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.

• MeSH
• Germ-Free Life MeSH
• Liver * metabolism   drug effects   enzymology   MeSH
• Metronidazole * pharmacology   MeSH
• Mice MeSH
• Gene Expression Regulation, Enzymologic drug effects   MeSH
• Gastrointestinal Microbiome * drug effects   MeSH
• Cytochrome P-450 Enzyme System * metabolism   genetics   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Metronidazole * MeSH
• Cytochrome P-450 Enzyme System * MeSH

The gut microbiota provides a wide range of beneficial functions for the host, and has an immense effect on the host's health status. The presence of microbiome in the gut may often influence the effect of an orally administered drug. Molecular mechanisms of this process are however mostly unclear. We investigated how the effect of a nonsteroidal drug nabumetone on expression of drug metabolizing enzymes (DMEs) in mice intestine and liver is changed by the presence of microbiota, here, using the germ free (GF) and specific pathogen free (SPF) BALB/c mice. First, we have found in a preliminary experiment that in the GF mice there is a tendency to increase bioavailability of the active form of nabumetone, which we have found now to be possibly influenced by differences in expression of DMEs in the GF and SPF mice. Indeed, we have observed that the expression of the most of selected cytochromes P450 (CYPs) was significantly changed in the small intestine of GF mice compared to the SPF ones. Moreover, orally administered nabumetone itself altered the expression of some CYPs and above all, in different ways in the GF and SPF mice. In the GF mice, the expression of the DMEs (CYP1A) responsible for the formation of active form of the drug are significantly increased in the small intestine and liver after nabumetone application. These results highlight the importance of gut microbiome in processes involved in drug metabolism in the both gastrointestinal tract and in the liver with possible clinical relevance.

• MeSH
• Anti-Inflammatory Agents, Non-Steroidal administration & dosage   metabolism   MeSH
• Administration, Oral MeSH
• Bacteria metabolism   MeSH
• Cytochrome P-450 CYP1A1 metabolism   MeSH
• Dysbiosis MeSH
• Liver drug effects   enzymology   MeSH
• Activation, Metabolic MeSH
• Mice, Inbred BALB C MeSH
• Nabumetone administration & dosage   metabolism   MeSH
• Gastrointestinal Microbiome * MeSH
• Cytochrome P-450 Enzyme System genetics   metabolism   MeSH
• Intestine, Small drug effects   enzymology   microbiology   MeSH
• Transcription Factors genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH
• Names of Substances
• Anti-Inflammatory Agents, Non-Steroidal MeSH
• Cytochrome P-450 CYP1A1 MeSH
• Nabumetone MeSH
• Cytochrome P-450 Enzyme System MeSH
• Transcription Factors MeSH

Gut microbiota provides a wide range of beneficial function for the host and has an immense effect on the host's health state. It has also been shown that gut microbiome is often involved in the biotransformation of xenobiotics; however, the molecular mechanisms of the interaction between the gut bacteria and the metabolism of drugs by the host are still unclear. To investigate the effect of microbial colonization on messenger RNA (mRNA) expression of liver cytochromes P450 (CYPs), the main drug-metabolizing enzymes, we used germ-free (GF) mice, lacking the intestinal flora and mice monocolonized by non-pathogenic bacteria Lactobacillus plantarum NIZO2877 or probiotic bacteria Escherichia coli Nissle 1917 compared to specific pathogen-free (SPF) mice. Our results show that the mRNA expression of Cyp1a2 and Cyp2e1 was significantly increased, while the expression of Cyp3a11 mRNA was decreased under GF conditions compared to the SPF mice. The both bacteria L. plantarum NIZO2877 and E. coli Nissle 1917 given to the GF mice decreased the level of Cyp1a2 mRNA and normalized it to the control level. On the other hand, the colonization by these bacteria had no effect on the expression of Cyp3a11 mRNA in the liver of the GF mice (which remained decreased). Surprisingly, monocolonization with chosen bacterial strains has shown a different effect on the expression of Cyp2e1 mRNA in GF mice. Increased level of Cyp2e1 expression observed in the GF mice was found also in mice colonized by L. plantarum NIZO2877; however, the colonization with probiotic E. coli Nissle 1917 caused a decrease in Cyp2e1 expression and partially restored the SPF mice conditions.

• Keywords
• Biotransformation Enzyme, Cyp2e1 Expression, Cyp3a11 mRNA, Intestinal Microbiota, Protease Inhibitor Cocktail Tablet,
• MeSH
• Escherichia coli genetics   growth & development   metabolism   MeSH
• Germ-Free Life MeSH
• Liver enzymology   MeSH
• Lactobacillus genetics   growth & development   metabolism   MeSH
• RNA, Messenger genetics   metabolism   MeSH
• Mice, Inbred BALB C MeSH
• Mice genetics   microbiology   MeSH
• Gastrointestinal Microbiome * MeSH
• Cytochrome P-450 Enzyme System genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice genetics   microbiology   MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• RNA, Messenger MeSH
• Cytochrome P-450 Enzyme System MeSH

BACKGROUND AND OBJECTIVES: The probiotic bacterium Escherichia coli strain Nissle 1917 has previously been shown to alter the pharmacokinetics of amiodarone. The aim of this study was to determine whether the probiotic bacterium Lactobacillus casei produces similar alterations in amiodarone disposition. METHODS: A suspension of live probiotic bacteria L. casei strain DN-114 001 (1.5 × 109 CFU/dose; probiotic pre-treated group) or a saline solution (control group) was administered directly into the stomach of male Wistar rats (N = 30 in each group) by oral gavage daily for 7 consecutive days. On the eighth day, all rats (N = 60) were given a single oral dose of an amiodarone hydrochloride suspension (model drug; 50 mg/kg). The concentrations of amiodarone and of its main metabolite N-desethylamiodarone were determined in rat plasma by high-performance liquid chromatography. RESULTS: Comparison of the pharmacokinetics of amiodarone in the control group and probiotic pre-treated group revealed that the peak plasma concentration of amiodarone was delayed by >2 h in the probiotic pre-treated group. The plasma level of N-desethylamiodarone was unchanged in the probiotic pre-medicated group and its pharmacokinetic parameters were not altered. CONCLUSIONS: The slower absorption of amiodarone in the probiotic pre-treated rats compared to the control ones and the unchanged pharmacokinetics of its main metabolite suggest that the probiotic strain of L. casei DN-114 001 has probably no clinical consequences as the difference was not statistically significant.

• MeSH
• Amiodarone administration & dosage   blood   pharmacokinetics   MeSH
• Administration, Oral MeSH
• Rats MeSH
• Lacticaseibacillus casei * MeSH
• Probiotics administration & dosage   pharmacology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Amiodarone MeSH