The ketogenic diet alters microbiome‐metabolome profiles to improve West syndrome therapy

ABSTRACT Importance The ketogenic diet (KD) is effective in managing epilepsy, particularly West syndrome (WS); however, the role of gut microbiome (GM) and metabolome in its efficacy remains unclear. Understanding these mechanisms could optimize the KD for WS treatment. Objective To identify microbiome‐metabolome signatures associated with KD efficacy in WS by analyzing changes in GM composition and metabolic pathways. Methods Fecal samples were collected from WS patients ( n = 16) and healthy children ( n = 24). Metagenome and metabolome analyses were performed to assess GM composition and metabolic profiles. Results WS patients showed GM imbalances compared to healthy children. Disease status contributed sufficiently to the GM. The abundance of Bacteroides , Parabacteroides , and Faecalibacterium was lower in WS (3.30% vs. 39.86%, P ‐adj = 0.140; 0.14% vs. 0.73%, P ‐adj = 0.023; 0.04% vs. 1.35%, P ‐adj = 0.018), whereas Bifidobacterium and Escherichia were higher (6.08% vs. 2.23%, P ‐adj = 0.140; 7.57% vs. 0.15%, P ‐adj Parabacteroides (particularly P. distasonis ) and Bacteroides (particularly B. fragilis ) increased (0.14% vs. 0.35%, P ‐adj = 0.034; 3.30% vs. 21.18%, P ‐adj = 0.380); Bifidobacterium (particularly B. breve ) and Escherichia (particularly E. coli ) decreased from 6.08% and 7.57% to 1.24% and 2.52%, respectively. Kyoto Encyclopedia of Genes and Genomes pathway analysis demonstrated that ATP‐binding cassette (ABC) transporters, fatty acid biosynthesis, tyrosine metabolism, and other pathways were significantly altered in patients with WS, and these alterations were reversed following ketogenic diet (KD) consumption. The KD also altered intestinal metabolites. Integrative analysis of microbial features, gene functions, and metabolites revealed that Bacteroides species and P. distasonis were significantly associated with ABC transporters, alanine aspartate and glutamate metabolism, and negatively correlated with 3‐sulfinoalanine, suggesting potential regulatory roles in metabolic pathways. Interpretation KD induces significant shifts in GM composition and metabolic pathways, which may contribute to its therapeutic efficacy in WS. The restoration of Bacteroides and Parabacteroides dominance, alongside alterations in gene functions and neurotransmitter‐related metabolites, suggests a potential mechanism for the antiepileptic effects of KD.