Abstract：
The low-carbohydrate ketogenic diet (KD) has long been practiced for weight loss, but the underlying mechanisms remain elusive. Gut microbiota and metabolites have been suggested to mediate the metabolic changes caused by KD consumption, although the particular gut microbes or metabolites involved are unclear. Here, we show that KD consumption enhances serum levels of taurodeoxycholic acid (TDCA) and tauroursodeoxycholic acid (TUDCA) in mice to decrease body weight and fasting glucose levels. Mechanistically, KD feeding decreases the abundance of a bile salt hydrolase (BSH)-coding gut bacterium, Lactobacillus murinus ASF361. The reduction of L. murinus ASF361 or inhibition of BSH activity increases the circulating levels of TDCA and TUDCA, thereby reducing energy absorption by inhibiting intestinal carbonic anhydrase 1 expression, which leads to weight loss. TDCA and TUDCA treatments have been found to protect against obesity and its complications in multiple mouse models. Additionally, the associations among the abovementioned bile acids, microbial BSH and metabolic traits were consistently observed both in an observational study of healthy human participants (n = 416) and in a low-carbohydrate KD interventional study of participants who were either overweight or with obesity (n = 25). In summary, we uncover a unique host-gut microbiota metabolic interaction mechanism for KD consumption to decrease body weight and fasting glucose levels. Our findings support TDCA and TUDCA as two promising drug candidates for obesity and its complications in addition to a KD.
摘要：
低碳水化合物生酮饮食（KD）长期以来一直被用来减肥，但是潜在的机制仍然难以捉摸。肠道菌群和代谢产物已被认为介导由KD消耗引起的代谢变化，尽管涉及的特定肠道微生物或代谢产物尚不清楚。这里,我们显示,消耗KD可提高小鼠血清中牛磺去氧胆酸(TDCA)和牛磺熊去氧胆酸(TUDCA)的水平,从而降低体重和空腹血糖水平.机械上,KD饲喂降低了胆盐水解酶（BSH）编码的肠道细菌的丰度，鼠乳杆菌ASF361。鼠乳杆菌ASF361的减少或BSH活性的抑制增加了TDCA和TUDCA的循环水平,从而通过抑制肠道碳酸酐酶1的表达来减少能量吸收，导致体重减轻。已发现TDCA和TUDCA治疗可在多种小鼠模型中预防肥胖及其并发症。此外,上述胆汁酸之间的关联，在一项针对健康人参与者的观察性研究(n=416)和一项针对超重或肥胖参与者的低碳水化合物KD干预性研究(n=25)中,均一致观察到微生物BSH和代谢特征.总之,我们发现了一种独特的宿主-肠道微生物群代谢相互作用机制,用于KD消耗以降低体重和空腹血糖水平。我们的发现支持TDCA和TUDCA作为两种有希望的药物候选肥胖及其并发症除了KD。
