Gut Microbiome Alters the Activity of Liver Cytochromes P450 in Mice With Sex-Dependent Differences

Jourová, Lenka; Vavrečková, Markéta; Zemanová, Nina; Anzenbacher, Pavel; Langová, Kateřina; Hermanová, Petra; Hudcovic, Tomáš; Anzenbacherová, Eva

doi:10.3389/fphar.2020.01303

Cited by 18 publications

(18 citation statements)

References 38 publications

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“…Our findings that Cyp3a11 mRNA expression and enzyme activity of CYP3A were lower in GF than SPF mice are in line with our previous studies [ 30 , 31 ], showing that the presence of microbiome is crucial in the synthesis of CYP3A. However, it is not clear if this phenomenon contributes to more efficient metabolism of metronidazole in SPF mice.…”

Section: Discussionsupporting

confidence: 83%

“…Interestingly, it was found that colonization by only a single non-pathogenic or probiotic bacteria strain alters the mRNA expression of some hepatic CYPs in originally GF mice [ 30 ]. Results of other studies have highlighted the role of gut microbiome and its metabolites in the regulation of CYPs expression, along with other factors [ 31 , 32 ]. Drug administration may also contribute into this complex equation and influence the expression of CYPs, differently in the GF and SPF mice.…”

Section: Discussionmentioning

confidence: 99%

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Gut microbiome affects the metabolism of metronidazole in mice through regulation of hepatic cytochromes P450 expression

et al. 2021

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Microbiome is now considered as a significant metabolic organ with an immense potential to influence overall human health. A number of diseases that are associated with pharmacotherapy interventions was linked with altered gut microbiota. Moreover, it has been reported earlier that gut microbiome modulates the fate of more than 30 commonly used drugs and, vice versa, drugs have been shown to affect the composition of the gut microbiome. The molecular mechanisms of this mutual relationship, however, remain mostly elusive. Recent studies indicate an indirect effect of the gut microbiome through its metabolites on the expression of biotransformation enzymes in the liver. The aim of this study was to analyse the effect of gut microbiome on the fate of metronidazole in the mice through modulation of system of drug metabolizing enzymes, namely by alteration of the expression and activity of selected cytochromes P450 (CYPs). To assess the influence of gut microbiome, germ-free mice (GF) in comparison to control specific-pathogen-free (SPF) mice were used. First, it has been found that the absence of microbiota significantly affected plasma concentration of metronidazole, resulting in higher levels (by 30%) of the parent drug in murine plasma of GF mice. Further, the significant interaction between presence/absence of the gut microbiome and effect of metronidazole application, which together influence mRNA expression of CAR, PPARα, Cyp2b10 and Cyp2c38 was determined. Administration of metronidazole itself influenced significantly mRNA expression of Cyp1a2, Cyp2b10, Cyp2c38 and Cyp2d22. Finally, GF mice have shown lower level of enzyme activity of CYP2A and CYP3A than their SPF counterparts. The results hence have shown that, beside direct bacterial metabolism, different expression and enzyme activity of hepatic CYPs in the presence/absence of gut microbiota may be responsible for the altered metronidazole metabolism.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Gut microbiome affects the metabolism of metronidazole in mice through regulation of hepatic cytochromes P450 expression

et al. 2021

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“…Jourova et al found that the degree of APAP liver injury in germ-free (GF) mice or mice cleared of gut microbiota was lower than in SPF mice. The expression of the P450 enzyme, which is involved in APAP metabolism in the liver, is closely linked to intestinal microorganisms (Jourova et al, 2020 ). The expression levels of CYP-1A2 and CYP-3A4 in the liver of GF mice were significantly lower than in SPF mice, which may explain the significant reduction of APAP-induced hepatotoxicity in GF mice (Jourova et al, 2020 ).…”

Section: The Gut Microbiota and Apap-induced Liver Injurymentioning

confidence: 99%

“…The expression of the P450 enzyme, which is involved in APAP metabolism in the liver, is closely linked to intestinal microorganisms (Jourova et al, 2020 ). The expression levels of CYP-1A2 and CYP-3A4 in the liver of GF mice were significantly lower than in SPF mice, which may explain the significant reduction of APAP-induced hepatotoxicity in GF mice (Jourova et al, 2020 ). Meanwhile, single-cell sequencing data showed that there were significantly fewer LY6C -positive monocytes and a lower proportion of activated non-parenchymal cells (hepatic stellate cells, sinusoidal endothelial cells, and Kupffer cells) in the liver of antibiotic-treated mice compared with SPF mice.…”

Section: The Gut Microbiota and Apap-induced Liver Injurymentioning

confidence: 99%

Gut Microbiota and Chemical-Induced Acute Liver Injury

Chen

2021

Front. Physiol.

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Background: Drug overdose or chemical exposures are the main causes of acute liver injury (ALI). Severe liver injury can develop into liver failure that is an important cause of liver-related mortality in intensive care units in most countries. Pharmacological studies have utilized a variety of comprehensive chemical induction models that recapitulate the natural pathogenesis of acute liver injury. Their mechanism is always based on redox imbalance-induced direct hepatotoxicity and massive hepatocyte cell death, which can trigger immune cell activation and recruitment to the liver. However, the pathogenesis of these models has not been fully stated. Many studies showed that gut microbiota plays a crucial role in chemical-induced liver injury. Hepatotoxicity is likely induced by imbalanced microbiota homeostasis, gut mucosal barrier damage, systemic immune activation, microbial-associated molecular patterns, and bacterial metabolites. Meanwhile, many preclinical studies have shown that supplementation with probiotics can improve chemical-induced liver injury. In this review, we highlight the pathogenesis of gut microorganisms in chemical-induced acute liver injury animal models and explore the protective mechanism of exogenous microbial supplements on acute liver injury.

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“… 54 Interestingly, sex differences in the effects of the microbiome on mRNA expression of liver CYP3A have been found in mice. 55 …”

Section: Discussionmentioning

confidence: 99%

Studies on CYP3A activity during the menstrual cycle as measured by urinary 6β‐hydroxycortisol/cortisol

Bergström

Lindahl

Warnqvist

et al. 2021

Pharmacology Res & Perspec

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The 6β‐OH‐cortisol/cortisol ratio (6β‐OHC/C) in urine is an endogenous marker of drug‐metabolizing enzyme cytochrome P450 3A (CYP3A). The primary aim of this single center, prospective, non‐interventional cohort study, was to investigate the variability of 6β‐OHC/C during the menstrual cycle. In addition, possible associations between the CYP3A activity and sex hormones, gut microbiota metabolite trimethylamine‐N‐Oxide (TMAO) and microRNA‐27b, respectively, were investigated. Serum and urinary samples from healthy, regularly menstruating women followed for two menstrual cycles were analyzed. Twenty‐six complete menstrual cycles including follicular, ovulatory, and luteal phase were defined based on hormone analyses in serum. 6β‐OHC/C were analyzed in urine and sex hormones, TMAO and miRNA‐27b were analyzed in serum at the same time points. 6β‐OHC/C did not vary between the follicular, ovulatory, or luteal phases. There was a difference in the relative miRNA‐27b expression between the follicular and ovulatory phase ( p = .03). A significant association was found between 6β‐OHC/C and progesterone during the follicular ( p = .005) and ovulatory ( p = .01) phases ( n = 26 for each phase). In addition, a significant association was found between the ratio and TMAO during the ovulatory ( p = .02) and luteal ( p = .002) phases. 6β‐OHC/C and gut microbiota TMAO were significantly associated ( p = .003) when evaluating all values, for all phases ( n = 78). Interestingly, the finding of an association between 6β‐OHC/C in urine and levels of TMAO in serum suggest that gut microbiota may affect CYP3A activity.

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Gut Microbiome Alters the Activity of Liver Cytochromes P450 in Mice With Sex-Dependent Differences

Cited by 18 publications

References 38 publications

Gut microbiome affects the metabolism of metronidazole in mice through regulation of hepatic cytochromes P450 expression

Gut microbiome affects the metabolism of metronidazole in mice through regulation of hepatic cytochromes P450 expression

Gut Microbiota and Chemical-Induced Acute Liver Injury

Studies on CYP3A activity during the menstrual cycle as measured by urinary 6β‐hydroxycortisol/cortisol

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