Data_Sheet_1_Genetically Obese Human Gut Microbiota Induces Liver Steatosis in Germ-Free Mice Fed on Normal Diet.PDF

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）可促成人类的遗传性肥胖表型。然而，遗传性肥胖相关肠道菌群对宿主肝脏代谢异常的影响目前仍知之甚少。本研究将一名遗传性肥胖人类供体在饮食减重方案实施前后的肠道菌群分别移植到无菌C57BL/6J雄性小鼠体内，分别命名为PreM组与PostM组。随后对悉生小鼠（gnotobiotic mice）的肠道菌群组成、肝脏病理状态及转录组应答反应进行了评估。在普通维持饲料喂养4周后，PreM组小鼠出现肝脏大泡性脂肪变性，伴随肝脏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组的肠道菌群组成存在显著差异，且更接近于各自的供体菌群。RNA测序（RNA-sequencing）结果显示，相较于PostM组，PreM组在肝脏脂肪变性病理发生前即呈现出促脂肪变性的转录应答特征，具体表现为脂质β氧化受到抑制、脂质吸收与胆固醇摄取被激活。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），可能是调控两组间肝脏脂质代谢转录谱的关键因子。本研究结果表明，源自遗传性肥胖人类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。这为肠道菌群在非酒精性脂肪性肝病（non-alcoholic fatty liver disease）发生发展中的致病作用提供了新的证据。