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

2020 ◽  
Vol 177 (1) ◽  
pp. 168-187 ◽  
Author(s):  
Joe Jongpyo Lim ◽  
Xueshu Li ◽  
Hans-Joachim Lehmler ◽  
Dongfang Wang ◽  
Haiwei Gu ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Target Genes ◽  
Metabolic Diseases ◽  
Corn Oil ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Dependent Manner ◽  
Integrated Network ◽  
Hepatic Transcriptome ◽  
Pcb Exposure

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 and germ-free 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 aryl hydrocarbon receptor, pregnane X receptor, and constitutive androstane receptor were more readily upregulated by PCBs in conventional 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 upregulated, whereas response to misfolded proteins-related pathways was downregulated by PCBs. At the high PCB dose, NADP, and arginine appear to interact with drug-metabolizing enzymes (ie, Cyp1–3 family), which are highly correlated with Ruminiclostridium and Roseburia, providing a novel explanation of gut-liver interaction from PCB-exposure. Utilizing the Library of Integrated Network-based Cellular Signatures L1000 database, therapeutics targeting anti-inflammatory and endoplasmic reticulum 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.

scholarly journals Pharmacological Activation of PXR and CAR Downregulates Distinct Bile Acid-Metabolizing Intestinal Bacteria and Alters Bile Acid Homeostasis

2018 ◽  
Vol 168 (1) ◽  
pp. 40-60 ◽  
Author(s):  
Joseph L Dempsey ◽  
Dongfang Wang ◽  
Gunseli Siginir ◽  
Qiang Fei ◽  
Daniel Raftery ◽  
...  
Keyword(s):  
Bile Acid ◽  
Gut Microbiota ◽  
Gut Microbiome ◽  
Corn Oil ◽  
Constitutive Androstane Receptor ◽  
Intestinal Bacteria ◽  
Pregnane X Receptor ◽  
Bile Salt Hydrolase ◽  
Dependent Manner ◽  
Germ Free

AbstractThe gut microbiome regulates important host metabolic pathways including xenobiotic metabolism and intermediary metabolism, such as the conversion of primary bile acids (BAs) into secondary BAs. The nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are well-known regulators for xenobiotic biotransformation in liver. However, little is known regarding the potential effects of PXR and CAR on the composition and function of the gut microbiome. To test our hypothesis that activation of PXR and CAR regulates gut microbiota and secondary BA synthesis, 9-week-old male conventional and germ-free mice were orally gavaged with corn oil, PXR agonist PCN (75 mg/kg), or CAR agonist TCPOBOP (3 mg/kg) once daily for 4 days. PCN and TCPOBOP decreased two taxa in the Bifidobacterium genus, which corresponded with decreased gene abundance of the BA-deconjugating enzyme bile salt hydrolase. In liver and small intestinal content of germ-free mice, there was a TCPOBOP-mediated increase in total, primary, and conjugated BAs corresponding with increased Cyp7a1 mRNA. Bifidobacterium, Dorea, Peptociccaceae, Anaeroplasma, and Ruminococcus positively correlated with T-UDCA in LIC, but negatively correlated with T-CDCA in serum. In conclusion, PXR and CAR activation downregulates BA-metabolizing bacteria in the intestine and modulates BA homeostasis in a gut microbiota-dependent manner.

Novel Interactions Between Circulating microRNAs and Gut Microbiota Composition in Human Obesity.

2020 ◽  
Author(s):  
Taís Silveira Assmann ◽  
Amanda Cuevas-Sierra ◽  
José Ignacio Riezu-Boj ◽  
Fermin Milagro ◽  
J Alfredo Martínez
Keyword(s):  
Gut Microbiota ◽  
Gut Microbiome ◽  
Target Genes ◽  
Metabolic Diseases ◽  
Bacterial Species ◽  
Microbiota Composition ◽  
Circulating Mirnas ◽  
Clinical Trial Registration ◽  
Body Adiposity ◽  
Gut Microbiota Composition

Abstract Background: Unbalances in microRNAs (miRNA) and gut microbiota patterns have been proposed as putative factors concerning onset and development of obesity and other metabolic diseases. However, the determinants that mediate the interactions between miRNAs and the gut microbiome impacting on obesity are scarcely understood. Thus, the aim of this article was to investigate possible interactions between circulating miRNAs and gut microbiota composition in obesity. Method: The analyzed sample comprised 78 subjects with obesity [cases, body mass index (BMI): 30 – 40 kg/m2] and 25 eutrophic individuals (controls, BMI £ 25 kg/m2). The expression of 96 miRNAs was investigated in plasma of all individuals using miRCURY LNA miRNA Custom PCR Panels (Exiqon). Bacterial DNA sequencing was performed following the Illumina 16S protocol. The FDR (Benjamini-Hochberg test, q-value) correction was used for multiple comparison analyses.Results: A total of 26 circulating miRNAs and 12 bacterial species were found differentially expressed between cases and controls. Interestingly, an interaction among three miRNAs (miR-130b-3p, miR-185-5p, and miR-21-5p) with Bacteroides eggerthi, and BMI levels was evidenced (r2= 0.148, P= 0.004). Those miRNAs that correlated with obesity-associated gut bacteria abundance are known to regulate target genes that participate in metabolism-related pathways, such as fatty acid degradation, carbohydrate digestion and absorption, insulin signaling, and glycerolipid metabolism. Conclusion: This study characterized an interaction between the abundance of 4 bacterial species and 14 circulating miRNAs in relation to body adiposity. Moreover, the current study also suggests that miRNAs may serve as a communication mechanism between the gut microbiome and human hosts. Clinical trial registration: clinicaltrials.gov (reg. no. NCT02737267).

Knockdown of ATP8B1 expression leads to specific downregulation of the bile acid sensor FXR in HepG2 cells: effect of the FXR agonist GW4064

2009 ◽  
Vol 296 (5) ◽  
pp. G1119-G1129 ◽  
Author(s):  
Pilar Martínez-Fernández ◽  
Loreto Hierro ◽  
Paloma Jara ◽  
Luis Alvarez
Keyword(s):  
Bile Acid ◽  
Hepg2 Cells ◽  
Target Genes ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Bile Secretion ◽  
Farnesoid X Receptor ◽  
Mrna Levels

Farnesoid X receptor (FXR) is a bile acid-sensing nuclear receptor that controls bile acid homeostasis. It has been suggested that downregulation of FXR contributes to the pathogenesis of an inherited disorder of bile secretion caused by mutations in ATP8B1. We have investigated the relationship between ATP8B1 knockdown and FXR downregulation in the human hepatoblastoma cell line HepG2. Transfection of HepG2 cells with ATP8B1 small interfering RNA (siRNA) duplexes led to a 60% reduction in the endogenous levels of ATP8B1 mRNA and protein and a concomitant decrease in FXR mRNA and protein content, as well as in FXR phosphorylation. This decrease was accompanied by a marked reduction in mRNA levels of a subset of FXR targets, such as bile salt export pump ( ABCB11), small heterodimer partner, and uridine 5′-diphosphate-glucuronosyltransferase. ATP8B1 inhibition specifically targeted FXR since mRNA expression of other prominent nuclear receptors, such as pregnane X receptor and constitutive androstane receptor, or liver-enriched transcription factors, such as hepatocyte nuclear factor 1α ( HNF-1α) and HNF-4α, was not altered. The expression of other key genes involved in bile acid synthesis, detoxification, and transport also remained unchanged upon ATP8B1 knockdown. Supporting the specificity of the effect, siRNA-mediated silencing of ABCB11, whose defect is associated with another inherited disorder of bile secretion, did not affect FXR expression. Treatment with the synthetic FXR agonist GW4064 was able to partially neutralize ATP8B1 siRNA-mediated FXR downregulation and fully counteract inhibition of FXR target genes. Collectively these findings indicate that ATP8B1 knockdown specifically downregulates FXR, and this action can be circumvented by treatment with FXR agonists.

scholarly journals Long Noncoding RNA NTT Context-Dependently Regulates MYB by Interacting With Activated Complex in Hepatocellular Carcinoma Cells

2021 ◽  
Vol 11 ◽  
Author(s):  
Ya-Sian Chang ◽  
Ya-Ting Lee ◽  
Ju-Chen Yen ◽  
Yuli C. Chang ◽  
Li-Li Lin ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Target Genes ◽  
Metabolic Diseases ◽  
Cellular Migration ◽  
Negative Regulator ◽  
Dependent Manner ◽  
Colon Cancers ◽  
Activated Complex

BackgroundLong noncoding RNA (lncRNA) mediates the pathogenesis of various diseases, including cancer and cardiovascular, infectious, and metabolic diseases. This study examined the role of lncRNA NTT in the development and progression of cancer.MethodsThe expression of NTT was determined using tissues containing complementary DNA (cDNA) from patients with liver, lung, kidney, oral, and colon cancers. The expression of cis-acting genes adjacent to the NTT locus (CTGF, STX7, MYB, BCLAF1, IFNGR1, TNFAIP3, and HIVEP2) was also assessed. We used knockdown and chromatin immunoprecipitation (ChIP) assays to identify the cis-acting genes that interact with NTT.ResultsNTT was most significantly downregulated in hepatocellular carcinoma (HCC), while a higher NTT level correlated with a shorter survival time of patients with HCC. Multivariate analysis indicated NTT was not an independent predictor for overall survival. MYB was significantly upregulated, and its increased expression was associated with dismal survival in HCC patients, similar to the results for NTT. NTT knockdown significantly decreased cellular migration. ChIP of HCC cell lines revealed that NTT is regulated by the transcription factor ATF3 and binds to the MYB promoter via the activated complex. Additionally, when NTT was knocked down, the expression of MYB target genes such as Bcl-xL, cyclinD1, and VEGF was also downregulated. NTT could play a positive or negative regulator for MYB with a context-dependent manner in both HCC tissues and animal model.ConclusionOur study suggests that NTT plays a key role in HCC progression via MYB-regulated target genes and may serve as a novel therapeutic target.

scholarly journals Constitutive Androstane Receptor-Mediated Inhibition of Metformin on Phase II Metabolic Enzyme SULT2A1

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Xiaowen Hu ◽  
Mengsiyu Li ◽  
Chunxue Zhang ◽  
Shuguang Pang
Keyword(s):  
Phase Ii ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Metabolic Enzyme ◽  
Downstream Target ◽  
Treatment Of Diabetes ◽  
Amp Activated Protein Kinase

Background. Metformin, as a first-line treatment for diabetes, interacts with many protein kinases and transcription factors which affect the expression of downstream target genes governing drug metabolism. Sulfotransferase, SULT2A1, one phase II metabolic enzyme, sulfonates both xenobiotic and endobiotic compounds to accelerate drug excretion. Herein, we designed experiments to investigate the effects and mechanisms of metformin on SULT2A1 expression in vitro. Methods. The hepatocellular carcinoma cell line, HepaRG, was cultured with different concentrations of metformin. The cell viability was measured using CCK8 kit. HepaRG was used to evaluate the protein expression of pregnane X receptor (PXR), the constitutive androstane receptor (CAR), SULT2A1, AMP-activated protein kinase (AMPK), and phosphorylation of AMPK (p-AMPK), respectively, at different concentrations of metformin with or without rifampin (human PXR activator) and CITCO (human CAR activator). The coregulators with CAR on SULT2A1 promoter response elements have also been characterized. Results. We showed that metformin did not affect the basic expression of SULT2A1 but could suppress the expression of SULT2A1 induced by the activator of human CAR. Investigations revealed that metformin which could block CAR nuclear translocation further suppress SULT2A1. In addition, we found that the prevented CAR transfer into the nucleus by metformin was partially an AMPK-dependent event. Conclusion. The present study indicated that the activation of AMPK-CAR pathway mediated the suppression of SULT2A1 by metformin. Metformin may affect the metabolism and clearance of drugs which are SULT2A1 substrates. The results that emerged from this work provide substantial insights into an appropriate medication in the treatment of diabetes patients.

scholarly journals Coordinated Roles of Pregnane X Receptor and Constitutive Androstane Receptor in Autoinduction of Voriconazole Metabolism in Mice

2012 ◽  
Vol 57 (3) ◽  
pp. 1332-1338 ◽  
Author(s):  
Masato Ohbuchi ◽  
Kouichi Yoshinari ◽  
Hayato Kaneko ◽  
Satoru Matsumoto ◽  
Akiko Inoue ◽  
...  
Keyword(s):  
Target Genes ◽  
Mammalian Species ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Human Hepatocytes ◽  
Mrna Levels ◽  
Wild Type ◽  
Primary Human Hepatocytes ◽  
Metabolic Activities ◽  
Species Specific

ABSTRACTThe antifungal efficacy of voriconazole (VRC) differs among host species, with potent efficacy in humans but less in rodents. We investigated the possible involvement of pregnane X receptor (PXR) and constitutive androstane receptor (CAR) in the species-specific efficacy of VRC through pharmacokinetic analyses using genetically modified mice and primary human hepatocytes. VRC (30 mg/kg) was orally administered to wild-type,Pxr-null,Car-null, andPxr- andCar-null (Pxr/Car-null) mice for 7 days. Hepatic VRC metabolism was significantly increased by VRC administration, and the elimination rates of plasma VRC were much higher on day 7 than on day 1 in wild-type mice. This autoinduction was also observed inPxr-null andCar-null mice but not inPxr/Car-null mice, suggesting coordinated roles of PXR and CAR in the autoinduction of VRC metabolism in mice. HepaticCyp3a11mRNA levels were increased by VRC administration, hepatic metabolic activities for VRC were correlated with CYP3A activities, and the induced VRC metabolism was inhibited by ketoconazole (a CYP3A inhibitor). In primary human hepatocytes, VRC barely increased mRNA levels ofCYP3A4andCYP2B6(human PXR/CAR target genes) at its therapeutic concentrations. In conclusion, these results suggest that VRC is metabolized mainly by CYP3A11 in mouse livers and that PXR- and CAR-mediated CYP3A11 induction, namely, autoinduction of VRC metabolism, is a primary reason for the ineffectiveness of VRC in mice. A limited ability of VRC to activate human PXR/CAR at its clinical concentration might explain the VRC efficacy in humans. Therefore, the ability to activate PXR/CAR might determine the VRC efficacy in different mammalian species.

Pregnane X receptor activation ameliorates DSS-induced inflammatory bowel disease via inhibition of NF-κB target gene expression

2007 ◽  
Vol 292 (4) ◽  
pp. G1114-G1122 ◽  
Author(s):  
Yatrik M. Shah ◽  
Xiaochao Ma ◽  
Keiichirou Morimura ◽  
Insook Kim ◽  
Frank J. Gonzalez
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Target Genes ◽  
Clinical Symptoms ◽  
Pregnane X Receptor ◽  
Receptor Activation ◽  
Dependent Manner ◽  
Cytokine Analysis ◽  
Inflammatory Bowel

Pregnane X receptor (PXR) expression was shown to be protective in inflammatory bowel disease (IBD). However, the mechanism by which PXR provides protection remains unclear. Wild-type and Pxr-null mice were treated with the PXR agonist pregnenolone-16α-carbonitrile or vehicle and administered 2.5% dextran sulfate sodium (DSS) in drinking water to induce IBD. Typical clinical symptoms were evaluated on a daily basis. In vivo intestinal permeability assays and proinflammatory cytokine analysis were performed. PXR agonist-treated mice were protected from DSS-induced colitis compared with vehicle-treated mice, as defined by body weight loss, diarrhea, rectal bleeding, colon length, and histology. Pregnenolone-16α-carbonitrile did not decrease the severity of IBD in Pxr-null mice. PXR agonist treatment did not increase epithelial barrier function but did decrease mRNA expression of several NF-κB target genes in a PXR-dependent manner. The present study clearly demonstrates a protective role for PXR agonist in DSS-induced IBD. The data suggest that PXR-mediated repression of NF-κB target genes in the colon is a critical mechanism by which PXR activation decreases the susceptibility of mice to DSS-induced IBD.

scholarly journals Understanding the Physiological Functions of the Host Xenobiotic-sensing Nuclear Receptors PXR and CAR on the Gut Microbiome using Genetically Modified Mice

2020 ◽  
Author(s):  
Mallory Little ◽  
Moumita Dutta ◽  
Hao Li ◽  
Adam Matson ◽  
Xiaojian Shi ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Gut Microbiome ◽  
Constitutive Androstane Receptor ◽  
Immune Surveillance ◽  
Specific Effect ◽  
Pregnane X Receptor ◽  
Bile Salt Hydrolase ◽  
Physiological Functions ◽  
Species Specific ◽  
Host Immune Surveillance

Abstract Background: Pharmacological activation of the host xenobiotic-sensing nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) is well-known to increase drug metabolism and reduce inflammation. Little is known regarding the physiological functions of PXR and CAR on the gut microbiome, which is an important regulator for the host immune surveillance and bile acid (BA) metabolism. We examined the gut microbiome composition and BA metabolites in high vs. low PXR/CAR-expressing mice, and in mice that are deficient in PXR, CAR, or both, at two developmental ages. We also utilized humanized PXR transgenic (hPXR-TG) mice to compare the species-specific effect of PXR on the gut microbiome. Results: We discovered bivalent hormetic functions of PXR and CAR in modulating the richness of the gut microbiome and inflammatory biomarkers: the high PXR/CAR expressers had higher microbial richness, pro-inflammatory bacteria (distinct taxa in Helicobacteraceae and Helicobacter), and fecal pro-inflammatory cytokines, suggesting higher immune surveillance to prevent the colonization of harmful bacteria. Interestingly, the absence of PXR or CAR also increased the microbial richness, and absence of both receptors synergistically increased the microbial richness. PXR and CAR deficiency increased the pro-inflammatory bacteria (Helicobacteraceae and Helicobacter). Most notably, deficiency in both PXR and CAR markedly increased the relative abundance of Lactobacillus, which is capable of bile salt hydrolase (BSH) activity. This corresponded to a decrease in major primary taurine-conjugated bile acids (BAs) in feces, which may lead to higher internal burden of taurine and unconjugated BAs, both of which are linked to inflammation, oxidative stress, and cytotoxicity. hPXR-TG mice had a distinct microbial profile as compared to wild-type mice, including a higher representation of Prevotella. hPXR-TG mice also had higher 12-OH BAs but lower 6-OH BAs, suggesting PXR’s species-specific role in modulating host hepatic BA synthesis. Conclusions: This study is the first to show that the host PXR and CAR profoundly influence the composition of the gut microbiome and its BA metabolites, with a bivalent hormetic relationship between PXR/CAR levels and microbial richness, unveiling the involvement of PXR/CAR-microbiome interactions in host immune surveillance and BA metabolism.

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