Several studies have indicated the beneficial anti-inflammatory effect of butyrate in inflammatory bowel disease (IBD) therapy implying attempts to increase butyrate production in the gut through orally administered dietary supplementation. Through the gut-liver axis, however, butyrate may reach directly the liver and influence the drug-metabolizing ability of hepatic enzymes, and, indirectly, also the outcome of applied pharmacotherapy. The focus of our study was on the liver microsomal cytochrome P450 (CYP) 2A5, which is a mouse orthologue of human CYP2A6 responsible for metabolism of metronidazole, an antibiotic used to treat IBD. Our findings revealed that specific pathogen-free (SPF) and germ-free (GF) mice with dextran sulfate sodium (DSS)-induced colitis varied markedly in enzyme activity of CYP2A and responded differently to butyrate pre-treatment. A significant decrease (to 50%) of the CYP2A activity was observed in SPF mice with colitis; however, an administration of butyrate prior to DSS reversed this inhibition effect. This phenomenon was not observed in GF mice. The results highlight an important role of gut microbiota in the regulation of CYP2A under inflammatory conditions. Due to the role of CYP2A in metronidazole metabolism, this phenomenon may have an impact on the IBD therapy. Butyrate administration, hence, brings promising therapeutic potential for improving symptoms of gut inflammation; however, possible interactions with drug metabolism need to be further studied.

• Keywords
• butyrate, cytochromes P450, germ-free mice, gut inflammation, gut–liver axis, hepatic drug metabolism, microbiome,
• MeSH
• Anti-Bacterial Agents adverse effects   pharmacology   therapeutic use   MeSH
• Anti-Inflammatory Agents pharmacology   MeSH
• Butyrates * pharmacology   MeSH
• Metronidazole pharmacology   MeSH
• Disease Models, Animal MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Dextran Sulfate adverse effects   MeSH
• Gastrointestinal Microbiome * MeSH
• Cytochrome P-450 Enzyme System metabolism   MeSH
• Colitis, Ulcerative * chemically induced   drug therapy   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Anti-Bacterial Agents MeSH
• Anti-Inflammatory Agents MeSH
• Butyrates * MeSH
• Metronidazole MeSH
• Dextran Sulfate MeSH
• Cytochrome P-450 Enzyme System MeSH

The development of inflammatory bowel disease (IBD) is associated with alterations in the gut microbiota. There is currently no universal treatment for this disease, thus emphasizing the importance of developing innovative therapeutic approaches. Gut microbiome-derived metabolite butyrate with its well-known anti-inflammatory effect in the gut is a promising candidate. Due to increased intestinal permeability during IBD, butyrate may also reach the liver and influence liver physiology, including hepatic drug metabolism. To get an insight into this reason, the aim of this study was set to clarify not only the protective effects of the sodium butyrate (SB) administration on colonic inflammation but also the effects of SB on hepatic drug metabolism in experimental colitis induced by dextran sodium sulfate (DSS) in mice. It has been shown here that the butyrate pre-treatment can alleviate gut inflammation and reduce the leakiness of colonic epithelium by restoration of the assembly of tight-junction protein Zonula occludens-1 (ZO-1) in mice with DSS-induced colitis. In this article, butyrate along with inflammation has also been shown to affect the expression and enzyme activity of selected cytochromes P450 (CYPs) in the liver of mice. In this respect, CYP3A enzymes may be very sensitive to gut microbiome-targeted interventions, as significant changes in CYP3A expression and activity in response to DSS-induced colitis and/or butyrate treatment have also been observed. With regard to medications used in IBD and microbiota-targeted therapeutic approaches, it is important to deepen our knowledge of the effect of gut inflammation, and therapeutic interventions were followed concerning the ability of the organism to metabolize drugs. This gut-liver axis, mediated through inflammation as well as microbiome-derived metabolites, may affect the response to IBD therapy.

• Keywords
• butyrate, cytochromes P450, drug metabolism, gut inflammation, gut–liver axis,
• Publication type
• Journal Article MeSH

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

Sexual differences and the composition/function of the gut microbiome are not considered the most important players in the drug metabolism field; however, from the recent data it is obvious that they may significantly affect the response of the patient to therapy. Here, we evaluated the effect of microbial colonization and sex differences on mRNA expression and the enzymatic activity of hepatic cytochromes P450 (CYPs) in germ-free (GF) mice, lacking the intestinal flora, and control specific-pathogen-free (SPF) mice. We observed a significant increase in the expression of Cyp3a11 in female SPF mice compared to the male group. However, the sex differences were erased in GF mice, and the expression of Cyp3a11 was about the same in both sexes. We have also found higher Cyp2c38 gene expression in female mice compared to male mice in both the SPF and GF groups. Moreover, these changes were confirmed at the level of enzymatic activity, where the female mice exhibit higher levels of functional CYP2C than males in both groups. Interestingly, we observed the same trend as with CYP3A enzymes: a diminished difference between the sexes in GF mice. The presented data indicate that the mouse gut microbiome plays an important role in sustaining sexual dimorphism in terms of hepatic gene expression and metabolism.

• Keywords
• germ-free mice, gut microbiome, liver cytochromes P450, metabolism of drugs, sex difference,
• Publication type
• Journal Article MeSH