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.

低碳水化合物生酮饮食（KD）长期以来一直被用于减肥，但其潜在机制仍然难以捉摸。尽管尚不清楚所涉及的特定肠道微生物或代谢物，但肠道微生物群和代谢物已被认为可以介导 KD 摄入引起的代谢变化。在这里，我们发现，摄入 KD 可以提高小鼠血清中牛磺脱氧胆酸 (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。从机制上讲，KD 喂养会降低编码胆汁盐水解酶 (BSH) 的肠道细菌鼠乳杆菌 ASF361 的丰度。 L. murinus ASF361 的减少或 BSH 活性的抑制会增加 TDCA 和 TUDCA 的循环水平，从而通过抑制肠道碳酸酐酶 1 表达来减少能量吸收，从而导致体重减轻。在多种小鼠模型中，TDCA 和 TUDCA 治疗被发现可以预防肥胖及其并发症。此外，在健康人类参与者 (n = 416) 的观察性研究和超重或肥胖参与者的低碳水化合物 KD 干预研究中，一致观察到上述胆汁酸、微生物 BSH 和代谢特征之间的关联（n = 25）。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，通过摄入 KD 来降低体重和空腹血糖水平。我们的研究结果支持 TDCA 和 TUDCA 作为除 KD 之外的两种有前景的治疗肥胖及其并发症的候选药物。