UCSF

Very low-carbohydrate, high-fat “ketogenic” diets (KDs) induce a pronounced shift in metabolic fuel utilization that elevates circulating ketone bodies; however, the downstream consequences of these compounds for host-microbiome interactions remains unknown. My thesis work shows 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 collected during 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 directly inhibit bifidobacterial growth. Finally, mono-colonizations and human microbiome transplantations into germ-free mice revealed that the KD-associated gut microbiota reduces the levels of pro-inflammatory Th17 cells in the gut. Together, these results highlight the importance of trans-kingdom chemical dialogues for mediating the host response to dietary interventions.