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.
It is well-known that the pregnane X receptor (PXR/Nr1i2) is a critical xenobiotic-sensing nuclear receptor enriched in liver and intestine and is responsible for drug-drug interactions (DDI), due to their versatile ligand binding domain (LBD) and target genes involved in xenobiotic biotransformation. PXR can be modulated by various xenobiotics including pharmaceuticals, nutraceuticals, dietary factors, and environmental chemicals. Microbial metabolites such as certain secondary bile acids (BAs) and the tryptophan metabolite indole-3-propionic acid (IPA) are endogenous PXR activators. Gut microbiome is increasingly recognized as an important regulator for host xenobiotic biotransformation and intermediary metabolism. PXR regulates and is regulated by the gut-liver axis. This review summarizes recent research advancements leveraging pharmaco-and toxico-metagenomic approaches that have redefined the previous understanding of PXR. Key topics covered in this review include 1) genome-wide investigations on novel PXR-target genes, novel PXR-DNA interaction patterns, and novel PXR-targeted intestinal bacteria; 2) key PXRmodulating activators and suppressors of exogenous and endogenous sources; 3) novel bidirectional interactions between PXR and gut microbiome under physiological, pathophysiological, pharmacological, and toxicological conditions; and 4) modifying factors of PXR-signaling including species-and sex difference, and time (age, critical windows of exposure, and circadian rhythm). The review also discusses critical knowledge gaps and important future research topics centering around PXR.
Longitudinal sampling of the stool has yielded important insights into the ecological dynamics of the human gut microbiome. However, due to practical limitations, the most densely sampled time series from the human gut are collected at a frequency of about once per day, while the population doubling times for gut commensals are on the order of minutes-to-hours. Despite this, much of the prior work on human gut microbiome time series modeling has, implicitly or explicitly, assumed that day-to-day fluctuations in taxon abundances are related to population growth or death rates, which is likely not the case. Here, we propose an alternative model of the human gut as a continuous flow ecosystem at a dynamical steady state, where population dynamics occur internally and the bacterial population sizes measured in stool represent an endpoint of these internal dynamics. We formalize this idea as stochastic logistic growth of a population held at a constant dilution rate. We show how this model provides a path toward estimating the growth phases of gut bacterial populations in situ. We assess our model predictions against densely-sampled human stool metagenomic time series data. Consistent with our model, donors with slower defecation rates tended to harbor a larger proportion of taxa in later growth phases, while faster defecation rates were associated with more taxa in earlier growth phases. We discuss how these growth phase estimates may be used to better inform metabolic modeling in flow-through ecosystems, like animal guts or industrial bioreactors.
Recent evidence suggests that complex diseases can result from early life exposure to environmental toxicants. Polybrominated diphenyl ethers (PBDEs), and polychlorinated biphenyls (PCBs) are persistent organic pollutants (POPs) and remain a continuing risk to human health despite being banned from production. Developmental BPA exposure mediated-adult onset of liver cancer via epigenetic reprogramming mechanisms has been identified. Here, we investigated whether the gut microbiome and liver can be persistently reprogrammed following neonatal exposure to POPs, and the associations between microbial biomarkers and disease-prone changes in the hepatic transcriptome in adulthood, compared to BPA. C57BL/6 male and female mouse pups were orally administered vehicle, BPA, BDE-99 (a breast milk-enriched PBDE congener), or the Fox River PCB mixture (PCBs), once daily for three consecutive days (postnatal days [PND] 2 to 4). Tissues were collected at PND5 and PND60. Among the three chemicals investigated, early life exposure to BDE-99 produced the most prominent developmental reprogramming of the gut-liver axis, including hepatic inflammatory and cancer-prone signatures. In adulthood, neonatal BDE-99 exposure resulted in a persistent increase in Akkermansia muciniphila throughout the intestine, accompanied by increased hepatic levels of acetate and succinate, the known products of A. muciniphila. In males, this was positively associated with permissive epigenetic marks H3K4me1 and H3K27, which were enriched in loci near liver cancer-related genes that were dysregulated following neonatal exposure to BDE-99. Our findings provide novel insights that early life exposure to POPs can have a life-long impact on disease risk, which may partly be regulated by the gut microbiome.
Perfluorinated carboxylic acids (PFCAs) are widespread environmental pollutants for which human exposure has been documented. PFCAs at high doses were known regulate xenobiotic transporters partly through PPARα and CAR in rodent models. Less is known regarding how various PFCAs at a lower concentration modulate transporters for endogenous substrates such as amino acids in human hepatocytes. Such studies are of particular importance because amino acids are involved in chemical detoxification and their transport system may serve as promising therapeutic targets for structurally similar xenobiotics. The focus of this study was to further elucidate how PFCAs modulate transporters involved in intermediary metabolism and xenobiotic biotransformation. We tested the hepatic transcriptomic response of HepaRG cells exposed to 45 M PFOA, PFNA, or PFDA in triplicates for 24 h (vehicle: 0.1% DMSO), as well as the prototypical ligands for PPARα (WY-14643, 45 µM) and CAR (CITCO, 2 µM). PFCAs with increasing carbon chain lengths (C8-C10) regulated more liver genes, with amino acid metabolism and transport ranked among the top enriched pathways and PFDA ranked as the most potent PFCA tested. Genes encoding amino acid transporters, which are essential for protein synthesis, were novel inducible targets by all 3 PFCAs, suggesting a potentially protective mechanism to reduce further toxic insults. None of the transporter regulations appeared to be through PPARα or CAR but potential involvement of Nrf2 is noted for all 3 PFCAs. In conclusion, PFCAs with increasing carbon chain lengths up-regulate amino acid transporters and modulate xenobiotic transporters to limit further toxic exposures in HepaRG cells.
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