Rapid Remodeling of the Human Gut Microbiome in Response to Short‐Term Animal Product Restriction and Associations with Host Molecular Phenotypes

ABSTRACT Diet strongly influences the gut microbiome, which in turn influences health, yet the effects of dietary patterns on microbiome composition and function in humans remain underexplored. A unique group of apparently healthy individuals from Greece, who alternate between omnivory and restriction of animal products for religious reasons (periodically restricted group, n = 200), has been profiled. Using 16S rRNA sequencing, plasma metabolomics, and proteomics, the impact of three‐to‐four weeks of dietary restriction on gut microbiome composition and function is assessed and associations with host plasma biology are explored. Findings are compared to a continuously omnivorous group profiled in parallel (non‐restricted group, n = 211). Animal product restriction reduced microbial diversity, primarily affecting rare taxa, and altered the abundance of nearly one‐third of bacterial genera. Inferred functional shifts included downregulation of pathways contributing to cholesterol biosynthesis and purine degradation, alongside upregulation of vitamin B2 and tryptophan biosynthesis, suggesting compensatory microbial responses to dietary nutrient depletion. Multi‐omics integration revealed four microbial‐metabolite‐protein clusters, including a diet‐responsive module associating Negativibacillus with metabolic regulator FGF21 and intermediate‐density lipoproteins. These findings demonstrate rapid adaptive plasticity of the human gut microbiome in response to short‐term dietary restriction and highlight candidate microbial and molecular pathways associated with animal product restriction and host biology.