Epigenetic modulation of colon epithelium functions via microbiota-produced regulators: implications for xenobiotic metabolism

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00027162%3A_____%2F24%3AN0000190" target="_blank" >RIV/00027162:_____/24:N0000190 - isvavai.cz</a>

Výsledek na webu

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DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Epigenetic modulation of colon epithelium functions via microbiota-produced regulators: implications for xenobiotic metabolism

Popis výsledku v původním jazyce

Přednáška. Abstrakt v publikaci: XXXI. XENOBIOCHEMICKÉ SYMPOSIUM, 18. – 20. 9. 2024, Kyjov, ČR; ISBN 978-80-7672-050-3, [L09]. The gut microbiome has gained an increasing attention as a principal factor contributing to the maintenance of intestinal homeostasis. The commensal microflora, in symbiosis with intestinal epithelial cells, including colon epithelial cells (colonocytes), helps to coordinate absorptive processes, to form intestinal barrier and to regulate mucosal immunity. Nevertheless, the major colon microbiota metabolites, which include short chain fatty acids (SCFAs) and products of tryptophan (Trp) metabolism (such as indole, tryptamine and various indole derivatives) can have a major impact also on activities of transcriptional factors controlling expression of xenobiotic-metabolizing enzymes (XMEs), such as the aryl hydrocarbon receptor (AhR). In the present study, we evaluated interactive effects of SCFAs, which may contribute to transcriptional regulation of XMEs via inhibition of histone deacetylase and chromatin structure regulation, and five intestinal bacterial Trp metabolites (indole, tryptamine, indole-3-acrylate, indole-3-pyruvate and indole-3-acetamide) that have been shown to activate AhR, on metabolism and bioactivation of benzo[a]pyrene (BaP). BaP is a genotoxic dietary carcinogen that is suspected to contribute, together with other dietary mutagens, to the development of colon carcinoma. Metabolism of BaP in intestinal epithelial cells is primarily under control of AhR that regulates expression and activity of cytochrome P450 family 1 (CYP1) enzymes. We found that butyrate and propionate significantly promoted the Trp metabolite-induced expression of CYP1 enzymes, as well as CYP1 enzymatic activity, in cell models derived from colon epithelial tumor cells. Pre-incubation of cells with SCFAs and Trp metabolites significantly increased formation of phenolic, diol and tetrol metabolites of BaP, as well as formation of covalent DNA adducts. A mixture of SCFAs at the ratio found in human colon also significantly promoted CYP1 expression and activity, in a manner similar to strong AhR ligand, 2,3,7,8- tetrachlorodibenzo-p-dioxin. The interactive effects of Trp metabolites and SCFAs thus substantially impacted metabolism and bioactivation of BaP in colon epithelial cells. The combined effects of these bacterial products derived from gut microbiota may thus prime intestinal epithelium to metabolize dietary carcinogens via CYP1-dependent metabolic pathways, as well as to modulate metabolism of endogenous AhR ligands produced within intestinal cells.

Název v anglickém jazyce

Epigenetic modulation of colon epithelium functions via microbiota-produced regulators: implications for xenobiotic metabolism

Popis výsledku anglicky

Přednáška. Abstrakt v publikaci: XXXI. XENOBIOCHEMICKÉ SYMPOSIUM, 18. – 20. 9. 2024, Kyjov, ČR; ISBN 978-80-7672-050-3, [L09]. The gut microbiome has gained an increasing attention as a principal factor contributing to the maintenance of intestinal homeostasis. The commensal microflora, in symbiosis with intestinal epithelial cells, including colon epithelial cells (colonocytes), helps to coordinate absorptive processes, to form intestinal barrier and to regulate mucosal immunity. Nevertheless, the major colon microbiota metabolites, which include short chain fatty acids (SCFAs) and products of tryptophan (Trp) metabolism (such as indole, tryptamine and various indole derivatives) can have a major impact also on activities of transcriptional factors controlling expression of xenobiotic-metabolizing enzymes (XMEs), such as the aryl hydrocarbon receptor (AhR). In the present study, we evaluated interactive effects of SCFAs, which may contribute to transcriptional regulation of XMEs via inhibition of histone deacetylase and chromatin structure regulation, and five intestinal bacterial Trp metabolites (indole, tryptamine, indole-3-acrylate, indole-3-pyruvate and indole-3-acetamide) that have been shown to activate AhR, on metabolism and bioactivation of benzo[a]pyrene (BaP). BaP is a genotoxic dietary carcinogen that is suspected to contribute, together with other dietary mutagens, to the development of colon carcinoma. Metabolism of BaP in intestinal epithelial cells is primarily under control of AhR that regulates expression and activity of cytochrome P450 family 1 (CYP1) enzymes. We found that butyrate and propionate significantly promoted the Trp metabolite-induced expression of CYP1 enzymes, as well as CYP1 enzymatic activity, in cell models derived from colon epithelial tumor cells. Pre-incubation of cells with SCFAs and Trp metabolites significantly increased formation of phenolic, diol and tetrol metabolites of BaP, as well as formation of covalent DNA adducts. A mixture of SCFAs at the ratio found in human colon also significantly promoted CYP1 expression and activity, in a manner similar to strong AhR ligand, 2,3,7,8- tetrachlorodibenzo-p-dioxin. The interactive effects of Trp metabolites and SCFAs thus substantially impacted metabolism and bioactivation of BaP in colon epithelial cells. The combined effects of these bacterial products derived from gut microbiota may thus prime intestinal epithelium to metabolize dietary carcinogens via CYP1-dependent metabolic pathways, as well as to modulate metabolism of endogenous AhR ligands produced within intestinal cells.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

30108 - Toxicology

Projekt

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Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2024

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů