Table_2_Genetically Obese Human Gut Microbiota Induces Liver Steatosis in Germ-Free Mice Fed on Normal Diet.XLSX

Dysbiotic gut microbiota contributes to genetically obese phenotype in human. However, the effect of genetic obesity-associated gut microbiota on host hepatic metabolic deteriorations remains largely unknown. Gut microbiota from a genetically obese human donor before and after a dietary weight loss program was transplanted into germ-free C57BL/6J male mice, grouped as PreM and PostM groups, respectively. The gut microbiome, liver pathology and transcriptome response in the gnotobiotic mice were evaluated. After being fed on normal chow diet for 4 weeks, PreM group developed liver macrovesicular steatosis accompanied with higher concentrations of hepatic triglyceride and cholesterol, while PostM group exhibited normal hepatic physiology. The gut microbiota in PreM and PostM groups was significantly different from each other and was more resembling with their respective donor. RNA-sequencing revealed that, in comparison with PostM group, PreM group showed a foregoing pro-steatotic transcriptional response in liver featuring by the repression of lipid beta-oxidation and the activation of lipid absorption and cholesterol uptake before the pathology of liver steatosis. Moreover, peroxisome proliferator-activated receptor alpha (PPARα), which was repressed in PreM group, may act as crucial regulator of the hepatic transcriptional profile of lipid metabolism between two groups. Our results show that gut microbiota from a genetically obese human promotes the onset of liver steatosis by impacting hepatic transcriptional profile of lipid metabolism in mice. This adds new evidence that gut microbiota may play a causative role in the development of non-alcoholic fatty liver disease.

肠道菌群失调（dysbiotic gut microbiota）可促成人类遗传性肥胖表型。然而，遗传性肥胖相关肠道菌群对宿主肝脏代谢损伤的影响仍未得到充分阐明。本研究将遗传性肥胖人类供体在膳食减重方案实施前后的肠道菌群，分别移植至无菌（germ-free）C57BL/6J雄性小鼠体内，对应分为PreM组与PostM组。随后对悉生（gnotobiotic）小鼠的肠道菌群、肝脏病理学及转录组应答情况进行评估。经普通饲料喂养4周后，PreM组小鼠出现肝脏大泡性脂肪变性，伴随肝内甘油三酯与胆固醇水平升高；而PostM组小鼠肝脏生理状态保持正常。PreM组与PostM组的肠道菌群存在显著差异，且分别与其供体的菌群特征高度相似。RNA测序结果显示，在肝脏脂肪变性病理出现前，相较于PostM组，PreM组小鼠肝脏已呈现促脂肪变性的转录应答特征：表现为脂质β氧化受到抑制，同时脂质吸收与胆固醇摄取通路被激活。此外，在PreM组中受到抑制的过氧化物酶体增殖物激活受体α（PPARα），可能是两组小鼠肝脏脂质代谢转录谱差异的关键调控因子。本研究结果表明，遗传性肥胖人类供体的肠道菌群可通过影响小鼠肝脏脂质代谢的转录谱，促进肝脏脂肪变性的发生。这为肠道菌群可能在非酒精性脂肪性肝病（non-alcoholic fatty liver disease, NAFLD）的发生发展中发挥致病作用提供了新的实验证据。