Gut Microbiome Critically Impacts PCB-induced Changes in Metabolic Fingerprints and the Hepatic Transcriptome in Mice

Abstract

Polychlorinated biphenyls (PCBs) are ubiquitously detected and have been linked to metabolic diseases. Gut microbiome is recognized as a critical regulator of disease susceptibility, however, little is known how PCBs and gut microbiome interact to modulate hepatic xenobiotic and intermediary metabolism. We hypothesized the gut microbiome regulates PCB-mediated changes in the metabolic fingerprints and hepatic transcriptome. Ninety-day-old female conventional (CV) and germ-free (GF) mice were orally exposed to the Fox River Mixture (synthetic PCB mixture, 6 or 30 mg/kg) or corn oil (vehicle control, 10 ml/kg), once daily for 3 consecutive days. RNA-Seq was conducted in liver, and endogenous metabolites were measured in liver and serum by LC-MS. Prototypical target genes of AhR, PXR, and CAR were more readily up-regulated by PCBs in CV conditions, indicating PCBs, to the hepatic transcriptome, act partly through the gut microbiome. In a gut microbiome-dependent manner, xenobiotic and steroid metabolism pathways were up-regulated, whereas response to misfolded proteins-related pathways were down-regulated by PCBs. At the high PCB dose, NADP and arginine appear to interact with drug-metabolizing enzymes (i.e. Cyp1-3 family), which are highly correlated with Ruminiclostridium and Roseburia, providing a novel explanation of gut-liver interaction from PCB-exposure. Utilizing the LINCS L1000 database, therapeutics targeting anti-inflammatory and ER stress pathways are predicted to be remedies that can mitigate PCB toxicity. Our findings demonstrate that habitation of the gut microbiota drives PCB-mediated hepatic responses. Our study adds knowledge of physiological response differences from PCB exposure and considerations for further investigations for gut microbiome-dependent therapeutics.

Pregnane X Receptor and the Gut-Liver Axis: A Recent Update

“…Third, novel endogenous PXR ligands and/or activators have been identified, which are microbial metabolites of BAs and tryptophan (Staudinger et al, 2001;Venkatesh et al, 2014). Along the same lines, novel bi-directional interactions of PXR and the gut microbiome have been discovered under physiological, pathophysiological, pharmacological, and toxicological conditions (Cheng et al, 2018;Li et al, 2018;Scoville et al, 2019;Lim et al, 2020;Kim et al, 2021;Little et al, 2021). Last but not least, modifying factors including sex (Fu et al, 2012;Barretto et al, 2021), timeincluding liver development (Hart et al, 2009), and early life exposures to PXR-activating xenobiotics (Li et al, 2016a;Li et al, 2016b), aging (Fu et al, 2012), and circadian rhythm, have been further elucidated.…”

“…At the dose of 30 mg/kg of PCBs, NADP and arginine are predicted to interact with the drug-metabolizing enzymes within the Cyp1-3 family, and this was also highly correlated with the presence of Ruminiclostridium and Roseburia. This suggests a novel role of the gut-liver axis in PCB-mediated effect on intermediary metabolism (Lim et al, 2020). In addition to the Fox River PCB mixture, the Aroclor1260 PCB mixture also altered the composition of the gut microbiome in a dietinduced obese mouse model and altered beta diversity in a PXR-dependent manner (Wahlang et al, 2021).…”

“…Following exposure to PXR-activating environmental chemicals, gut dysbiosis has been observed (Cheng et al, 2018;Li et al, 2018;Scoville et al, 2019;Cruz et al, 2020;Lim et al, 2020;Gomez et al, 2021), although caution is needed in interpreting the results, as these environmental toxicants may also have off-target effects on the gut microbiome independent from PXR activation. Oral exposure to BDE-47 and BDE-99, which are known to activate PXR and CAR in mouse liver (Pacyniak et al, 2007), produced profound gut dysbiosis as evidenced by decreased alpha diversity and 45 differentially regulated bacteria in the large intestinal content of adult male mice (Li et al, 2018).…”

Polychlorinated Biphenyls (PCBs): Risk Factors for Autism Spectrum Disorder?

“…While the enteric nervous system is distinct from the autonomic nervous system, it is similar to the sympathetic and parasympathetic nervous systems in that it is derived from the neural crest [215]. There is growing clinical evidence that an altered gut microbiome is associated with ASD [216,217], and recent studies demonstrate that PCBs can alter the gut microbiome [218][219][220][221][222]. For example, in one of the latter studies [222], developmental exposure of mice to a PCB mixture that mimics the PCB congener profile found in the serum of mothers at increased risk of having a child with ASD [37,195], altered intestinal physiology in weanling mice, coincident with changes in the microbiome [196].…”

LC–MS Based Metabolomics Study of the Effects of EGCG on A549 Cells

“…Metabolomics is an exciting tool to detect small metabolic compounds and monitor small global molecule endogenous metabolite changes induced by biochemical reactions in biological systems (Dunn et al, 2011;Griffin et al, 2011;Reaves and Rabinowitz, 2011;Gu et al, 2012;Carroll et al, 2015;Zampieri et al, 2017;McCartney et al, 2018;Yan and Xu, 2018;Yeung, 2018;Shi et al, 2019;Eghlimi et al, 2020;He et al, 2020;Lim et al, 2020;Wei et al, 2021). Metabolomics is a promising approach to searching potential biomarkers and novel therapeutic strategies for lung cancer (Luengo et al, 2017;Seijo et al, 2019;Noreldeen et al, 2020;Schmidt et al, 2021).…”