The potential impact of the microbiota on drug pharmacokinetics has also been examined using more indirect approaches. changes in host gene expression and the generation of unique metabolites. Metabolic Function of the Gut Microbiota The gut microbiome within an individual is established relatively early in life (Yatsunenko et al., 2012). Infants at postnatal day 3, for example, have Ginkgolide J been found to harbor a gut microbiota population represented by an abundance of (Dogra et al., 2015and and low levels of and and Gram positive and and and some species of spp. also exert toxic actions and contribute to the loss of colonic epithelial cells, loss of intestinal barrier integrity, as well as damage to host DNA. N-nitrosocompounds, which can be produced by bacteria such as clusters XI/XIVa and sulfate- or sulfite-reducing bacteria (Shen et al., 2014), which is thought to ultimately result in an increase in the formation of proinflammatory and genotoxic secondary bile acids, such as deoxycholate. Contribution of the Gut Microbiota to Intestinal Immune Homeostasis The gastrointestinal tract is a site of exposure to both deleterious pathogens and commensal bacteria (Danese, 2011; Zhang and Li, 2014; Bates and Diehl, 2014). The default state of the gut is one of hyporesponsiveness where the host response to pathogens is attenuated and the presence of commensal bacteria and food antigens is tolerated. Within the colon, the commensal bacteria colonize within the outer loose layer of mucus (Johansson et al., 2011) and contribute to intestinal homeostasis by activating resident immune cells (macrophages, neutrophils, innate lymphoid cells, B cells, and T cells) such that they produce antimicrobial factors (Maranduba et al., 2015). The adaptive immune response within the gut is particularly sensitive to the presence of microorganisms. The differentiation of na?ve CD4 T cells is a highly regulated process involving the formation of four subsets, T-helper (TH)1, TH2, TH17, and Treg cells, each of which is characterized by their secretion of predominant cytokines. TH1 cells are best known for their production of IFNis of particular note as it has been found to enhance production of IL22, via the aryl hydrocarbon receptor (AHR), and thereby offer protection against colonic inflammation (Zelante et al., 2013). In the gut, secretion of IL22 by innate lymphoid and TH17 cells can promote proliferation of the gut epithelial cells (Kumar et al., 2013). The AHR is a member of the basic helix-loop-helix Per-Arnt-Sim family (Kohle and Bock, 2009; Murray et al., 2014) that has been historically of interest because of its ability to regulate the expression levels of drug metabolizing enzymes and transporters. Genes typically upregulated by the AHR are cytochromes CYP1A1 and CYP1B1 (phase 1); GSTA1, GSTA2, and UDP-glucuronosyltransferase UGT1A1 (phase Ginkgolide J 2); and multidrug resistance associated protein MRP3/ABCC3 (phase 3). The ability of the AHR also to regulate immune function and intestinal homeostasis in a manner that appears to involve microbiota-generated metabolites is currently of high interest. With this in mind, Hubbard et al. (2015) focused on our emerging understanding of the metabolic formation of endogenous AHR ligands from tryptophan and indole by both the host and gut microbiota. In addition, they speculated on how the absence or presence of these metabolites may impact gut homeostasis, barrier function, and the gut inflammatory response via their AHR modulating activities. The extent to which the tryptophan metabolites by the.Analyses of the fecal microbiota of 19 patients involved in this study indicate that those requiring higher Ginkgolide J doses of tacrolimus also harbor an abundance of fecal which are often associated with a healthy gut (Scott et al., 2015) corresponds to an optimal drug-metabolizing capacity in the gut. Xenobiotics that have been shown to be subjected to microbial metabolism in the gut include arsenic and polyaromatic hydrocarbons. response to drugs. In this issue of to propose that the gut microbiome be considered an additional drug target. As we begin to address how the gut microbiota and host tissues interact to metabolize drugs and xenobiotics, we must first examine the physiologic roles of the gut microbiota. We then consider the multiple mechanisms by which the gut microbiota contributes to drug metabolism, including changes in host gene expression and the generation of unique metabolites. Metabolic Function of the Gut Microbiota The gut Ginkgolide J microbiome within an individual is established relatively early in life (Yatsunenko et al., 2012). Infants at postnatal day 3, for example, have been found to harbor a gut microbiota population represented by an abundance of (Dogra et al., 2015and and low levels of and and Gram positive and and and some species of spp. also exert toxic actions and contribute to the loss of colonic epithelial cells, loss of intestinal barrier integrity, as well as damage to host DNA. N-nitrosocompounds, which can be produced by bacteria such as clusters XI/XIVa and sulfate- or sulfite-reducing bacteria (Shen et al., 2014), which is thought to ultimately result in an increase in the formation of proinflammatory and genotoxic secondary bile acids, such as deoxycholate. Contribution of the Gut Microbiota to Intestinal Immune Homeostasis The gastrointestinal tract is a site of exposure to both deleterious pathogens and commensal bacteria (Danese, 2011; Zhang and Li, 2014; Bates and Diehl, 2014). The default state of the gut is one of hyporesponsiveness where the host response to pathogens is attenuated and the presence of commensal bacteria and food antigens is tolerated. Within the colon, the commensal bacteria colonize within the outer loose layer of mucus (Johansson et al., 2011) and contribute to intestinal homeostasis by activating resident immune cells (macrophages, neutrophils, innate lymphoid cells, B cells, and T cells) such that they produce IGLL1 antibody antimicrobial factors (Maranduba et al., 2015). The adaptive immune response within the gut is particularly sensitive to the presence of microorganisms. The differentiation of na?ve CD4 T cells is a highly regulated process involving the formation of four subsets, T-helper (TH)1, TH2, TH17, and Treg cells, each of which is characterized by their secretion of predominant cytokines. TH1 cells are best known for their production of IFNis of particular note as it has been found to enhance production of IL22, via the aryl hydrocarbon receptor (AHR), and thereby offer protection against colonic inflammation (Zelante et al., 2013). In the gut, secretion of IL22 by innate lymphoid and TH17 cells can promote proliferation of the gut epithelial cells (Kumar et al., 2013). The AHR is a member of the basic helix-loop-helix Per-Arnt-Sim family (Kohle and Bock, 2009; Murray et al., 2014) that has been historically of interest because of its ability to regulate the manifestation levels of drug metabolizing enzymes and transporters. Genes typically upregulated from the AHR are cytochromes CYP1A1 and CYP1B1 (phase 1); GSTA1, GSTA2, and UDP-glucuronosyltransferase UGT1A1 (phase 2); and multidrug resistance associated protein MRP3/ABCC3 (phase 3). The ability of the AHR also to regulate immune function and intestinal homeostasis in a manner that appears to involve microbiota-generated metabolites is currently of high interest. With this in mind, Hubbard et al. (2015) focused on our growing understanding of the metabolic formation of endogenous AHR ligands from tryptophan and indole by both the sponsor and gut microbiota. In addition, they speculated on how the absence or presence of these metabolites may effect gut homeostasis, barrier function, and the gut inflammatory response via their AHR modulating activities. The degree to which the tryptophan metabolites from the gut microbes activate or inhibit the AHR is definitely addressed by the work performed by Cheng et al. (2015). Here, evidence is definitely provided that these microbial tryptophan metabolites show varying properties with respect to their ability either to activate or to inhibit the AHR and are shown to act as SAhRMs or selective AHR modulators in that they take action inside a cell-context and gene-specific manner. Of particular interest are the tryptophan metabolites tryptamine and indole-3 acetate. Role of the Gut Microbiota in Bile Acid Rate of metabolism The gut microbiota takes on an extensive part in bile acid metabolism.