Superfund Research Program
Gut Microbiome - Host Interactions in Response to TCDD Exposure
Project Leader: Syed A. Hashsham
Grant Number: P42ES004911
Funding Period: 2013-2020
- Project Summary
Major accomplishments of Syed Hashsham, Ph.D., and his team during the previous extension year pertained to the determination of the disruption of the host immune system balance in response to dioxin exposure and the role of the gut microbiota therein. Analysis of immunological gene expression (e.g., T-cell differentiation) data obtained from germ-free mice associated with SFB and treated with TCDD was carried out. Genes that responded to TCDD in the presence of SFB did not show a significant response in the absence of SFB, and vice versa (Stedtfeld et al., 2017a). In addition, regulatory T-cells measured in collaboration with the TCDD Impedes the Minimal Activation Threshold Required for Initiation of B Cell Differentiation: An Integrated Experimental and Computational Modeling Approach Project were less impacted by TCDD in mice colonized with SFB. TCDD-induced host response was also significantly modulated by the presence of SFB in the gut microbiome, providing insight into therapeutic potential between AhR ligands and key commensals (Stedtfeld et al., 2017b). Leveraging the proteomics and metabolomics expertise of Pacific Northwest National Lab (PNNL), project researchers have also demonstrated that the observations made at the mRNA and microRNA level are replicated at the proteome level (Starke et al., 2019).
In collaboration with the Geochemical Control on the Sorption, Bioavailability, Formation, and Long-term Environmental Fate of Polychlorinated Dibenzo-p-Dioxins Project, the team examined the bioavailability of TCDD sequestered to activated carbon (AC) on the transcriptomic response of SFB and gut microbiota. The expression of genes associated with SFB significantly increased with TCDD but no change was observed when TCDD was sequestered by AC (Stedtfeld et al., 2017c). AC also appeared to have a minimal influence on microbial community structure. This conclusion was further confirmed using metabolomic analysis of the fecal pellets. Mouse studies were conducted to evaluate the influence other dioxin-like compounds (2,3,4,7,9-PeCDF, and 2,3,7,8-TCDF) and compare it with the effects observed with TCDD. However, instead of using germ-free mice, this study was conducted using traditional C57BL/6 mice with modified gut microbiome using environmental doses of antibiotics. After the antibiotic administration, the mice were also inoculated with SFB and Bifidobacterium adolescentis. Results show that mice with microbiota perturbed by antibiotics had a greater imbalance of regulatory T-cells in response to TCDD. Microbial community analysis of these samples has been conducted using Illumina and data have been analyzed for a set of 176 samples. The project team is working on the associated manuscript which will be submitted during the requested extension period.