Y. Zhang, X. Li, X. Zhang, Y. Wang, Z. Chen, X. Lin, X. Zheng, H. Hao, et al. (2026). Ketogenic Diet Modulates Depressive-Like Behavior via Gut Bacterial Metabolism of Tyrosine. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 40(10), e71966. https://doi.org/10.1096/fj.202504666RRR

PubMed 42186771

[Abstract]
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.