- 學位論文
探討活菌以及巴斯德殺菌的Akkermansia muciniphila對於GAN飲食誘導小鼠非酒精性脂肪肝炎的影響
Investigation the Effects of Live and Pasteurized Akkermansia muciniphila in GAN Diet-Induced NASH Mouse Model
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摘要
非酒精性脂肪肝病 (non-alcoholic fatty liver disease, NAFLD) 是全球最常見的慢性肝臟疾病之一，影響全球約30%的人口。若患者未得到即時的治療，則可能會進展為非酒精性脂肪肝炎 (non-alcoholic steatohepatitis, NASH)、肝硬化、甚至是肝癌。NAFLD與NASH的發病機制主要源自於不健康的飲食習慣，進而引發代謝功能失調、全身性的發炎反應以及腸道菌相混亂等。近年來，隨著腸道菌相研究的興起，次世代益生菌Akkermansia muciniphila被發現不論是活菌或是巴斯德殺菌形式，皆具有治療NASH的潛力。而從台灣健康人體的糞便中分離出的A. muciniphila NTUH_Amu01對於NASH的治療效果尚不清楚，因此本研究旨在探討活菌以及巴斯德殺菌的A. muciniphila NTUH_Amu01與標準菌株ATCC BAA-835對於Gubra-Amylin NASH (GAN) 飲食誘導NASH小鼠的治療效果。然而，結果顯示A. muciniphila對於NASH的治療效果有限，甚至會部分加劇NASH的病情。攝取活菌以及巴斯德殺菌形式的標準菌株皆會使體重變化顯著提高，並惡化肝臟NASH的病理症狀。此外，攝取活菌形式的NTUH_Amu01與標準菌株均會使肝臟更為腫大、禁食血糖顯著提高，並伴隨胰島素阻抗更為嚴重的情形。有趣的是，經巴斯德殺菌的標準菌株具有部分抗發炎的效果，包括顯著降低肝臟促發炎細胞激素TNF-α與IL-6的含量，並部分抑制肝臟NLRP3發炎小體途徑的活化。另一方面，腸道菌相的結果中顯示，攝取標準菌株可能會增加肥胖相關菌株; 而攝取活菌形式破壞血糖的恆定則可能與影響血糖調控的菌株含量改變有關，顯示出A. muciniphila的介入可能會導致腸道菌相失調，從而削弱治療效果。綜上所述，A. muciniphila不適合做為治療NASH的補充品，其中活菌形式更有可能會導致NASH更為嚴重，因此未來仍需更多的研究來確保其健康效益與安全性。
並列摘要
Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases worldwide, affecting approximately 30% of the global population. If left untreated, NAFLD can progress to non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma. The pathogenesis of NAFLD is primarily driven by unhealthy diets, leading to metabolic dysfunction, increased lipogenesis, inflammation, and liver fibrosis. With the advancements in gut microbiota research, the next-generation probiotic Akkermansia muciniphila has been found to possess therapeutic potential for NASH regardless of its live or pasteurized forms. Recently, a novel A. muciniphila strain- NTUH_Amu01 was isolated from healthy Taiwanese fecal, which remains unknown on its therapeutic effects on NASH. Therefore, this study aims to investigate whether oral administration of live and pasteurized A. muciniphila strain NTUH_Amu01 and standard strain ATCC BAA-835 could alleviate the Gubra-Amylin NASH (GAN) diet-induced NASH mice model. The results indicate that the therapeutic efficacy of A. muciniphila in NASH is limited and may even worsen the disease. Both live and pasteurized standard strain significantly increased body weight gain and worsen the severity of NASH in the liver. Furthermore, the consumption of live NTUH_Amu01 and the standard strain led to further liver enlargement, significantly increased fasting blood glucose levels, and exacerbated insulin resistance. Interestingly, the pasteurized standard strain exhibited partial anti-inflammatory effects by significantly reducing the levels of pro-inflammatory cytokines TNF-α and IL-6 in the liver and partially inhibiting the activation of the NLRP3 inflammasome pathway. On the other hand, the gut microbiota analysis revealed that consuming the standard strain might increase obesity-related bacterial strains. Additionally, the disruption of blood glucose homeostasis by consuming live A. muciniphila could be associated with changes in the abundance of bacterial strains involved in blood glucose regulation, suggesting that A. muciniphila intervention may cause gut microbiota dysbiosis, thereby weakening its therapeutic effects. In conclusion, A. muciniphila may not be suitable as a therapeutic supplement for NASH, and the use of live A. muciniphila could even exacerbate NASH. Therefore, further research is needed to ensure its health benefits and safety.
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