Gut microbial metabolic flux disorder in hypertension

ABSTRACT Hypertension is a major risk factor for cardiovascular diseases such as stroke and heart failure. Recent studies have shown that changes in the composition and function of the gut microbiota are closely related to the onset and development of hypertension. However, the individual differences in gut microbiota species make it difficult for traditional analysis methods to effectively reveal the pathogenic mechanisms of hypertension. In contrast, the inter-individual variability in gut microbial metabolites is much smaller, allowing for better cross-individual comparisons and reducing confounding factors in analysis. The interactions between gut microbiota and metabolites are highly complex, and network analysis can systematically capture this complexity. In this study Flux Balance Analysis (FBA) was utilized to predict the metabolic flux of gut microbiota and constructed cross-feeding networks. Random Forest and XGBoost models were employed to identify metabolites associated with hypertension. A differential microbial correlation network was used to analyze important metabolically related microbial sub-networks, and ultimately, the metabolic abnormalities and metabolite-related pathways were analyzed at the network level using the metabolite correlation network and cross-feeding networks. It was observed that the interaction patterns among 25 species—collectively referred to as the KEPR guild, with the most abundant genera being Eubacterium, Ruminococcus, Klebsiella, and Parabacteroides—changed, leading to alterations in 12 metabolites, such as choline (chol), 1-butanol (btoh), trimethylamine (tma), cytidine (cytd), and betaine (glyb) etc. Choline can be oxidized to form betaine, thereby affecting host blood pressure. Abnormalities in siroheme and methanethiol may result in reduced secretion of hydrogen sulfide by microbes, which in turn impacts blood pressure regulation mechanisms. The changes in these 12 metabolites may also enhance the degradation of mucin-type O-glycans and reduce butyrate metabolic activity, weakening the protective ability of intestinal epithelial cells. This may lead to inflammation and oxidative stress, exacerbating endothelial cell damage and consequently resulting in endothelial dysfunction and increased blood pressure. The findings of this study provide new insights into the pathogenic mechanisms of hypertension and offer potential targets for clinical intervention.