The alarming prevalence of inflammatory bowel disease (IBD) in early childhood is associated with imbalances in the microbiome, the immune response, and environmental factors. Some pathogenic Escherichia coli (E. coli) strains have been found in IBD patients, where they may influence disease progression. Therefore, the discovery of new harmful bacterial strains that have the potential to drive the inflammatory response is of great importance. In this study, we compared the immunomodulatory properties of two E. coli strains of serotype O6: the probiotic E. coli Nissle 1917 and the uropathogenic E. coli O6:K13:H1. Using the epithelial Caco-2 cell line, we investigated the different abilities of the strains to adhere to and invade epithelial cells. We confirmed the potential of E. coli Nissle 1917 to modulate the Th1 immune response in a specific manner in an in vitro setting by stimulating mouse bone marrow-derived dendritic cells (BM-DCs). In gnotobiotic in vivo experiments, we demonstrated that neonatal colonization with E. coli Nissle 1917 achieves a stable high concentration in the intestine and protects mice from the progressive effect of E. coli O6:K13:H1 in developing ulcerative colitis in an experimental model. In contrast, a single-dose treatment with E. coli Nissle 1917 is ineffective in achieving such high concentrations and does not protect against DSS-induced ulcerative colitis in mice neonatally colonized with pathobiont E. coli O6:K13:H1. Despite the stable coexistence of both E. coli strains in the intestinal environment of the mice, we demonstrated a beneficial competitive interaction between the early colonizing E. coli Nissle 1917 and the late-arriving strain O6:K13:H1, suggesting its anti-inflammatory potential for the host. This study highlights the importance of the sequence of bacterial colonization, which influences the development of the immune response in the host gut and potentially impacts future quality of life.

• Keywords
• DSS-experimental colitis, Escherichia coli, immune modulation, mouse model, priority effect,
• Publication type
• Journal Article MeSH

Butyrate, a metabolite produced by gut bacteria, has demonstrated beneficial effects in the colon and has been used to treat inflammatory bowel diseases. However, the mechanism by which butyrate operates remains incompletely understood. Given that oral butyrate can exert either a direct impact on the gut mucosa or an indirect influence through its interaction with the gut microbiome, this study aimed to investigate three key aspects: (1) whether oral intake of butyrate modulates the expression of genes encoding short-chain fatty acid (SCFA) transporters (Slc16a1, Slc16a3, Slc16a4, Slc5a8, Abcg2) and receptors (Hcar2, Ffar2, Ffar3, Olfr78, Olfr558) in the colon, (2) the potential involvement of gut microbiota in this modulation, and (3) the impact of oral butyrate on the expression of colonic SCFA transporters and receptors during colonic inflammation. Specific pathogen-free (SPF) and germ-free (GF) mice with or without DSS-induced inflammation were provided with either water or a 0.5% sodium butyrate solution. The findings revealed that butyrate decreased the expression of Slc16a1, Slc5a8, and Hcar2 in SPF but not in GF mice, while it increased the expression of Slc16a3 in GF and the efflux pump Abcg2 in both GF and SPF animals. Moreover, the presence of microbiota was associated with the upregulation of Hcar2, Ffar2, and Ffar3 expression and the downregulation of Slc16a3. Interestingly, the challenge with DSS did not alter the expression of SCFA transporters, regardless of the presence or absence of microbiota, and the effect of butyrate on the transporter expression in SPF mice remained unaffected by DSS. The expression of SCFA receptors was only partially affected by DSS. Our results indicate that (1) consuming a relatively low concentration of butyrate can influence the expression of colonic SCFA transporters and receptors, with their expression being modulated by the gut microbiota, (2) the effect of butyrate does not appear to result from direct substrate-induced regulation but rather reflects an indirect effect associated with the gut microbiome, and (3) acute colon inflammation does not lead to significant changes in the transcriptional regulation of most SCFA transporters and receptors, with the effect of butyrate in the inflamed colon remaining intact.

• Keywords
• butyrate, butyrate receptors, butyrate transporters, colitis, dextran sulfate, germ-free (GF), microbiota, short chain fatty acid (SCFA),
• Publication type
• Journal Article MeSH

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