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.