Genomic diversity and underlying metabolic variations of the human gut microbiome between populations at single nucleotide resolution

Understanding microbial genomic diversity across populations is crucial for advancing personalized medicine and addressing regional health disparities. However, with 70% of current gut microbial genome data from Europeans and the Americans, regions like East Asia, including China, remain underrepresented, limiting our understanding of global microbial genomic diversity and its health impacts. Here, we present the Global gut Microbiome Reference (GMR), a comprehensive dataset of 478,588 high-quality microbial genomes from Chinese (247,134) and non-Chinese (231,454) populations, covering 6,664 species, 26.4% of which are potential newly classified. Analysis of single nucleotide variations (SNVs) across 304 globally prevalent species revealed that 24.7%, especially from the Lachnospiraceae and Ruminococcaceae families, showed significant genetic differences between Chinese and non-Chinese populations, primarily linked to antibiotic resistance, virulence, and other health-related functions. By integrating these new species into the MetaPhlAn4 database, we enhanced species profiling by up to 22.8%, and established replicable abundance associations to host phenotypic traits between cohorts. Additionally, we found that microbial strain diversity at the SNV level, independent of abundance, was associated with host phenotypic traits, such as cardiometabolic-related risk factors like obesity. In vitro experiments with Bacteroides fragilis_A further highlighted the regulatory role of microbial SNVs in metabolites related to cardiometabolic health. These findings emphasize the need to consider gut microbial genetic diversity in population studies for better insights into regional microbiome differences and their health implications.