PROJECT SUIVIMARY (See instructions): Role of key microbial populations of the gut microbiome in formulating host response as a result of 2,3,7,8- tetrahlorodibenzo-p-dioxin (TCDD) exposure is only beginning to be studied. Evidence suggests that gut microbiome is intricately linked to the host response and is also impacted directly and indirectly by exposure to environmental contaminants. In this project two such interactions are proposed to be studied using C57BL/6 germ free, mono-associated, cocktail associated and traditionally raised mouse models. The first is related to Treg/Th17 immune regulatory system and its dysbiosis in response to dioxin exposure and the second is related to choline-trimethylamine (TMA) pathway and its modulation. Dysbiosis of Treg/Th17 system has a broad range of health effects due to its central role in the immune regulatory system. It may lead to autoimmune diseases such as arthritis, inflammatory bowel disease, and skin cancer. Recently, specific members of the gut community, such as segmented filamentous bacteria (SFBs for which whole genome sequences are now available) and cluster IV and XlVa Clostridia, and Bacteroides fragilis have been implicated in regulating the Treg/Th17 system. The Treg/Th17 balance is also impacted by dioxin because AhR promotes the generation of Foxp3+ Treg and suppresses the differentiation to IL-17 producing ROR-yt Thi7. Thus specific populations of the gut microbiome, the Treg/Th17 balance, and TCDD via its AhR system are interconnected. Its mis-regulation may lead to disease outcomes. Project 4 establishes these specific and opposing "mechanisms" of regulation in germ-free mice using SFBs, 6. fragilis, and cluster IV and XlVa Clostridia and studies the role of these gut microbial populations in making the host less or more susceptible to health effects of dioxins. Evaluation of the transcriptome response of cluster IV and XlVa Clostridia and SFBs in response to TCDD, 2,3,4,7,9-PeCDF, and 2,3,7,8-TCDF exposure is also proposed. Project 4 also examines the effects of TCDD and related compounds on the metabolism of choline by the host and the gut microbiome, and the potential roles in the development of fatty liver and altering urinary trimethylamine/trimethylamine-N-oxide (TMA/TMAO) ratios. The effects are being studied in collaboration with Projects 1 (Kaminski/Kaplan), 3 (Zacharewski), 5 (Zylstra), and 6 (Boyd) and Research Support Cores A and B. The results are disseminated to communities and researchers through the Community Engagement Core and Research Translation Core. Student projects are designed to be incorporated in the Training Core.
Selected bacterial members of the gut are emerging as regulators of the immune system. In this project, the role of three leading groups of bacteria in modulating the immune system and their interaction with the host in response to dioxin exposure will be evaluated using germ-free mouse models. Results of this study will be useful in determining the protective role of gut bacteria against environmental exposure to dioxin.
|Cole, James R; Tiedje, James M (2014) History and impact of RDP: a legacy from Carl Woese to microbiology. RNA Biol 11:239-43|
|Cole, James R; Wang, Qiong; Fish, Jordan A et al. (2014) Ribosomal Database Project: data and tools for high throughput rRNA analysis. Nucleic Acids Res 42:D633-42|
|Rhodes, Albert N; Fulthorpe, Roberta R; Tiedje, James M (2013) Probing the functional diversity of global pristine soil communities with 3-chlorobenzoate reveals that communities of generalists dominate catabolic transformation. Appl Environ Microbiol 79:6932-40|
|Forgacs, Agnes L; Dere, Edward; Angrish, Michelle M et al. (2013) Comparative analysis of temporal and dose-dependent TCDD-elicited gene expression in human, mouse, and rat primary hepatocytes. Toxicol Sci 133:54-66|
|Kopec, Anna K; Boverhof, Darrell R; Nault, Rance et al. (2013) Toxicogenomic evaluation of long-term hepatic effects of TCDD in immature, ovariectomized C57BL/6 mice. Toxicol Sci 135:465-75|
|Zhang, Qiang; Kline, Douglas E; Bhattacharya, Sudin et al. (2013) All-or-none suppression of B cell terminal differentiation by environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Appl Pharmacol 268:17-26|
|Fullerton, Aaron M; Roth, Robert A; Ganey, Patricia E (2013) 2,3,7,8-TCDD enhances the sensitivity of mice to concanavalin A immune-mediated liver injury. Toxicol Appl Pharmacol 266:317-27|
|Angrish, Michelle Manente; Dominici, Claudia Yvette; Zacharewski, Timothy Richard (2013) TCDD-elicited effects on liver, serum, and adipose lipid composition in C57BL/6 mice. Toxicol Sci 131:108-15|
|Zhang, Qiang; Bhattacharya, Sudin; Andersen, Melvin E (2013) Ultrasensitive response motifs: basic amplifiers in molecular signalling networks. Open Biol 3:130031|
|Nault, Rance; Forgacs, Agnes L; Dere, Edward et al. (2013) Comparisons of differential gene expression elicited by TCDD, PCB126, *NF, or ICZ in mouse hepatoma Hepa1c1c7 cells and C57BL/6 mouse liver. Toxicol Lett 223:52-9|
Showing the most recent 10 out of 342 publications