Gut microbiome stratification reveals functional metabolic signatures linked to host health

The human gut microbiome exhibits reproducible taxonomic configurations, yet the ecological processes linking them to health remain unclear. We applied the five-enterosignature (ES) model to 5,169 metagenomes of Le French Gut participants and developed a rule-based framework that stratifies continuous microbiome variation into interpretable partitions. Across these partitions, hydrogen disposal pathways formed distinct functional gradients, reproduced in an international meta-cohort (n = 5,107). Partitions dominated by Prevotella enterosignature showed greater sulfate-reduction potential, ES-Firmicutes-associated partitions greater methanogenesis potential, and ES-Bacteroides-enriched partitions greater acetogenesis potential. The latter were also characterized by oxidative-stress and mucin-degradation signatures, altered fecal mucin O-glycosylation, and less favorable health indicators, including more frequent digestive symptoms, higher perceived stress, and more psychotropic drug prescriptions. These patterns were also accompanied by distinct dietary profiles. Our findings link hydrogen metabolism, redox-associated functions, mucin utilization, diet, and host health, and support enterosignature-based partitioning for cross-cohort comparisons and future stratified interventions.