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Metatranscriptomic Analysis of the Mouse Gut Microbiome Response to the Persistent Organic Pollutant 2,3,7,8-Tetrachlorodibenzofuran

ABSTRACT: Persistent organic pollutants (POPs) are important environmental chemicals and continued study of their mechanism of action remains a high priority. POPs, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,7,8-tetrachlorodibenzofuran (TCDF), and polychlorinated biphenyls (PCBs), are widespread environmental contaminants that are agonists for the aryl hydrocarbon receptor (AHR). Activation of the AHR modulates the gut microbiome community structure and function, host immunity, and the host metabolome. In the current study, male C57BL6/J mice were exposed, via the diet, to 5 ug/kg body weight (BW) TCDF or 24 ug/kg BW of TCDF every day for 5 days. The functional and structural changes imparted by TCDF exposure to the gut microbiome and host metabolome were explored via 16S rRNA gene amplicon sequencing, metabolomics, and bacterial metatranscriptomics. Significant changes included increases in lipopolysaccharide (LPS) biosynthesis gene expression after exposure to 24 ug/kg BW of TCDF. Increases in LPS biosynthesis were confirmed with metabolomics and LPS assays using serum obtained from TCDF-treated mice. Significant increases in gene expression within aspartate and glutamate metabolism were noted after exposure to 24 ug/kg BW of TCDF. Together, these results suggest that after exposure to 24 ug/kg BW of TCDF, the gut microbiome increases the production of LPS and glutamate to promote localized gut inflammation, potentially using glutamate as a stress response.

ORGANISM(S): Mouse Mus Musculus

TISSUE(S): Intestine

SUBMITTER: Robert Nichols

PROVIDER: ST001299 | MetabolomicsWorkbench | Mon Jan 06 00:00:00 GMT 2020

REPOSITORIES: MetabolomicsWorkbench

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Project description:Background: Exposure to persistent organic pollutants (POPs) and disruptions in the gastrointestinal microbiota have been positively correlated with a predisposition to factors such as obesity, metabolic syndrome, and type 2 diabetes; however, it is unclear how the microbiome contributes to this relationship. Objective: This study aimed to explore the association between early-life exposure to a potent aryl hydrocarbon receptor (AHR) agonist and persistent disruptions in the microbiota, leading to impaired metabolic homeostasis later in life. Methods: This study utilized metagenomics, NMR- and mass spectrometry-based metabolomics, and biochemical assays to analyze the gut microbiome composition and function, as well as the physiological and metabolic effects of early-life exposure to 2,3,7,8-tetrachlorodibenzofuran (TCDF) in conventional, germ-free (GF), and Ahr-null mice. The impact of TCDF on Akkermansia muciniphila (A. muciniphila) in vitro was assessed using optical density (OD 600), flow cytometry, transcriptomics, and mass spectrometry-based metabolomics. Results: TCDF-exposed mice exhibited disruption in the gut microbiome community structure and function, characterized by lower abundances of A. muciniphila, lower levels of cecal short chain fatty acids (SCFAs) and indole-3-lactic acid (ILA), and a reduction in gut hormones GLP-1 and PYY. Importantly, microbial and metabolic phenotypes associated with early-life POP exposure were transferable to GF recipients in the absence of POP carry-over. In addition, AHR-independent interactions between POPs and the microbiota were observed, significantly affected the growth, physiology, gene expression, and metabolic activity of A. muciniphila, resulting in suppressed activity along the ILA pathway. Conclusions: These data point to the complex effects of POPs on the host and microbiota, providing strong evidence that early-life, short-term, and self-limiting POP exposure can adversely impact the microbiome, persisting into later life with associated health implications.

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Metatranscriptomic Analysis of the Mouse Gut Microbiome Response to the Persistent Organic Pollutant 2,3,7,8-Tetrachlorodibenzofuran

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