Microbiome is a functional modifier of P450 drug metabolism

Abstract

Host cytochrome P450s (P450s) play important roles in the bioactivation and detoxification of numerous therapeutic drugs, environmental toxicants, dietary factors, as well as endogenous compounds. Gut microbiome is increasingly recognized as our "second genome" that contributes to the xenobiotic biotransformation of the host, and the first pass metabolism of many orally exposed chemicals is a joint effort between host drug metabolizing enzymes including P450s and gut microbiome. Gut microbiome contributes to the drug metabolism via two distinct mechanisms: direct mechanism refers to the metabolism of drugs by microbial enzymes, among which reduction and hydrolysis (or deconjugation) are among the most important reactions; whereas indirect mechanism refers to the influence of host receptors and signaling pathways by microbial metabolites. Many types of microbial metabolites, such as secondary bile acids (BAs), short chain fatty acids (SCFAs), and tryptophan metabolites, are known regulators of human diseases through modulating host xenobiotic-sensing receptors. To study the roles of gut microbiome in regulating host drug metabolism including P450s, several models including germ free mice, antibiotics or probiotics treatments, have been widely used. The present review summarized the current information regarding the interactions between microbiome and the host P450s in xenobiotic biotransformation organs such as liver, intestine, and kidney, highlighting the remote sensing mechanisms underlying gut microbiome mediated regulation of host xenobiotic biotransformation. In addition, the roles of bacterial, fungal, and other microbiome kingdom P450s, which is an understudied area of research in pharmacology and toxicology, are discussed.

Figure 1.

Summary of the regulation of P450s within the gut-liver axis. Distinct microbial metabolites produced from the intestine, such as butyrate (from fermentation of fibers), secondary bile acids [BAs] (from primary bile acids), as well as indoles and indole-3-propionic acid (IPA) (from tryptophan), are known activators of certain host receptors, such as AHR (butyrate and indoles) and PXR (IPA). Certain microbial metabolites may enter the circulation and reach the liver to modulate the host receptor signaling and targeted P450 gene expression. Microbiome modifiers, such as germ free condition, the use of antibiotics/probiotics, age, gender, host genetics, and exposure to other drugs and environmental chemicals, may shift the composition and functions of gut microbiome, leading to altered host receptor signaling and target gene expression. Microbial P450s as a separate entity in the intestine have been shown to contribute to lipid metabolism as well as oxidation of xenobiotics. Trp: tryptophan; 1°: primary; 2°: secondary.