The Human Diets & Microbiome Initiative: A five-country analysis of geographic and dietary drivers of gut microbiome composition and genomic variation

Human diet and lifestyle vary widely across cultures, shaping global diversity in gut microbiome composition and function. However, comparable cross-population studies have been limited by methodological heterogeneity. The Human Diets and Microbiome Initiative (THDMI) integrates standardized recruitment, dietary assessment, and shotgun metagenomics across 1,976 participants from the United States, United Kingdom, Spain, Mexico, and Japan to disentangle biological from technical variation. We observed pronounced geographic differences in nutrient intake, food consumption, and microbial composition, with both shared and country-specific taxa linked to diet quality. Sparse canonical correlation and machine-learning analyses revealed that microbiome–diet associations were largely population-specific, with limited cross-country generalization. Strain-level analyses further uncovered significant genomic differentiation of gut microbes, reflecting localized dietary and ecological pressures. Together, these results show that while core microbial responses to healthy eating exist, the structure and function of the human gut microbiome are profoundly shaped by culture, geography, and long-term dietary practices.