Scope The intestinal microbiota transforms a wide range of available substrates, including polyphenols. Microbial catabolites of polyphenols can contribute in significant ways to the health promoting properties of their parent polyphenols. This work aimed to identify intestinal metabolites of xanthohumol (XN), a prenylated flavonoid found in hops (Humulus lupulus) and beer, as well as to identify pathways of metabolism of XN in the gut. Methods and results To investigate intestinal metabolism, XN and related prenylated flavonoids, isoxanthohumol (IX) and 8-prenylnaringenin (8PN) were added to growing cultures of intestinal bacteria, Eubacterium ramulus and E. limosum. We used liquid chromatography coupled with mass spectrometry to identify metabolites of the flavonoids from the cultures. The metabolic capacity of E. limosum appears to be limited to O-demethylation. Evidence from our study indicates that E. ramulus hydrogenates XN to form α,β-dihydroxanthohumol (DXN) and metabolizes the potent phytoestrogen 8PN into the chalcones, O-desmethylxanthohumol (DMX) and O-desmethyl-α,β-dihydroxanthohumol (DDXN). Conclusion Microbial metabolism is likely to affect both activity and toxicity of XN and derivatives. This study along with others highlights that attention should be focused on metabolites, in particular, products of intestinal microbial metabolism.

Xanthohumol [ (E)-6′-methoxy-3′-(3-methylbuten-2-yl) -2′,4′,4″-trihydroxychalcone], the principal prenylated flavonoid from hops, has a complex bioactivity profile and 13C-labelled isotopomers of this compound are of potential use as molecular probes and as analytical standards to study metabolism and mode-of-action. 1,3-[13C]2-Xanthohumol was prepared by an adaptation of the total synthesis of Khupse and Erhardt in 7 steps and 5.7% overall yield from phloroglucinol by a route incorporating a cascade Claisen-Cope rearrangement to install the 3′-prenyl moiety from a 5′-prenyl aryl ether and an aldol condensation between 1-[13C] -2′,4′-bis(benzyloxymethyloxy) -6′-methoxy-3′-(3-methylbuten-2-yl)acetophenone and 1′- [13C]-4-(methoxymethyloxy) benzaldehyde. The 13C-atom in the methyl ketone was derived from 1-[13C]-acetyl chloride while that in the aryl aldehyde was derived from [13C]-iodomethane. Tri- and penta-13C-labelled xanthohumols were similarly prepared by applying minor modifications to the route.

The energy intake exceeding energy expenditure (EE) results in a positive energy balance, leading to storage of excess energy and weight gain. Here, we investigate the potential of a newly synthesized compound as an inducer of EE for the management of diet-induced obesity and insulin resistance. Xanthohumol (XN), a prenylated flavonoid from hops, was used as a precursor for the synthesis of a pyrazole derivative tested for its properties on high-fat diet (HFD)-induced metabolic impairments. In a comparative study with XN, we report that 4-(5-(4-hydroxyphenyl)-1-methyl-1H-pyrazol-3-yl)-5-methoxy-2-(3-methylbut-2-en-1-yl)­benzene-1,3-diol (XP) uncouples oxidative phosphorylation in C2C12 cells. In HFD-fed mice, XP improved glucose tolerance and decreased weight gain by increasing EE and locomotor activity. Using an untargeted metabolomics approach, we assessed the effects of treatment on metabolites and their corresponding biochemical pathways. We found that XP and XN reduced purine metabolites and other energy metabolites in the plasma of HFD-fed mice. The induction of locomotor activity was associated with an increase in inosine monophosphate in the cortex of XP-treated mice. Together, these results suggest that XP, better than XN, affects mitochondrial respiration and cellular energy metabolism to prevent obesity in HFD-fed mice.

Mol. Nutr. Food Res. 2019, 63, https://doi.org/10.1002/mnfr.201800923 DOI: https://doi.org/10.1002/mnfr.201800923 Gut microbial metabolism of xanthohumol produces estrogenic metabolites, notably 8‐prenylnaringenin. In article number https://doi.org/10.1002/mnfr.201800923, Jan F. Stevens and co‐workers show that 8‐prenylnaringenin is not the end product of metabolism by gut microbes, shedding new light on the perceived pro‐estrogenicity of xanthohumol.