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bioRxiv · 10.64898/2025.12.08.693055

The FERM Guild: A Differentially Correlated Microbial Module Drives Hypertension via Metabolic Flux Perturbations

Lai, W.·Zhang, Y.·Huang, S.·Lai, S.·Lin, F.·Wang, Z.·Sun, S.·Yang, F. l.
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Abstract

BackgroundHypertension 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. ResultsParsimonious Flux Balance Analysis (pFBA), integrated with Double Machine Learning (DoubleML), identified 17 metabolites significantly associated with hypertension (p < 0.05, RobustnessV alue > 0.1). These included meso-2,6-diaminoheptanedioate, p-hydroxyphenylacetic acid, cellobiose, dextran 40 (1,6--D-glucan), L-glutamic acid, kestopentaose, among others. Differential microbial correlation network analysis identified a key microbial sub-network, the FERM guild, consisting of 19 species, with prominent genera including Faecalibacterium,Enterobacter,Roseburia, and Methanobrevibacter. Using 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 genus 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 genus and other species. ConclusionsOur 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.

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Lai, W., Zhang, Y., Huang, S., Lai, S., Lin, F., Wang, Z., Sun, S., Yang, F. l.. 2025-12-11. The FERM Guild: A Differentially Correlated Microbial Module Drives Hypertension via Metabolic Flux Perturbations. https://doi.org/10.64898/2025.12.08.693055

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