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Human gut microbiota influences drug-metabolizing enzyme hepatic Cyp3a: A human flora-associated mice study
Masao Togao1, Takashi Kurakawa2, Shinnosuke Tajima1
1Safety Research Department, Yakult Central Institute.
Abstract:
Several studies revealed that gut microbiota affects the hepatic drug-metabolizing enzyme cytochrome P450 (Cyp). We hypothesized that individual gut microbiota variations could contribute to CYP activity. Human flora-associated (HFA) mice are established from germ-free mice using human feces and are often used to determine the effect of the human gut microbiota on the host. This study generated two groups of HFA mice using feces from two healthy individuals. Then, the composition of gut microbiota and hepatic Cyp activity was compared to analyze the effects of gut microbiota in healthy individuals on hepatic Cyp activity. A principal coordinate analysis based on the UniFrac distance for the composition of the cecal and fecal microbiota revealed apparent differences between the recipient groups. Hepatic Cyp, which is a marked difference in Cyp3a activity and Cyp3a11 gene expression, was observed between the recipient groups. Cyp2c and Cyp1a activities did not differ between recipient groups, with significantly lower enzymatic activities in recipients than in germ-free mice. These results indicate that the human gut microbiota affects hepatic Cyp activity. Especially, human gut microbiota composition differences have a pronounced effect on Cyp3a activity via Cyp3a11 gene expression regulation. Therefore, human gut microbiota variations among individuals may affect numerous drug metabolism, leading to drug efficacy and toxicity.
Insights
Individual gut microbiota differences significantly impact drug metabolism by altering hepatic cytochrome P450 (CYP) activity, particularly CYP3A. This highlights the role of gut bacteria in drug efficacy and toxicity.
Area of Science:
- Pharmacology
- Microbiology
- Genetics
Background:
- Gut microbiota influences the activity of hepatic drug-metabolizing enzymes, including cytochrome P450 (CYP).
- Individual variations in gut microbiota composition may contribute to differences in CYP activity.
Purpose of the Study:
- To investigate the effect of distinct human gut microbiota compositions on hepatic CYP activity in human flora-associated (HFA) mice.
- To analyze how variations in gut microbiota influence specific CYP enzymes and their gene expression.
Main Methods:
- Generated two groups of HFA mice using fecal samples from two healthy individuals.
- Compared gut microbiota composition and hepatic CYP activity (including Cyp3a, Cyp2c, and Cyp1a) between HFA mouse groups.
- Utilized principal coordinate analysis based on UniFrac distance to assess microbiota differences.
Main Results:
- Significant differences in gut microbiota composition were observed between the HFA mouse groups.
- Marked differences in hepatic Cyp3a activity and Cyp3a11 gene expression were found between groups.
- Cyp2c and Cyp1a activities were lower in HFA mice compared to germ-free mice but did not differ between HFA groups.
Conclusions:
- Human gut microbiota composition significantly affects hepatic CYP activity.
- Individual gut microbiota variations, particularly in composition, have a pronounced effect on Cyp3a activity through Cyp3a11 gene regulation.
- These findings suggest that variations in human gut microbiota can influence drug metabolism, impacting drug efficacy and toxicity.
