Human commensal microorganisms play a critical role in regulating host physiology and health status. Xenobiotics can induce complex changes of gut-microbiota and cause significantly impacts on host health, but the detailed mechanisms are not fully established. This dissertation project focused on the impacts of two representative natural products: aflatoxin B1 (AFB1) and green tea polyphenols (GTPs) on gut-microbiota dependent metabolisms and overall host physiological changes in model rats. The hypothesis is that the dynamics of gut-microbiome induced by xenobiotics may disrupt gut-microbiota dependent metabolisms and metabolic pathways, which contribute to the adverse health outcomes or promotion of host health status. Through 16S rRNA gene survey and metagenomic analysis, we found that AFB1 and GTPs modified gut-microbiota community structure and gene orthalogs with respect to energy metabolism, obesity, and inflammation. Adverse outcome pathways (AOPs) and nutritional beneficial effects were analyzed by integrating data collected from multipal analytical platforms, different bioinformatics and biostatistics tools, as well as the reference data from validated pathological endpoints. We found that AFB1 significantly disrupted production of SCFAs, secretion and metabolism of bile acids, absorption of LCFAs, catabolism of phenylalanine, and the metabolisms of pyruvic acid, amino acids, and carbohydrates. These changes are associated with the alterations of community structure. The pathways all have key positions in the global metabolism of gut-microbiota and host health. Hence, gut-microbiota may partially be involved in the pathological mechanism of AFB1-exposure induced adverse health outcomes in F344 rat model, and presumably also in humans. On the other hand, GTPs caused reduction of calorific carbohydrates, elevation of vitamin production, decreases of bile constituents, and modified metabolic pattern of amino acids in the gut of GTPs-treated SD rats. A further examination on the key differential metabolites indicated a boost of gut-microbiota dependent mitochondrial TCA/Urea cycle following GTPs administration. Based on previous microbiome data and clinical chemical analysis, we believe that such changes may be a major contributor to the anti-obesity function of GTPs.