Very little is known about the developmental regulation of drug-metabolizing enzymes and transporters (together called drug-processing genes [DPGs]) in liver, placing newborns and children at a much higher risk of adverse drug reactions (ADRs). Using RNA-Seq, we have shown that drug metabolism is the top most differentially regulated pathway in the entire liver transcriptome of germ-free (GF) mice, suggesting that there is a novel interaction between gut microbiome and hepatic DPGs. One of the key functions of gut microbiome is to produce secondary bile acids (BAs), which can activate two most critical xenobiotic-sensing nuclear receptors in liver, namely the pregnane X receptor (PXR) and constitutive androstane receptor (CAR). During development, profound changes occur in the intestinal bacteria and the secondary BA profiles, suggesting that gut microbiome may at least in part contribute to the developmental regulation of DPGs in liver. No systematic studies have been performed to characterize the regulation of all DPGs by gut microbiome during development, and little is known regarding how targeting the gut microbiome by antibiotics or probiotics re- programs the ontogeny of DPGs in liver. Therefore the goal of this research is to utilize multidisciplinary approaches, including GF and genetically-engineered mice, BA metabolomics, Next-Generation Sequencing, and human fecal samples, to unveil the role of gut microbiota in modulating PXR and CAR signaling and the subsequent ontogenic re-programming of DPGs in liver. Our central hypothesis is: the developmental changes in the gut microbiome at least in part contribute to the regulation of the ontogeny of DPGs in liver, through altering secondary BAs in the gut to modify the PXR and/or CAR signaling in liver. We will test our hypothesis in 2 Aims:
Aim 1 A will use RNA-Seq to quantify mRNAs of 281 critical DPGs in livers of GF and conventional (Conv) mice at 6 developmental ages, and validate the proteins and activities of differentially regulated DPGs. We will also use ChIP-Seq to quantify how gut bacteria modulate PXR/CAR DNA binding to certain DPGs, and correlate DPG ontogeny with the ontogeny of gut microbiome (metagenomics) and BA profiles (UPLC-MS/MS).
Aim 1 B will introduce secondary BAs to GF mice in various PXR- and CAR-knockout and humanized transgenic) at various ages to test our hypothesis that secondary BAs restore the normal ontogeny of certain DPGs.
Aim 2 will use GF mice colonized with human fecal bacteria from various developmental ages, to determine the roles of antibiotics and the probiotic L. acidophilus in re-programming the ontogeny of human microbiome and the subsequent changes in the host DPGs during liver development. The proposed work will unveil a novel link between the ontogeny of gut microbiome and the developmental changes of drug- processing capacities during development, and will lead to a paradigm shift in pediatric pharmacology, by establishing a new concept in considering ADRs in children, which are the bug-drug interactions, in addition to the known drug-drug and food-drug interactions.

Public Health Relevance

Although the gut micro-biome has attracted much attention in the areas of obesity and metabolic syndrome, much less is known about the role of intestinal bacteria, antibiotics, and probiotics on drug metabolism in humans during development. The proposed research will unveil the critical role of the major xenobiotic-sensing nuclear receptors in intestinal bacteria-mediated alterations in xenobiotic metabolism and disposition in laboratory animals and humans during liver development. Thus this research is relevant to the NIH's mission that pertains to developing fundamental knowledge that will help to improve the quality of life for newborns and children who are at a much higher risk of adverse drug reactions.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM111381-05
Application #
9544995
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Okita, Richard T
Project Start
2014-09-10
Project End
2019-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Washington
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Dempsey, Joseph; Zhang, Angela; Cui, Julia Yue (2018) Coordinate regulation of long non-coding RNAs and protein-coding genes in germ-free mice. BMC Genomics 19:834
Li, Cindy Yanfei; Dempsey, Joseph L; Wang, Dongfang et al. (2018) PBDEs Altered Gut Microbiome and Bile Acid Homeostasis in Male C57BL/6 Mice. Drug Metab Dispos 46:1226-1240
Morgan, Edward T; Dempsey, Joseph L; Mimche, Sylvie M et al. (2018) Physiological Regulation of Drug Metabolism and Transport: Pregnancy, Microbiome, Inflammation, Infection, and Fasting. Drug Metab Dispos 46:503-513
Li, Cindy Yanfei; Lee, Soowan; Cade, Sara et al. (2017) Novel Interactions between Gut Microbiome and Host Drug-Processing Genes Modify the Hepatic Metabolism of the Environmental Chemicals Polybrominated Diphenyl Ethers. Drug Metab Dispos 45:1197-1214
Fu, Zidong Donna; Selwyn, Felcy P; Cui, Julia Yue et al. (2017) RNA-Seq Profiling of Intestinal Expression of Xenobiotic Processing Genes in Germ-Free Mice. Drug Metab Dispos 45:1225-1238
Cheng, Sunny Lihua; Bammler, Theo K; Cui, Julia Yue (2017) RNA Sequencing Reveals Age and Species Differences of Constitutive Androstane Receptor-Targeted Drug-Processing Genes in the Liver. Drug Metab Dispos 45:867-882
Dempsey, Joseph L; Cui, Julia Yue (2017) Long Non-Coding RNAs: A Novel Paradigm for Toxicology. Toxicol Sci 155:3-21
Fu, Zidong Donna; Cui, Julia Yue (2017) Remote Sensing between Liver and Intestine: Importance of Microbial Metabolites. Curr Pharmacol Rep 3:101-113
Cui, Julia Yue; Klaassen, Curtis D (2016) RNA-Seq reveals common and unique PXR- and CAR-target gene signatures in the mouse liver transcriptome. Biochim Biophys Acta 1859:1198-1217
Selwyn, Felcy Pavithra; Cheng, Sunny Lihua; Klaassen, Curtis D et al. (2016) Regulation of Hepatic Drug-Metabolizing Enzymes in Germ-Free Mice by Conventionalization and Probiotics. Drug Metab Dispos 44:262-74

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