Fig. 7

Network interactions reveal host-microbiome interactions (HMI) driven by estrogen status. a–d The HMI network (a) was first built from Spearman’s nonparametric rank correlation coefficient (P < 0.05) between host parameters and microbial genera. Each node was colored according to the “data type” and sized based on “betweenness centrality,” which quantifies the influence of a node in connecting other nodes within network values. Edges (lines) represent statistically significant correlations and are colored light black for positive and blue for negative correlations. Next, nodes were grouped as modules (a set nodes connected to each other by many links, while connected by few links to nodes of other groups) and the first three largest modules of the network were taken to show the relationship between specific genera and host parameters (b-d). e Partial least square (PLS) regression loading score plot. The plot illustrates the association of between host parameters (dependent variables colored blue) and microbial genera (explanatory variables colored red). Samples from five different groups were observations (green dots). Leave one-out cross-validation (LOO-CV) was applied. The global goodness of fit (Q²cum) and the predictive quality of the models (R²Y and R²X cum) values were inserted on the top left corner of the figure. f Diagram illustrating a proposed mechanism. Endogenous estrogens in the female mice, exogenous supplementation of 17β-estradiol (17β-E) to male (M+17β-E) and ovariectomized female (OVX+17β-E) mice and dietary supplementation of isoflavones (ISO) to male mice upregulate nuclear transcription factors (KLF4) that target IAP, which, in turn, increases the endogenous IAP activity in the gut. Elevated IAP activity leads to decreased Proteobacteria and Firmicutes to Bacteroidetes ratio (FIR/BAC), increased Bifidobacterium to Enterobacteriacea ratio (B/E), and the abundance of Akkermansia genera, decreasing LPS-producing bacteria (e.g., Proteobacteria) while increasing LPS-suppressing bacteria (e.g., Bifidobacterium and Akkermansia mucinophila). These changes lower LPS production (LPS biosynthesis and related proteins) and intestinal permeability, resulting in reduced metabolic endotoxemia (serum LPS/LPS binding proteins/soluble CD14). The subsequent reduction of inflammatory cytokines leads to the suppression of low-grade chronic inflammation and metabolic syndrome. AI, atherogenic index; TG, triglyceride; IAP, intestinal alkaline phosphatase; E2, 17β-estradiol