Reductive Metabolism of Xanthohumol and 8‐Prenylnaringenin by the Intestinal Bacterium Eubacterium ramulus

Abstract

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.

Where to Look into the Puzzle of Polyphenols and Health? The Postbiotics and Gut Microbiota Associated with Human Metabotypes

“…[ 67 ] Although the human gut microbial Eubacterium limosum is involved in the in vivo synthesis of 8PN, [ 68 ] however, three main issues prevent the clear establishment of possible human 8PN‐related metabotypes: i) low amounts of 8PN can be already present in the food product (hops and beer), [ 156 ] ii) 8PN can also be formed by the action of human cytochromes, [ 157 ] and iii) 8PN is not the final catabolite but another intermediate since it can be further metabolized by Eubacterium ramulus to yield O ‐desmethylxanthohumol (DMX) and O ‐desmethyl‐ α , β ‐dihydroxanthohumol (DDXN) as recently described in vitro (Figure 3). [ 151 ] This latter point should be confirmed in vivo. Overall, at this moment and following the definition of “metabotype,” we can conclude that no human metabotypes can be clearly associated with the metabolism of hops prenylflavonoids.…”

“…A) Proanthocyanidins and flavan‐3‐ols (catechin), [ 150 ] B) citrus flavanones (hesperidin), [ 146 ] C) lignans (secoisolariciresinol), [ 85,148 ] and D) prenyl‐flavanones (xanthohumol). [ 151 ] HPP‐2‐ol, 1‐(hydroxyphenyl)‐3‐(2′′,4′′,6′′‐trihydroxyphenyl)‐propan‐2‐ol; PV, phenylvalerolactone; HPV, hydroxyphenyl valerolactone; DHPV, dihydroxyphenylvalerolactone; HPV, hydroxyphenylvalerolactone; PVA, phenylvaleric acid; HPVA, hydroxyphenylvaleric acid; DHPVA, dihydroxyphenylvaleric acid; HPPA, hydroxyphenylpropionic acid; DHPPA, dihydroxyphenylpropionic acid; HPAA, hydroxyphenylacetic acid; DHPAA, dihydroxyphenylacetic acid; HBA, hydroxybenzoic acid; DHBA, dihydroxybenzoic acid; HA, hippuric acid; HHA, hydroxyhippuric acid.…”

Association of Moderate Beer Consumption with the Gut Microbiota and SCFA of Healthy Adults

“…In addition, isoxanthohumol present in hops, together with other prenylated flavonoids, can be metabolized to render 8-prenylnaringenin, through an O-demethylation that is carried out by Eubacterium limosum [ 13 ]. Moreover, metabolization by Eubacterium ramulus transforms prenylated flavonoids into its chalcones, and likely affects both the activity and toxicity of ingested molecules [ 14 ].…”

An NADH-Dependent Reductase from Eubacterium ramulus Catalyzes the Stereospecific Heteroring Cleavage of Flavanones and Flavanonols

“…7A). For intact E. ramulus cells, however, reduction of xanthohumol rather than isoxanthohumol was recently reported (19). Fcr did not reduce C-C double bonds present in the C-ring of flavonols (e.g., quercetin) and flavones (e.g., apigenin) and also did not accept cinnamic acids as substrates (Fig.…”