Meta-analysis of the uncultured gut microbiome across 11,115 global metagenomes reveals a candidate signature of health

The human gut microbiome is important for host health, yet over 60% of gut species remain uncultured and inaccessible to experimental manipulation. Here, we analyze 11,115 human gut metagenomes from 39 countries, 13 noncommunicable diseases, and healthy individuals to understand the clinical relevance of the uncultured microbiome worldwide. We identify 317 species linked to distinct clinical states, noting an overrepresentation of uncultured bacteria in healthy subjects. The genus CAG-170 emerged as the strongest health-associated lineage across multiple diseases and geographies, standing as the most central taxon based on ecological networks of healthy populations. We find that CAG-170 is temporally stable, with its abundance and subspecies diversity negatively correlated with gut imbalance over time. Functional predictions show CAG-170 species have greater vitamin B12 biosynthesis capacity and cross-feeding potential, providing important biological insights into this elusive genus. Our findings shed light on the underexplored role of uncultured gut species in health and disease. • Meta-analysis of 11,115 gut metagenomes links uncultured species to human health • Healthy individuals show enrichment and greater diversity of uncultured bacteria • The genus CAG-170 contains uncultured taxa with the strongest health signatures • CAG-170 is ecologically important in healthy populations Silva et al. perform a global analysis of over 11,000 gut microbiomes and reveal that uncultured bacteria are key markers of gut health. The uncultured genus CAG-170 is strongly linked to low gut dysbiosis and high vitamin B12 production and plays key ecological roles in the healthy gut.