基于肠道产甲烷菌研究乙酸抑制肥胖的作用机制

Short-chain fatty acids (SCFAs) produced by intestinal microflora fermentation are closely associated with body weight and obesity. The supplemention of exogenous SCFAs, especially the acetic acid, has significant effects on prevention and treatment of body weight gain in the high-fat diet induced obese (DIO) mice. In our previous work, we found that dietary supplementation of SCFAs including the acetic acid can normalize the structure of the gut bacteria. Thus, we hypothesize that exogenous acetic acid may also have an impact on archaea such as methanogens (usually functions by interacting with acedogenic hydrogenogens), which in turn may affect intestinal function and nutrient absorption and ultimately inhibit body weight gain. In this project, using both the normal wild type and the germ free C57BL/6J mice fed with the high-fat diet to induce obesity, the effects of exogenous acetic acid supplementation on the intestinal methanogens, acedogenic hydrogenogens and endogenous acetic acid production will be examined. Then the methanogens will be transplanted into germ free mice intestine, to investigate the effect of exogenous acetic acid on body weight gain in the DIO mice and the association between the methanogens and acetic acid. Finally, the effects of the methanogens on the intestinal mucus barrier and absorptive functions will be examined. This project will be helpful and meaningful for understanding the mechanisms of acetic acid regulating body weight and for the prevention and treatment of obesity.

肠道菌群发酵产生的短链脂肪酸与体重调控和肥胖发生密切相关；外源性短链脂肪酸补充对高脂诱导的肥胖小鼠体重增加具有显著的预防和治疗作用，其中以乙酸作用最为明显。针对其作用机制，我们前期研究结果发现，补充乙酸等短链脂肪酸可使肠道细菌结构趋于正常化。我们推测，外源性乙酸也可能会对肠道产甲烷菌等古菌（与产氢产乙酸菌为互营菌）产生影响，进而影响肠道功能和营养素吸收，最终抑制体重。本项目拟以普通和无菌C57BL/6J幼年小鼠为研究对象，高脂饲料喂养诱导肥胖，采用乙酸进行喂养干预，首先观察外源补充乙酸对肠道产甲烷菌、产氢产乙酸菌以及内源性乙酸生成的影响；继而给无菌小鼠肠道移植产甲烷菌，观察外源补充乙酸对高脂饲料诱导下体重的影响；最后探讨产甲烷菌的变化对肠道黏液屏障和吸收等功能的影响，以明确其可能的机制。本项目对于揭示乙酸调控体重的机制，对于肥胖防治，均有重要的意义

肥胖已经成为全球公共健康问题，并且带来了巨大的经济负担。因此，迫切需要改进肥胖预防和控制策略。乙酸已经在临床试验中用于预防和控制肥胖，但其机制尚不清楚。大多数研究将乙酸抑制高脂饮食诱导肥胖小鼠的机制归因于食欲和能量代谢的调节。但还没有人关注外源乙酸是否对肠道菌群生成的内源乙酸和肠道产甲烷古菌产生影响。因此，我们推测，外源性乙酸可能对肠道菌群发酵产生的内源性乙酸产生影响，同时可能对肠道产甲烷古菌产生影响，进而影响宿主代谢。基于以上假设，我们采用补充外源乙酸的高脂饲料诱导肥胖小鼠建立动物模型，分别对小鼠粪便、血清和肝脏中乙酸进行分析，结果显示，外源乙酸对肠道菌群内源产生乙酸的影响并不明显，并且大部分外源乙酸通过上消化道吸收进入循环系统。因此，我们提出外源乙酸可能对宿主其他代谢产生影响。经过分析，我们发现乙酸是胆固醇合成底物，而胆固醇又是胆汁酸合成底物，其对肥胖有明显的抑制作用。因此，我们分析了小鼠肝脏、血清和粪便中胆汁酸的含量，发现外源乙酸可以触发肝脏胆汁酸的合成，这或许是乙酸抑制高脂饮食诱导肥胖的新机制，需进一步研究。另外，我们采用宏基因组测序对乙酸干预肥胖小鼠粪便菌群进行分析，结果表明，乙酸干预对粪便菌群包括产甲烷菌均有影响，但其对宿主代谢的影响需进一步深入研究。本项目对于揭示乙酸调控体重的机制和肥胖的预防和治疗均有重要的意义。