Improvements in Metabolic Syndrome by Xanthohumol Derivatives Are Linked to Altered Gut Microbiota and Bile Acid Metabolism

Abstract

Scope: Two hydrogenated xanthohumol (XN) derivatives, α,β-dihydro-XN (DXN) and tetrahydro-XN (TXN), improved parameters of metabolic syndrome (MetS), a critical risk factor of cardiovascular disease (CVD) and type 2 diabetes, in a diet-induced obese murine model. It is hypothesized that improvements in obesity and MetS are linked to changes in composition of the gut microbiota, bile acid metabolism, intestinal barrier function, and inflammation.

Methods and results: To test this hypothesis, 16S rRNA genes were sequenced and bile acids were measured in fecal samples from C57BL/6J mice fed a high-fat diet (HFD) or HFD containing XN, DXN or TXN. Expression of genes associated with epithelial barrier function, inflammation, and bile acid metabolism were measured in the colon, white adipose tissue (WAT), and liver, respectively. Administration of XN derivatives decreases intestinal microbiota diversity and abundance-specifically Bacteroidetes and Tenericutes-alters bile acid metabolism, and reduces inflammation. In WAT, TXN supplementation decreases pro-inflammatory gene expression by suppressing macrophage infiltration. Transkingdom network analysis connects changes in the microbiota to improvements in MetS in the host.

Conclusion: Changes in the gut microbiota and bile acid metabolism may explain, in part, the improvements in obesity and MetS associated with administration of XN and its derivatives.

Keywords: bile acid; gut microbiota; metabolic syndrome; xanthohumol.

Figure 1.. Principal coordinates analyses (PCoA) of gut microbiota based upon different distance matrices for the HFD-CON and HFD-XN, HFD-DXN and HFD-TXN supplementation.

Each point represents a mouse fecal sample, plotted by a principal component on the X-axis and another principal component on the Y-axis. The percentage on each axis indicates the contribution value to discrepancy among samples. (A) Bray-Curtis dissimilarity. (B) Unweighted UniFrac distance. (C) Weighted UniFrac distance. Ellipses are drawn at 0.95 C.I., t-distribution. Significant dissimilarity by dietary treatments across samples is observed. (ADONIS; adj-p = 0.001, R² = 0.396; permutation = 999). (D) Alpha diversity index (observed species) was calculated on the rarefied ASV count data (chi-squared = 26.0, df = 3, p-value = 9.4 × 10–6; Kruskal-Wallis rank sum test). Metrics are plotted against HFD control and different xanthohumol treatments, i.e., XN, DXN, and TXN; with median (line), and hinges as first and third quartiles (25th and 75th percentiles).

Figure 2.. Transkingdom microbe-gene-host phenotype regulatory network –

the network reconstructed from microbiota abundances (Tables 2–4), bile acid levels (Table 5), and host gene expression (Tables 6–7) in mice consuming either CON or TXN. Microbes – circles; host genes – triangles; host phenotypes – squares; orange edges denote positive correlations; blue edges denote negative correlations; three major microbial subnetworks defined by black circles; green color indicates a decrease; red color indicates an increase.