Ketogenic Diet Modulates Depressive‐Like Behavior via Gut Bacterial Metabolism of Tyrosine

Emerging evidence suggests the therapeutic potential of ketogenic diet (KD) for mood disorders such as depression, yet the underlying mechanisms are poorly understood. Here we report a gut microbe-to-brain signaling pathway through which KD protects against depressive-like behavior in mice. We show that KD feeding triggers a prompt and dynamic remodeling of the gut microbiome, the depletion of which abrogates the protective effect of KD against depressive-like behavior in stressed mice. Colonization with Roseburia intestinalis (R. intestinalis), which is enriched by 1-week KD, sustains the protective effect of KD against depressive-like behavior in mice. The protective effect of KD is linked to the reduction of a host-microbe co-metabolite p-Cresol sulfate (p-CS), the supplementation of which negates the protective effect of KD against depressive-like behavior. Mechanistically, p-CS enters the brain and activates lateral habenula (LHb) to counteract the protective effect of KD. Our findings uncover a gut microbiota-brain axis mechanism for KD consumption to protect against depressive-like behavior.