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.

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.