Exploring Population Differences in the Human Gut Microbiome: From Microbial Abundance to Genomic Variants

The human gut microbiota demonstrated significant population-specific differences driven by various factors such as host genetics, diet, and lifestyle, especially between the Han Chinese and non-Chinese populations. However, most previous studies focused on taxonomic composition and relative abundances, neglecting crucial roles of microbial genomic variations in shaping metabolic functions and characteristics due to the lack of a high-quality gut reference genome catalog. Existing catalogs are often biased toward Western populations and rely on publicly available datasets that lack detailed metadata to ensure robust geographical and demographic coverage, particularly for the Han Chinese population, which is marked by significant dietary and lifestyle diversity across regions. To bridge this gap, we constructed a high-quality gut reference genome catalog comprising 271,601 non-redundant genomes representing 5,785 prokaryotic species by using metagenomic sequencing data from 9,320 public-available samples across 22 countries and 3,584 newly sequenced Han Chinese samples across 29 provinces and regions. Based on our catalog, we conducted a systematical investigation of gut microbial differences between the Han Chinese and non-Chinese populations through discovery and replication cohorts. Our analyses revealed geography as the primary driver of microbial variation, surpassing age, sex, and BMI. We identified 625 novel genome clusters with population-specific traits and significant functional differences in the phosphotransferase system, and 126 species with distinct prevalence linked to vitamin biosynthesis, drug resistance, and carbohydrate metabolism. Furthermore, beta diversity analysis highlighted greater inter-population differences, while alpha diversity analysis indicated non-Chinese populations exhibited higher species-level diversity on abundance, and Han Chinese populations displayed greater strain-level diversity on single nucleotide polymorphisms. These findings provide valuable insights into population-specific microbial diversity, laying the groundwork for future research on its functional and health implications.