Impact of Microbiome on Hepatic Metabolizing Enzymes and Transporters in Mice during Pregnancy

Han, Lyrialle W.; Wang, Lu; Shi, Yuanyuan; Dempsey, Joseph L.; Pershutkina, Olesya; Dutta, Moumita; Bammler, Theo K.; Cui, Julia Yue; Mao, Qingcheng

doi:10.1124/dmd.120.000039

Cited by 8 publications

(19 citation statements)

References 56 publications

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“…CYP2C19 activity in humans is known to decrease during pregnancy [36]. Our previous study also showed downregulation of Cyp2c50 in pregnancy, regardless of the microbiome status [12]. Cyp2c50 plays an important role as arachidonic acid epoxygenase and is considered a major metabolizing enzyme for the production of epoxyeicosatrienoic acids (EETs) [37].…”

Section: Plos Onementioning

confidence: 93%

“…Details of the animal studies were the same as previously described [ 12 ]. Briefly, all animals (pregnant and non-pregnant mice) were maintained with the same autoclaved diet, non-acidified water, and autoclaved bedding.…”

Section: Methodsmentioning

confidence: 99%

“…Total RNA was extracted from frozen liver tissues from CV and GF mice (n = 6, 5, 6, and 5 for CVNP, CVP, GFNP, and GFP mice, respectively) and sequenced as previously described [12]. Briefly, we performed paired-end RNA sequencing using Illumina NovaSeq 6000 and prepared the transcriptomic library using NEBNext 1 Ultra™ RNA Library Prep Kit for Illumina 1 .…”

Section: Rna-seq Transcriptomics Analysismentioning

confidence: 99%

“…We have previously used germ-free mice to investigate how the microbiome affects hepatic drug processing genes during pregnancy and found that the lack of microbiome can have a significant impact on the expression and/or activity of key hepatic drug processing genes during pregnancy [ 12 ]. For example, mouse hepatic cytochrome P450 (CYP) Cyp3a genes have multiple isoforms ( Cyp3a11 , Cyp3a16 , Cyp3a41 , Cyp3a44) , and Cyp3a11 is considered the murine ortholog of human CYP3A4 , a major human CYP enzyme known to metabolize numerous endogenous and exogenous substrates.…”

Section: Introductionmentioning

confidence: 99%

“…By gaining insights into these changes, we may better understand the sources of inter-individual variability of pregnancy-related diseases and therapeutic effects of medications during pregnancy. In the previous study, we used targeted transcriptomic, proteomic, and metabolomic approaches to determine the effects of the microbiome on the expression of hepatic drug processing genes during pregnancy [ 12 ]. However, the effects of pregnancy and the microbiome on overall hepatic metabolism have yet to be determined.…”

Section: Introductionmentioning

confidence: 99%

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Key hepatic metabolic pathways are altered in germ-free mice during pregnancy

et al. 2021

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Pregnancy is associated with metabolic changes to accommodate the mother and her growing fetus. The microbiome has been shown to modulate host metabolism of endogenous and exogenous substances. However, the combined effects of pregnancy and the microbiome on host metabolism have not been investigated. The objective of this study was to investigate how the microbiome affects overall hepatic metabolic processes during pregnancy. We assessed these changes within 4 groups of C57BL/6 mice: conventional non-pregnant, conventional pregnant, germ-free non-pregnant, and germ-free pregnant mice. We performed RNA-seq analysis on liver tissues and LC-MS/MS analysis of the plasma to assess the effects of pregnancy and the microbiome on hepatic transcriptome and untargeted plasma metabolome to describe metabolic changes as results of both pregnancy and lack of microbiome. By integrating transcriptomics and metabolomics data, we identified eight metabolic pathways that were significantly enriched for differentially expressed genes associated with pregnancy in both conventional and germ-free mice. Notably, of the eight pathways, 4 pathways (retinol metabolism, arachidonic acid metabolism, linoleic acid metabolism, and steroid hormone biosynthesis) which are all critical for normal pregnancy and fetal development were affected by the germ-free status in pregnant mice, but not at all in non-pregnant mice, indicating that the alterations in these four pathways caused by the lack of microbiome are unique for pregnancy. These results provide novel insight into the role of the microbiome in modulating host metabolic processes critical for maternal health and fetal development during pregnancy.

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Section: Plos Onementioning

confidence: 93%

Section: Methodsmentioning

confidence: 99%

Section: Rna-seq Transcriptomics Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Key hepatic metabolic pathways are altered in germ-free mice during pregnancy

et al. 2021

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Normal variation of the gut microbiota affects hepatic cytochrome P450 activity in mice

Togao

Tajima

Kurakawa

et al. 2021

Pharmacology Res & Perspec

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Several studies revealed that substantial artificial changes in the gut microbiota resulted in modification of hepatic cytochrome P450 3a (Cyp3a) in mice. Consequently, we hypothesized that “normal” variation of the gut microbiota might also alter hepatic Cyp activity and lead to individual differences in drug metabolism. Therefore, this study investigated the effects of normal gut microbiota variation on hepatic Cyp activity under the same genetic and environmental conditions using ex‐germ‐free mice. Using the feces of three breeder BALB/c mice (Jcl, Slc, and Crj), germ‐free BALB/cYit mice were conventionalized (Yit‐Jcl, Yit‐Slc, and Yit‐Crj). The gut microbiota composition and hepatic Cyp activity of these donors and recipients were evaluated. 16S rRNA sequencing revealed clear differences of the gut microbiota among donors and among recipients. Cyp3a activity was significantly higher in Slc mice than in Jcl and Crj mice. Notably, among recipients, Cyp3a activity was significantly higher in Yit‐Slc and Yit‐Crj mice than in Yit‐Jcl mice. Cyp2b activity was significantly higher in Slc mice than in Jcl and Crj mice. Cyp2b activity was significantly higher in Yit‐Slc mice than in Yit‐Jcl mice. Additionally, in correlation analysis, some genera displayed significant positive or negative correlations with Cyp activity, particular the strong positive correlation between Clostridium sensu stricto 1 with Cyp3a activity. In conclusion, this study demonstrated that normal variation of the gut microbiota affected hepatic Cyp3a and Cyp2b activity, which might result in individual differences of drug metabolism.

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The breath volatilome is shaped by the gut microbiota

Hernandez-Leyva,

Berna,

Liu

et al. 2024

Preprint

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The gut microbiota is widely implicated in host health and disease, inspiring translational efforts to implement our growing body of knowledge in clinical settings. However, the need to characterize gut microbiota by its genomic content limits the feasibility of rapid, point-of-care diagnostics. The microbiota produces a diverse array of xenobiotic metabolites that disseminate into tissues, including volatile organic compounds (VOCs) that may be excreted in breath. We hypothesize that breath contains gut microbe-derived VOCs that inform the composition and metabolic state of the microbiota. To explore this idea, we compared the breath volatilome and fecal gut microbiomes of 27 healthy children and found that breath VOC composition is correlated with gut microbiomes. To experimentally interrogate this finding, we devised a method for capturing exhaled breath from gnotobiotic mice. Breath volatiles are then profiled by gas-chromatography mass-spectrometry (GC-MS). Using this novel methodology, we found that the murine breath profile is markedly shaped by the composition of the gut microbiota. We also find that VOCs produced by gut microbes in pure culture can be identifiedin vivoin the breath of mice monocolonized with the same bacteria. Altogether, our studies identify microbe-derived VOCs excreted in breath and support a mechanism by which gut bacterial metabolism directly contributes to the mammalian breath VOC profiles.

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Impact of Microbiome on Hepatic Metabolizing Enzymes and Transporters in Mice during Pregnancy

Cited by 8 publications

References 56 publications

Key hepatic metabolic pathways are altered in germ-free mice during pregnancy

Key hepatic metabolic pathways are altered in germ-free mice during pregnancy

Normal variation of the gut microbiota affects hepatic cytochrome P450 activity in mice

The breath volatilome is shaped by the gut microbiota

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