Interindividual variability in gut microbial formation of the hop phytoestrogen 8-prenylnaringenin results in elevated but sub-toxic internal exposures.

The gut microbiome converts the prenylated polyphenol isoxanthohumol (iXN), a natural constituent of hops found in beer, into 8-prenylnaringenin (8-PN), a potent phytoestrogen associated with endocrine-disrupting effects. Following oral exposure, interindividual differences in microbiome composition may lead to variable systemic 8-PN concentrations and consequently to differences in susceptibility to toxicity. To characterize the contribution of gut microbiota to health effects of hop polyphenols, a human physiologically based kinetic (PBK) model that includes microbial 8-PN formation was developed. Ex vivo fecal fermentation coupled to LC–MS/MS revealed substantial interindividual variation in biotransformation capacity. Derived kinetic parameters were incorporated into the PBK model, which was subsequently used to predict systemic 8-PN exposure while accounting for interindividual variability. Model simulations indicated that high iXN metabolizers experience approximately two-fold more internal 8-PN exposure than low metabolizers. Estrogenicity of the predicted uterine 8-PN concentrations was assessed via alkaline phosphatase induction in Ishikawa cells. Even in high metabolizers, systemic 8-PN concentrations appeared to remain below levels of concern regarding endocrine disruption. These findings highlight the importance of accounting for interindividual variability in gut microbial biotransformation when predicting xenobiotic toxicokinetics and illustrate the applicability of microbiome-competent PBK modeling for predicting the systemic fate of gut microbial metabolites.