Ketogenic diet inhibits glioma progression by promoting gut microbiota-derived butyrate production

The ketogenic diet (KD) is a potential therapeutic strategy for glioma; however, the underlying mechanisms remain unclear. Herein, we first identify that glioma patients exhibit a distinct gut microbial profile characterized by reduced butyrate-producing bacteria abundance, particularly R. faecis, along with decreased butyrate levels. Notably, KD reshapes the gut microbiota especially enriching A. muciniphila in a mucin-2-dependent manner, elevates butyrate production, and activates caspase-3 in microglia. These changes promote an anti-tumor microglial phenotype, ultimately suppressing glioma progression in mice. Crucially, KD's anti-glioma effect is notably abolished by antibiotics treatment; germ-free condition; or specific depletion of mucin-2, microglia, or microglial caspase-3. Furthermore, butyrate, A. muciniphila, R. faecis, or A. muciniphila plus R. faecis restores KD-induced microglial caspase-3 activation and the anti-tumor phenotype of microglia in antibiotics-treated or germ-free mice. These findings highlight that targeting the gut microbiota by KD or supplementing with butyrate could be an effective strategy for glioma therapy.