This study investigates the impact of a 2-week dietary intervention on human immunity and the microbiota. Twenty participants consumed either a vegan or ketogenic diet for 2 weeks, in a crossover design. Using multiomics approaches, including flow cytometry, transcriptomics, proteomics, metabolomics, and metagenomics, the researchers assessed the effects of each diet and the dietary switch on host immunity and the microbiome. The results showed that the ketogenic diet significantly upregulated pathways and enriched cells associated with the adaptive immune system, while the vegan diet had a significant impact on the innate immune system, including upregulation of antiviral immunity pathways. Both diets significantly altered the microbiome and host-associated amino acid metabolism, with a strong downregulation of microbial pathways following the ketogenic diet compared to baseline and the vegan diet. The study also observed a tightly connected network between datasets driven by compounds associated with amino acids, lipids, and the immune system. These findings highlight the divergent effects of the ketogenic and vegan diets on host immunity and the microbiome, suggesting that controlled dietary interventions can significantly impact these systems.This study investigates the impact of a 2-week dietary intervention on human immunity and the microbiota. Twenty participants consumed either a vegan or ketogenic diet for 2 weeks, in a crossover design. Using multiomics approaches, including flow cytometry, transcriptomics, proteomics, metabolomics, and metagenomics, the researchers assessed the effects of each diet and the dietary switch on host immunity and the microbiome. The results showed that the ketogenic diet significantly upregulated pathways and enriched cells associated with the adaptive immune system, while the vegan diet had a significant impact on the innate immune system, including upregulation of antiviral immunity pathways. Both diets significantly altered the microbiome and host-associated amino acid metabolism, with a strong downregulation of microbial pathways following the ketogenic diet compared to baseline and the vegan diet. The study also observed a tightly connected network between datasets driven by compounds associated with amino acids, lipids, and the immune system. These findings highlight the divergent effects of the ketogenic and vegan diets on host immunity and the microbiome, suggesting that controlled dietary interventions can significantly impact these systems.