Very low-carbohydrate, high-fat ketogenic diets (KDs) induce a pronounced shift in metabolic fuel utilization that elevates circulating ketone bodies; however, the consequences of these compounds for host-microbiome interactions remain unknown. Here, we show that KDs alter the human and mouse gut microbiota in a manner distinct from high-fat diets (HFDs). Metagenomic and metabolomic analyses of stool samples from an 8-week inpatient study revealed marked shifts in gut microbial community structure and function during the KD. Gradient diet experiments in mice confirmed the unique impact of KDs relative to HFDs with a reproducible depletion of bifidobacteria. In vitro and in vivo experiments showed that ketone bodies selectively inhibited bifidobacterial growth. Finally, mono-colonizations and human microbiome transplantations into germ-free mice revealed that the KD-associated gut microbiota reduces the levels of intestinal pro-inflammatory Th17 cells. Together, these results highlight the importance of trans-kingdom chemical dialogs for mediating the host response to dietary interventions.

极低碳水化合物、高脂肪生酮饮食 (KD) 会引起代谢燃料利用率的显着变化，从而提高循环酮体；然而，这些化合物对宿主-微生物组相互作用的影响仍然未知。在这里，我们发现 KD 以不同于高脂肪饮食 (HFD) 的方式改变人类和小鼠肠道微生物群。一项为期 8 周的住院研究粪便样本的宏基因组学和代谢组学分析揭示了 KD 期间肠道微生物群落结构和功能的显着变化。小鼠的梯度饮食实验证实了 KD 相对于 HFD 的独特影响，可重复消除双歧杆菌。体外和体内实验表明酮体选择性抑制双歧杆菌生长。最后，单定植和人类微生物组移植到无菌小鼠体内表明，与川崎病相关的肠道微生物群降低了肠道促炎 Th17 细胞的水平。总之，这些结果强调了跨界化学对话对于调节宿主对饮食干预的反应的重要性。