The human gut harbors a complex microbial ecosystem that plays a pivotal role in host xenobiotic metabolism. While host metabolic pathways primarily facilitate the detoxification and excretion of exogenous compounds via oxidative and conjugative reactions, gut microbes often metabolize these substances through hydrolytic and reductive transformations, occasionally resulting in the formation of toxic or bioactive intermediates. This review highlights the importance of the host-microbiota co-metabolic axis in determining the fate and toxicity of common dietary and environmental organic compounds. Through comprehensive analysis, we detail the metabolic profiles of representative xenobiotics-including N-nitrosamines, trimethylamine N-oxide (TMAO), indoxyl sulfate, nicotine, polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs), phthalates, chlorophenols, and emerging contaminants such as 6PPD-quinone-underscoring the dual roles of host enzymes (e.g., CYPs, UGTs, SULTs) and microbial counterparts (e.g., β-glucuronidase, cut genes, NicX) in modulating toxicity. We further discussed the potential importance of fecal samples in assessing the toxicity of organic compounds, as well as the metabolic activation effects of certain phase II enzymes under specific conditions. Collectively, this review emphasizes that neglecting gut microbial contributions and phase II metabolites in environmental epidemiological studies can lead to fragmented or misleading interpretations of xenobiotic toxicity. A deeper understanding of co-metabolic enzymes and intermediate metabolites is essential to explain inter-individual variability in toxicity and to develop microbiota-targeted interventions for environmental pollutant-related diseases.
Yang et al. (Sun,) studied this question.