Germfree C57BL/6J mice are resistant to high fat diet-induced insulin resistance and have altered cholesterol metabolism. Mus musculus

Germfree (GF) mice have been used as a model to study the contribution of the intestinal microbiota to metabolic energy balance of the host. Despite a wealth of knowledge accumulated since the 1940’s, the response of GF mice to a high fat diet is largely unknown. In the present study, we compared the metabolic consequences of a high fat (HF) diet on GF and conventional (Conv) C57BL/6J mice. As expected, Conv mice developed obesity and glucose intolerance with a HF diet. In contrast, GF mice remained lean and resisted the HF diet-induced insulin resistance. The anti-obesity phenotype of GF/HF mice was accompanied by reduced caloric intake, diminished food efficiency, and excessive fecal lipid excretion contributed to the reduced food efficiency. In addition, HF diet-induced hypercholesterolemia was ameliorated, which was partially due to an increase in fecal cholesterol excretion. However, hepatic cholesterols were increased in GF/HF mice. Elevated nuclear SREBP2 proteins and the up-regulation of cholesterol biosynthesis genes support the increased liver cholesterol biosynthesis in GF/HF mice. The resistance to HF diet-induced metabolic abnormalities in GF mice was also associated with a reduced immune response, indicated by low plasma pro-inflammatory and anti-inflammatory markers. These data suggest that the gut microbiota of Conv mice contributes to HF diet-induced obesity, insulin resistance, dyslipidemia and hepatic steatosis in mice. Thus, results of the present study describe the metabolic responses of GF mice to a HF diet and further our understandings of the relationship between the gut microbiota and the host. Overall design: Germfree and conventional C57BL/6J mice were fed with a high fat diet for 11 weeks. Then, all mice were sacrified under 10-h food deprevation, and liver samples of germfree (n=14) and conventional (n=16) were examined.

无菌（Germfree, GF）小鼠常被用作模型，以研究肠道菌群对宿主代谢能量平衡的调控作用。尽管自1940年代以来已积累了大量研究成果，但无菌小鼠对高脂饮食的响应在很大程度上仍未明确。本研究比较了高脂（High Fat, HF）饮食对无菌与常规（Conventional, Conv）C57BL/6J小鼠的代谢影响。正如预期，常规小鼠在饲喂高脂饮食后出现肥胖与葡萄糖耐受不良。与之相反，无菌小鼠维持瘦体型，并可抵抗高脂饮食诱导的胰岛素抵抗。无菌/高脂饮食组小鼠的抗肥胖表型伴随热量摄入减少、食物利用率降低，且粪便脂质排泄增加进一步加剧了食物利用率的下降。此外，高脂饮食诱导的高胆固醇血症得到缓解，这一现象部分源于粪便胆固醇排泄量的增加。然而，无菌/高脂饮食组小鼠的肝脏胆固醇水平却有所升高。核SREBP2蛋白水平升高以及胆固醇生物合成基因的上调，佐证了无菌/高脂饮食组小鼠肝脏胆固醇生物合成增强的结论。无菌小鼠抵抗高脂饮食诱导的代谢异常还与免疫应答减弱相关，表现为血浆促炎与抗炎标志物水平偏低。上述数据表明，常规小鼠的肠道菌群参与介导了高脂饮食诱导的小鼠肥胖、胰岛素抵抗、血脂异常与肝脂肪变。因此，本研究明确了无菌小鼠对高脂饮食的代谢响应，并进一步加深了我们对肠道菌群与宿主间相互关系的认知。
总体实验设计：将无菌与常规C57BL/6J小鼠饲喂高脂饮食11周。随后，所有小鼠在禁食10小时后处死，采集无菌组（n=14）与常规组（n=16）的肝脏样本进行检测。