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Updated: Jun 24, 2026
Ileectomy-induced Bile Overaccumulation in Mouse Intestine
Published on: August 21, 2017
Intestinal flora induces the expression of Cyp3a in the mouse liver
1Department of Clinical Pharmacokinetics, Hoshi University, Ebara, Shinagawa-ku, Tokyo, Japan.
Abstract:
In order to determine the effects of intestinal flora on the expression of cytochrome P450 (CYP), the mRNA expression of CYP was compared between specific pathogen-free (SPF) and germ-free (GF) mice. Most of the major CYP isozymes showed higher expression in the livers of SPF mice compared with GF mice. Nuclear factors such as pregnane X receptor (PXR) and constitutive androstane receptor (CAR), as well as transporters and conjugation enzymes involved in the detoxification of lithocholic acid (LCA), also showed higher expression in SPF mice. The findings suggest that in the livers of SPF mice, LCA produced by intestinal flora increases the expression of CYPs via activation of PXR and CAR. Drugs such as antibiotics, some diseases and ageing, etc. are known to alter intestinal flora. The present findings suggest that such changes also affect CYP and are one of the factors responsible for individual differences in pharmacokinetics.
Insights
Intestinal flora significantly impacts liver enzyme expression, particularly cytochrome P450 (CYP) enzymes. This study reveals that gut bacteria influence drug metabolism by altering CYP levels through specific nuclear receptors.
Area of Science:
- Pharmacology
- Microbiology
- Biochemistry
Background:
- Intestinal flora plays a crucial role in host physiology.
- Cytochrome P450 (CYP) enzymes are vital for drug metabolism and detoxification.
- The influence of gut microbiota on CYP expression remains incompletely understood.
Purpose of the Study:
- To investigate the effect of intestinal flora on the mRNA expression of major cytochrome P450 (CYP) isozymes.
- To elucidate the mechanisms by which gut microbiota influences CYP expression, focusing on nuclear receptors and detoxification pathways.
Main Methods:
- Comparison of CYP mRNA expression between specific pathogen-free (SPF) and germ-free (GF) mice.
- Analysis of nuclear factors (PXR, CAR), transporters, and conjugation enzymes involved in lithocholic acid (LCA) detoxification.
Main Results:
- SPF mice exhibited significantly higher expression of most major CYP isozymes compared to GF mice.
- Expression of pregnane X receptor (PXR), constitutive androstane receptor (CAR), and LCA detoxification enzymes were elevated in SPF mice.
- Lithocholic acid (LCA), produced by intestinal flora, appears to upregulate CYP expression via PXR and CAR activation.
Conclusions:
- Intestinal flora, through LCA production, enhances hepatic CYP expression by activating PXR and CAR.
- Alterations in gut microbiota composition (due to antibiotics, disease, or aging) can affect CYP expression.
- Changes in intestinal flora are a significant factor contributing to inter-individual variability in pharmacokinetics.
