Novel Interactions between Gut Microbiome and Host Drug-Processing Genes Modify the Hepatic Metabolism of the Environmental Chemicals Polybrominated Diphenyl Ethers

Li, Cindy Yanfei; Lee, Soowan; Cade, Sara; Kuo, Lih; Schultz, Irvin R.; Bhatt, Deepak; Prasad, Bhagwat; Bammler, Theo K.; Cui, Julia Yue

doi:10.1124/dmd.117.077024

Cited by 39 publications

(47 citation statements)

References 61 publications

(80 reference statements)

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“…Using RNA-Seq, we recently demonstrated that BDE-47 and BDE-99 differentially regulated many other phase-I drug-metabolizing enzymes (i.e., enzymes involved in oxidation, reduction, and hydrolysis), phase-II enzymes (i.e., enzymes involved in conjugation), as well as transporters in mouse liver. We also demonstrated that the lack of gut microbiota in GF mice altered the oxidative metabolites of BDE-47 and BDE-99 and profoundly modified the PBDE-mediated transcriptomic responses in liver (Li et al, 2017). This provided the first evidence that there is a novel interaction between gut microbiota and PBDEs that influences the host hepatic xenobiotic biotransformation.…”

Section: Introductionmentioning

confidence: 62%

“…The mRNA of Cyp7a1 (Fig. 9A) as well as the mRNAs of other BA-processing genes in liver were retrieved from our previously published RNA-Seq dataset (Li et al, 2017) and are accessible though the NCBI Gene Expression Omnibus Series accession number GSE101650. Intestinal mRNAs of various BA-processing genes were determined using reverse-transcription qPCR.…”

Section: Downloaded Frommentioning

confidence: 99%

“…Targeted Proteomics by LC-MS/MS. The procedure is similar to a previous publication with a few modifications (Selwyn et al, 2015a;Li et al, 2017). Briefly, the membrane proteins of the mouse livers were isolated using a Pierce Mem-PER Plus Membrane Protein Extraction Kit (Thermo Fisher Scientific).…”

Section: Downloaded Frommentioning

confidence: 99%

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PBDEs Altered Gut Microbiome and Bile Acid Homeostasis in Male C57BL/6 Mice

Dempsey

Wang

et al. 2018

Drug Metab Dispos

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Polybrominated diphenyl ethers (PBDEs) are persistent environmental contaminants with well characterized toxicities in host organs. Gut microbiome is increasingly recognized as an important regulator of xenobiotic biotransformation; however, little is known about its interactions with PBDEs. Primary bile acids (BAs) are metabolized by the gut microbiome into more lipophilic secondary BAs that may be absorbed and interact with certain host receptors. The goal of this study was to test our hypothesis that PBDEs cause dysbiosis and aberrant regulation of BA homeostasis. Nine-week-old male C57BL/6 conventional (CV) and germ-free (GF) mice were orally gavaged with corn oil (10 mg/kg), BDE-47 (100 mol/kg), or BDE-99 (100mol/kg) once daily for 4 days ( = 3-5/group). Gut microbiome was characterized using 16S rRNA sequencing of the large intestinal content in CV mice. Both BDE-47 and BDE-99 profoundly decreased the alpha diversity of gut microbiome and differentially regulated 45 bacterial species. Both PBDE congeners increased and Erysipelotrichaceae spp., which have been reported to have anti-inflammatory and antiobesity functions. Targeted metabolomics of 56 BAs was conducted in serum, liver, and small and large intestinal content of CV and GF mice. BDE-99 increased many unconjugated BAs in multiple biocompartments in a gut microbiota-dependent manner. This correlated with an increase in microbial 7-dehydroxylation enzymes for secondary BA synthesis and increased expression of host intestinal transporters for BA absorption. Targeted proteomics showed that PBDEs downregulated host BA-synthesizing enzymes and transporters in livers of CV but not GF mice. In conclusion, there is a novel interaction between PBDEs and the endogenous BA-signaling through modification of the "gut-liver axis".

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Section: Introductionmentioning

confidence: 62%

Section: Downloaded Frommentioning

confidence: 99%

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PBDEs Altered Gut Microbiome and Bile Acid Homeostasis in Male C57BL/6 Mice

Dempsey

Wang

et al. 2018

Drug Metab Dispos

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“…in hPXR-TG mice may partially explain the differences in beta diversity observed between the two PXR species differences. Bacteria in this family have been associated with traditional societies' microbiota, with multiple studies nding a correlation between Paraprevotellaceae abundance and carbohydrate-heavy diets [15,96,97]. Interestingly, male hPXR-TG mice of both ages exhibited an increase in the relative concentration of propionic acid compared to WT mice, which is a conjugated form of the SCFA propionate.…”

Section: Discussionmentioning

confidence: 99%

“…xenobiotic-processing genes [15]. Therefore, the gut microbiome is an important direct and indirect regulator of host xenobiotic biotransformation pathways.…”

Section: Introductionmentioning

confidence: 99%

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

Little

Dutta

et al. 2020

Preprint

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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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Effects of gut microbiota on in vivo metabolism and tissue accumulation of cytochrome P450 3A metabolized drug: Midazolam

Togao

Kawakami

Otsuka

et al. 2020

Biopharm & Drug Disp

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The link between drug‐metabolizing enzymes and gut microbiota is well established. In particular, hepatic cytochrome P450 (CYP) 3A activities are presumed to be affected by gut microbiota. However, there is no direct evidence that the gut microbiota affects CYP3A metabolism or the clearance of clinically relevant drugs in vivo. Our purpose was to evaluate the effects of gut microbiota on in vitro and in vivo drug metabolism and on the clearance of midazolam, which is a standard CYP3A metabolized drug. Hepatic Cyp3a activity and in vitro midazolam hydroxylase activity were compared using specific pathogen‐free (SPF) and germ‐free (GF) mice. In a pharmacokinetics (PK) study, SPF and GF mice were intraperitoneally injected with 60 mg/kg of midazolam, and plasma and tissue concentrations were measured. Hepatic Cyp3a activity and midazolam hydroxylase activity were significantly lower in GF mice than in SPF mice. Notably, in the PK study, the area under the plasma concentration–time curve from time zero to infinity and the elimination half‐life were approximately four‐fold higher in GF mice compared with SPF mice. Furthermore, the concentration of midazolam in the brain 180 min after administration was about 14‐fold higher in GF mice compared with SPF mice. Together, our results demonstrated that the gut microbiota altered the metabolic ability of Cyp3a and the tissue accumulation of midazolam.

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Novel Interactions between Gut Microbiome and Host Drug-Processing Genes Modify the Hepatic Metabolism of the Environmental Chemicals Polybrominated Diphenyl Ethers

Cited by 39 publications

References 61 publications

PBDEs Altered Gut Microbiome and Bile Acid Homeostasis in Male C57BL/6 Mice

PBDEs Altered Gut Microbiome and Bile Acid Homeostasis in Male C57BL/6 Mice

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

Effects of gut microbiota on in vivo metabolism and tissue accumulation of cytochrome P450 3A metabolized drug: Midazolam

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