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

Abstract

Scope: We previously showed that two hydrogenated xanthohumol (XN) derivatives, α,βdihydro-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 dietinduced obese murine model. We hypothesized that improvements in obesity and MetS are linked to changes in the composition of the gut microbiota, bile acid metabolism, intestinal barrier function and inflammation. Methods and results: To test this hypothesis, we sequenced 16S rRNA genes and measured bile acids in fecal samples from C57BL/6J mice fed a high-fat diet (HFD) or HFD containing XN, DXN or TXN. We measured the expression of genes associated with epithelial barrier function, inflammation, and bile acid metabolism, in the colon, white adipose tissue (WAT), and liver, respectively. Administration of XN derivatives decreased intestinal microbiota diversity and abundance, specifically Bacteroidetes and Tenericutes, altered bile acid metabolism, and reduced inflammation. In WAT, TXN supplementation decreased pro-inflammatory gene expression by suppressing macrophage infiltration. Transkingdom network analysis connected 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.

Metabolically Healthy Obese Children and the Role of the Gut Microbiota

“…Recently, several animal studies concluded that an optimal healthy-like gut microbiota may bestow a more propitious obese phenotype [16,17]. For instance, the abundance of Bacteroidetes and Tenericutes were closely aligned with bile acid metabolism and obesity-related in ammation in a murine model of the metabolic syndrome [18]. In our study, we corroborate this nding: reduced abundance of Tenericutes in the MUO group compared with the metabolically healthy groups (MHO and Con).…”

Xanthohumol microbiome and signature in healthy adults (the XMaS trial): a phase I triple-masked, placebo-controlled clinical trial

“…Xanthohumol is a flavonoid constituent of the hops plant (Humulus lupulus), exerting antioxidant, antiinflammatory, cancer chemopreventive, antihyperglycemic, and anti-hyperlipidemic activities [1][2][3]. Xanthohumol also acts as a prebiotic for intestinal microbiota and can alter the gut microbial composition in conjunction with its bacterial metabolites [4,5]. Based on mechanisms of action supported by preclinical models, patients with numerous clinical conditions could potentially benefit from xanthohumol supplementation ( Table 1).…”

“…Using in vitro binding studies and in silico models, xanthohumol and its metabolites are ligands for the FXR and preliminary in vitro data indicates xanthohumol activates FXR-regulated genes at low concentrations, supporting xanthohumol functions as a pharmacologic agonist of FXR [4,13]. The FXR receptor is known to regulate intestinal permeability as well as innate immunity including production of the pro-inflammatory cytokines: interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12p70, tumor necrosis factor alpha (TNF-α), and interferongamma (IFN-γ) [15,16].…”

Gastrointestinal Disorders and Metabolic Syndrome: Dysbiosis as a Key Link and Common Bioactive Dietary Components Useful for their Treatment

“…Zhang et al (2020) investigated the effects of xanthohumol derivatives (α,β-dihydroxanthohumol and tetrahydroxanthohumol) on obesity and MS in C57BL/6J male mice treated with 30 mg/kg/day body weight for 13 weeks [ 186 ]. Decreases in liver weight, fasting plasma glucose, and insulin level were noted in mice treated with tetrahydroxanthohumol while decreases in plasma leptin level and adipose tissue inflammation was associated with both xanthohumol derivatives.…”