之腸道菌相調節與機理研究

The mechanistic study of Lactobacillus mali APS1 on manipulation of gut microbiome in high-fat diet-induced obesity and non-alcoholic fatty liver disease animal model

陳詠宗(Yung-Tsung Chen)

指導教授 ： 楊寧蓀

共同指導教授 ： 陳明汝(Ming-Ju Chen)

國立臺灣大學/生物資源暨農學院/生物科技研究所/博士(2018年)

https://doi.org/10.6342/NTU201801119

摘要

肥胖在已開發國家及開發中國家為常見之疾病。許多疾病常伴隨著肥胖而發生，例如慢性發炎以及非酒精性脂肪肝。然而，目前對於肥胖及非酒精性脂肪肝之療效仍需更進一步的探討與改善。許多文獻指出於肥胖及非酒精性脂肪肝病症中，腸道菌群扮演著重要的角色，而利用益生菌改變腸道菌相可有效改善肥胖症狀。然而探討益生菌可否藉由改變腸道菌群並減緩非酒精性脂肪肝及其影響之機制仍未清楚了解；除此之外，結合益生菌與控制飲食攝取於調節肥胖腸道菌群及其代謝物影響之研究相當稀少。先前的研究結果已證實，糖液克菲爾所分離之馬利乳酸桿菌APS1具有許多益處，其中包括可有效抑制高脂飼糧誘導肥胖小鼠之影響。因此，本研究目的為探討糖液克菲爾APS1菌株對於高脂飼糧誘導大鼠非酒精性脂肪肝之影響以及探討結合APS1菌株與低脂飲食於已肥胖小鼠是否可促進改善肥胖之影響。於本實驗結果我們發現餵食APS1菌株可調節高脂飼糧誘導肥胖大鼠腸道菌相，減少與非酒精性脂肪肝相關之特定菌群和降低體增重，且可增加肝臟組織中SIRT-1/Nrf-2轉錄因子活性及調控下游與脂質代謝和氧化壓力相關分子路徑，降低肝臟脂質累積及增加肝臟抗氧化活性。而結合APS1菌株與低脂飲食可改善肥胖腸道菌群，促進增加已肥胖小鼠之體減重及降低體脂肪堆積。此外，餵食APS1菌株可調節脂質代謝相關之血清代謝物和腸道荷爾蒙表現以及增加糞便中短鏈脂肪酸丁酸表現量。本研究動物實驗結果可證實，糖液克菲爾分離之APS1菌株可調節宿主腸道微生物體，增加血清中腸道荷爾蒙及糞便中短鏈脂肪酸之表現，促進肝臟組織SIRT-1/Nrf-2蛋白質活性表現而降低肝臟脂質形成與堆積，且可改善宿主血清中與脂質代謝相關之代謝物表現。最後，本研究結果提供科學證據證明馬利乳酸桿菌APS1具改善代謝症候群之潛力益生菌，未來可應用於機能性食品開發。

關鍵字

腸道菌相 ； 馬利乳酸桿菌APS1 ； 非酒精性脂肪肝 ； 肥胖 ； 短鏈脂肪酸

並列摘要

To date, obesity is a widespread disease in developing and developed countries. Some syndromes are accompanied with obesity, such as low grade inflammation and non-alcoholic fatty liver disease (NAFLD). Currently, there are no approved clinical treatment for non-alcoholic fatty liver disease and the difficulty of long-term management has produced a high rate of failure for obesity patients. Therefore, improving the efficacy of obesity and NAFLD treatment is a significant goal. A number of studies indicate that gut microbiota dominates and plays an important role in obesity and non-alcoholic fatty liver disease. Using probiotics to manipulate the gut microbiota has been as the potential approach for improving obesity. However, it remains unclear whether the probiotic can ameliorate the non-alcoholic fatty liver through manipulating the gut microbiota, in addition, the study on the effect of combination of probiotics and diet control in the regulation of obesity-related gut microbiota and metabolites is quite rare. In our previous studies, Lactobacillus mali APS1 (APS1), which is isolated from sugary kefir, has been demonstrated to confer several health benefits in vivo, including amelioration of high-fat diet (HFD)-induced obesity in mice. Therefore, this study aimed to investigate the effect of APS1 on high-fat diet-induced NAFLD and the efficacy of a combination of APS1 and dieting on improvement of obesity in vivo. The results showed that APS1 manipulated the gut microbiota, resulting in reducing the abundance of specific NAFLD-associated bacteria, and significantly reduced hepatic lipid accumulation and increased hepatic antioxidant activity by regulating SIRT-1/Nrf-2 signaling pathway in HFD-fed rats. The combination of APS1 and dieting accelerated body weight loss and reduced fat accumulation though manipulating obesity-associated gut microbiota in preexisting obese mice. Additionally, APS1 intervention modulated the lipid metabolism-associated metabolites, appetitive hormones and increased fecal butyric acid concentration. In conclusion, this study highlighted that APS1 strain isolated from sugary kefir regulating the host gut microbiota and inducing the expressions of short-chain fatty acids and intestinal hormones resulted in reduction of body fat accumulation and hepatic steatosis in vivo. This study provided scientific evidences to show that Lactobacillus mali APS1 can be the potential probiotic to improve metabolic disorder syndrome in the application of functional food.

並列關鍵字

gut microbiota ； Lactobacillus mali APS1 ； non-alcoholic fatty liver disease ； obesity ； short chain fatty acids

參考文獻

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