Exploration on Biotransformation and Metabolic Modulation by the Gut Microbiome

The gut microbiota has attracted many scientific attentions due to its essential role in maintaining the physiological homeostasis of its mammalian host. The dysbiosis of the gut microbiota has been associated with adverse health outcomes including cancer. However, direct molecular evidence and mechanistic understanding of the gut microbiota in carcinogenesis are scarce. The overarching goal of my dissertation study is to advance our knowledge on how the human gut flora mechanistically maintains host homeostasis and induces cancer. To accomplish the goal, three specific arms were developed: (i) examine the effect of the gut microbiota on impacting the endogenous metabolic processes of the host; (ii) determine the role of the gut microbiome in mediating metabolism of xenobiotics; and (iii) decipher the global metabolic repertoire of the gut microbiome at the species resolution.First, by comparing multiple source-varying DNA adduct species in conventional-raised and microbiota-depleted mice, we found the presence of the gut microbiota could alleviate the DNA damages resulted from immune-response and oxidative stress, but elevate DNA damages of lipid peroxidation specifically in liver. Second, a combination of in vitro and in vivo experiment on exposing benzo[a]pyrene to the gut microbiota was conducted to inspect if the gut microbiota can regulate the host xenobiotic metabolism, resulting in differed genotoxic burden. The benzo[a]pyrene-induced DNA adduct was significantly higher in mice conventionally raised compared to the mice depleted with their gut microbiota, but the hepatic expression of genes accountable to benzo[a]pyrene metabolism remained unchanged. Thus, the gut microbiota was suspected as the direct reason to the increased genotoxic burden of ingested benzo[a]pyrene. Finally, we constructed a gut bacterial metabolomic database aiming to answer the capability of facilitating different metabolic functions in the diverse species of the gut microbiota. The database can be applied to estimate the metabolic similarity of an unknown bacterial isolates and a known bacterium, and to prioritize bacteria that are important in influencing certain metabolic pathways. These findings improve our understanding on the mechanisms of the gut microbiota in regulating mammalian physiology and involving in cancer development, which can be resourceful for the development of microbiota-based therapeutic approaches.