Modelling the role of microbial p-cresol in colorectal genotoxicity
Modelling the role of microbial p-cresol in colorectal genotoxicity
Background: A greater understanding of mechanisms explaining the interactions between diet and the gut microbiota in colorectal cancer is desirable. Genotoxic microbial metabolites present in the colon may be implicated in carcinogenesis and potentially influenced by diet. Aims: We hypothesised that microbial p-cresol is a colonic genotoxin and set out to model potential exposures in the colon and the effects of these exposures on colonic cells. Methods: Batch culture fermentations with human faecal inoculate were used to determine the synthesis of p-cresol and other metabolites in response to various substrates. The fermentation supernatants were evaluated for genotoxicity and the independent effects of p-cresol on colonic cells were studied in vitro. Results: In batch culture fermentation, supplementary protein increased the synthesis of phenols, indoles and p-cresol, whereas supplementary fructoligosaccharide (FOS) increased the synthesis of short chain fatty acids. The p-cresol was the greatest predictor of genotoxicity against colonocytes in the fermentation supernatants. Spiking fermentation supernatants with exogenous p-cresol further increased DNA damage, and independently p-cresol induced DNA damage in a dose-dependent manner against HT29 and Caco-2 cells and influenced cell cycle kinetics. Conclusions: In the colon p-cresol may reach physiologically significant concentrations which contribute to genotoxic exposures in the intestinal lumen, p-cresol production may be attenuated by substrate, and therefore diet, making it a potential modifiable biomarker of genotoxicity in the colon.
Caco-2 Cells, Cell Cycle/drug effects, Colorectal Neoplasms/metabolism, Cresols/metabolism, DNA Damage, Diet/adverse effects, Fatty Acids, Volatile/metabolism, Feces/microbiology, Fermentation, Gastrointestinal Microbiome/genetics, HT29 Cells, Humans, Indoles/metabolism, Intestinal Mucosa/drug effects, Models, Biological, Phenols/metabolism
398-411
Al Hinai, Eiman Abdulla
9754aa3d-6529-4b10-b0c1-bbc579659f7c
Kullamethee, Piyarach
bdab8c81-404b-4af9-b4d1-a145ab8f6bec
Rowland, Ian R.
0cfbfdaf-648e-4e44-a59a-ddf708c2ebd0
Swann, Jonathan
7c11a66b-f4b8-4dbf-aa17-ad8b0561b85c
Walton, Gemma E.
a167f493-b3bf-4063-acdf-acdfa8c1137c
Commane, Daniel M.
4cca28bd-1850-4c35-b686-a1371bd57048
2019
Al Hinai, Eiman Abdulla
9754aa3d-6529-4b10-b0c1-bbc579659f7c
Kullamethee, Piyarach
bdab8c81-404b-4af9-b4d1-a145ab8f6bec
Rowland, Ian R.
0cfbfdaf-648e-4e44-a59a-ddf708c2ebd0
Swann, Jonathan
7c11a66b-f4b8-4dbf-aa17-ad8b0561b85c
Walton, Gemma E.
a167f493-b3bf-4063-acdf-acdfa8c1137c
Commane, Daniel M.
4cca28bd-1850-4c35-b686-a1371bd57048
Al Hinai, Eiman Abdulla, Kullamethee, Piyarach, Rowland, Ian R., Swann, Jonathan, Walton, Gemma E. and Commane, Daniel M.
(2019)
Modelling the role of microbial p-cresol in colorectal genotoxicity.
Gut Microbes, 10 (3), .
(doi:10.1080/19490976.2018.1534514).
Abstract
Background: A greater understanding of mechanisms explaining the interactions between diet and the gut microbiota in colorectal cancer is desirable. Genotoxic microbial metabolites present in the colon may be implicated in carcinogenesis and potentially influenced by diet. Aims: We hypothesised that microbial p-cresol is a colonic genotoxin and set out to model potential exposures in the colon and the effects of these exposures on colonic cells. Methods: Batch culture fermentations with human faecal inoculate were used to determine the synthesis of p-cresol and other metabolites in response to various substrates. The fermentation supernatants were evaluated for genotoxicity and the independent effects of p-cresol on colonic cells were studied in vitro. Results: In batch culture fermentation, supplementary protein increased the synthesis of phenols, indoles and p-cresol, whereas supplementary fructoligosaccharide (FOS) increased the synthesis of short chain fatty acids. The p-cresol was the greatest predictor of genotoxicity against colonocytes in the fermentation supernatants. Spiking fermentation supernatants with exogenous p-cresol further increased DNA damage, and independently p-cresol induced DNA damage in a dose-dependent manner against HT29 and Caco-2 cells and influenced cell cycle kinetics. Conclusions: In the colon p-cresol may reach physiologically significant concentrations which contribute to genotoxic exposures in the intestinal lumen, p-cresol production may be attenuated by substrate, and therefore diet, making it a potential modifiable biomarker of genotoxicity in the colon.
Text
Modelling the role of microbial p cresol in colorectal genotoxicity
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More information
Accepted/In Press date: 5 October 2016
e-pub ahead of print date: 25 October 2018
Published date: 2019
Keywords:
Caco-2 Cells, Cell Cycle/drug effects, Colorectal Neoplasms/metabolism, Cresols/metabolism, DNA Damage, Diet/adverse effects, Fatty Acids, Volatile/metabolism, Feces/microbiology, Fermentation, Gastrointestinal Microbiome/genetics, HT29 Cells, Humans, Indoles/metabolism, Intestinal Mucosa/drug effects, Models, Biological, Phenols/metabolism
Identifiers
Local EPrints ID: 440784
URI: http://eprints.soton.ac.uk/id/eprint/440784
ISSN: 1949-0976
PURE UUID: 517a09e5-5263-4e4b-85a1-19b7534a52b7
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Date deposited: 18 May 2020 16:33
Last modified: 17 Mar 2024 04:00
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Contributors
Author:
Eiman Abdulla Al Hinai
Author:
Piyarach Kullamethee
Author:
Ian R. Rowland
Author:
Gemma E. Walton
Author:
Daniel M. Commane
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