The FERM guild: a differentially correlated microbial module drives hypertension via metabolic flux perturbations

Hypertension is a major risk factor for cardiovascular diseases, with changes in gut microbiota composition and function being closely associated with its onset and progression. However, the high inter-individual variability in gut microbiota complicates the identification of pathogenic mechanisms using traditional methods. In contrast, the smaller variability in gut microbial metabolites offers a more reliable and consistent basis for cross-individual comparisons. Parsimonious flux balance analysis (pFBA), integrated with double machine learning (DoubleML), identified 17 metabolites significantly associated with hypertension ( P < 0.05, robustness value [RV] >0.1). These included meso-2,6-diaminoheptanedioate, p-hydroxyphenylacetic acid, cellobiose, dextran 40 (1,6-α-D-glucan), L-glutamic acid, and kestopentaose, among others. Differential microbial correlation network analysis identified a key microbial subnetwork, termed the FERM guild, consisting of 19 species, with prominent genera including Faecalibacterium, Enterobacter, Roseburia , and Methanobrevibacter . Using Gene Set Enrichment Analysis (GSEA), the dysregulation of this guild was found to be strongly associated with a set of 17 hypertension-related metabolites ( P = 0.017). Further analysis revealed that the contribution of FERM genera to key metabolites is significantly associated with blood pressure ( P < 0.05), even without significant differences in their abundance; additionally, an imbalance exists between FERM genera and other species. Our findings reveal that hypertension is associated with a disruption of gut microbial diversity, structure, and metabolic function. Seventeen key metabolites related to blood pressure regulation were identified, exhibiting pro- or anti-hypertensive potential and linked to functional microbial modules. These results highlight the gut microbiota and its metabolites as promising targets for therapeutic intervention in hypertension.

IMPORTANCE

Hypertension remains a major global public health burden; however, most studies on its relationship with the gut microbiota rely on traditional species-abundance analyses, which are limited by substantial inter-individual variability. In contrast, microbial metabolites show greater stability across individuals and thus offer a more reliable entry point for mechanistic research. By integrating metabolic modeling, causal inference, and network analysis, this study identified 17 key metabolites significantly associated with blood pressure and uncovered a functionally coordinated microbial community (FERM) whose contribution to critical metabolic fluxes (rather than its taxonomic abundance) was closely linked to hypertension. These findings reveal a metabolite-centered mechanism connecting microbial functions to host blood pressure regulation and provide new potential targets for microbiome-based interventions.