在台灣，常見糖尿病患者出現由克雷伯氏肺炎桿菌(Klebsiella pneumoniae)感染而造成的化膿性肝膿瘍，但其致病機轉仍不清楚。已知人類的腸道存有為數眾多且種類豐富的腸道菌群，此菌群的組成與宿主的免疫力有著密切關係。本研究利用streptozotocin誘導的糖尿病小鼠以探討肝臟損傷與腸道菌及腸道免疫力變化之間的關係。結果顯示，小鼠誘導糖尿病一個月後，由小鼠血中的肝臟轉胺酶增加和肝臟殺菌力下降可知其肝臟已出現損傷，而小鼠也出現腸道菌數增加、菌叢失衡、腸道菌與致病性Klebsiella pneumoniae的轉移增加、腸道黏膜免疫力下降等情形。然而，糖尿病小鼠在餵食死的益生菌(乳酸菌)或益生素(果寡糖)後，腸道菌間的平衡和腸道黏膜抗菌蛋白的表現皆明顯地恢復，肝臟的損傷情形也減少了。此外，藉由益生菌或益生素的餵食，糖尿病小鼠腸道中iNOS的表現增加和肝門靜脈血中的NO及內毒素含量增加亦可受到抑制，而餵食iNOS抑制劑L-NAME也有同樣的作用。L-NAME可降低肝臟庫氏細胞中IL-1β的表現且可有效恢復糖尿病小鼠肝臟的殺菌能力，因此iNOS的調控將可能成為治療糖尿病小鼠肝臟損傷過程中的有效方向。

Diabetic patients with pyogenic liver abscesses caused by Klebsiella pneumoniae (K. pneumoniae) usually found in Taiwan but the pathogenic mechanism for this observation is still unclear. It is known a vast array of microbes reside in human intestine and their composition are closely related to host’s immunity. Thus, diabetic C57BL/6 mice induced by streptozotocin were used to investigate the correlation between liver injury progression and changes of intestinal microbiome as well as immunity. When diabetic mice were induced for a month, the results revealed that liver injury was occurred according to increased plasma ALT levels and decreased hepatic bacterial clearance, in addition, intestinal bacteria overgrowth, enteric dysbiosis, increased intestinal bacterial translocation especially pathogenic K. pneumonia, and dysfunctional mucosal immune system were also observed. However, treating with the probiotic, Lactobacillus salivarius or the prebiotic, fructo-oligosaccharides could significantly improve the broken intestinal homeostasis, restored mucosal antibacterial protein, and lessened liver injury progression in diabetic mice. Moreover, increased intestinal iNOS activity and nitrate as well as endotoxin in portal vein were restored not only by probiotic and prebiotic but also by pharmacological inhibitor of iNOS, L-NAME in diabetic mice. Then, through decreasing IL-1β expression in Kupffer cells by L-NAME, hepatic bacterial clearance was significantly restored in diabetic mice. Therefore, iNOS may be a useful target for prevention of liver injury progression in diabetic patients.

Acknowledgement…………………………………………………...i
Abstract in Chinese.....................................................................ii
Abstract in English......................................................................iii
Introduction..................................................................................1
Materials and Methods................................................................9
Results.......................................................................................19
Discussion ..................................................................................27
Figures........................................................................................33
Tables.........................................................................................63
Appendix.....................................................................................68
References..................................................................................70

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