The human gut microbiome plays an important biological role in host health, yet over 60% of gut species remain uncultured and hence inaccessible to experimental manipulation. Here we analysed 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 identified 317 uncultured species linked to distinct health states, with most microbiome signatures being disease specific. Uncultured bacteria were more abundant in healthy controls, with the genus CAG-170 predicted as the strongest biomarker of health. The genetic diversity and abundance of CAG-170 negatively correlated with gut microbiome imbalance over time, and ecological modelling identified it as the top candidate keystone genus among healthy populations globally. Functional prediction analysis showed CAG-170 species have greater capabilities for vitamin B12 biosynthesis but lack key genes involved in arginine production, offering new biological insights into this elusive genus. Our findings shed light on the underexplored role of uncultured gut species in health and disease.