Interindividual variation in gut microbial formation of 8-prenylnaringenin results in increased, but sub-estrogenic, internal exposure

The gut microbiome converts the prenylated polyphenol isoxanthohumol, a natural constituent of hops found in beer, to 8-prenylnaringenin (8-PN), a potent phytoestrogen, raising concerns about potential endocrine-disruption. Interindividual differences in microbiome composition may result in varying internal exposures to 8-PN and susceptibility to toxicity. To improve the understanding of 8-PN toxicokinetics, a human physiologically based kinetic (PBK) model was extended to include gut microbial 8-PN formation. Respective parameters were obtained from ex vivo fermentations using pooled and individual stool samples to predict average internal exposure while accounting for interindividual differences. This revealed twofold higher internal 8-PN exposure in high metabolizers compared to low metabolizers. Further, we measured estrogenicity of predicted uterus concentrations of 8-PN using alkaline phosphatase assays and found that even in high metabolizers, systemic 8-PN concentrations remain below estrogenicity thresholds. This study broadly demonstrates the applicability of microbiome-competent PBK modeling for quantifying health impacts of gut microbial metabolites.