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

Two hydrogenated xanthohumol (XN) derivatives, a,b-dihydro-XN(DXN) and tetrahydro-XN (TXN), improved parameters of metabolicsyndrome (MetS), a critical risk factor of cardiovascular disease (CVD) andtype 2 diabetes, in a diet-induced obese murine model. It is hypothesized thatimprovements in obesity and MetS are linked to changes in composition ofthe gut microbiota, bile acid metabolism, intestinal barrier function, andinflammation. To test this hypothesis, 16S rRNA genes weresequenced and bile acids were measured in fecal samples from C57BL/6Jmice 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 decreasesintestinal microbiota diversity and abundance - specifically Bacteroidetes andTenericutes - alters bile acid metabolism, and reduces inflammation. In WAT,TXN supplementation decreases pro-inflammatory gene expression bysuppressing macrophage infiltration. Transkingdom network analysisconnects changes in the microbiota to improvements in MetS in the host.Conclusion: Changes in the gut microbiota and bile acid metabolism mayexplain, in part, the improvements in obesity and MetS associated withadministration of XN and its derivatives.