Activation of proestrogens from hops by human intestinal bacteria: conversion of isoxanthohumol into the potent phytoestrogen 8-prenylnaringenin

摘要

Hop, an essential ingredient in beer, contains different prenylflavonoids, among which 8-prenylnaringenin (8-PN) would be the most potent phytoestrogen currently known. Therefore, hop extracts are now marketed to relief menopausal complaints but efficiency varies greatly among individuals. As variability in biological activity was also noted for other phytoestrogens and related with variable intestinal bacterial metabolism, the goal of this work was to investigate whether intestinal bacteria also determine the final activity of hop phytoestrogens by combining batch incubations with SHIME, rat and human studies. Batch incubations learned that 8-PN is stable towards microbial degradation but that isoxanthohumol (IX), another hop prenylflavonoid, can be activated into 8-PN by bacterial O-demethylation. Although IX shows no estrogenic activity, it is present in hop products in 10- to 30-fold higher concentrations than 8-PN, showing that intestinal IX activation may significantly increase 8-PN exposure. SHIME experiments showed up to 80% IX conversion, mainly in the distal colon. Experiments with 51 fecal samples indicated significant interindividual variations, with high, moderate and low 8-PN producers. An experiment with germ-free and human microbiota associated rats and a human intervention trial confirmed the importance of variable intestinal IX activation and provided a definitive explanation for the variable biological activity of hop products. As the final activity of all phytoestrogens depends on variable intestinal metabolism, 100 fecal samples were incubated with precursors from all classes. This learned that the activation of different phytoestrogen classes occurs through separate pathways, with within-class correlations between different metabolites. Moreover, the production of specific metabolites was related to certain intestinal conditions. As variable IX activation implies variable 8-PN exposure, technological applications were investigated to balance the 8-PN exposure between individuals. To do this, an efficiently 8-PN producing Eubacterium limosum strain was selected. Its application as probiotic to increase intestinal 8-PN production was shown in vitro and in the rat model. In conclusion, it was demonstrated for the first time that the exposure to the potent phytoestrogen 8-PN mainly depends on the product IX concentrations and the variable intestinal metabolic potential to activate IX. Moreover, strategies were developed to balance the 8-PN exposure in all individuals.