Abstract
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.
Highlights
The colon is the most common site for intestinal tumours[1] with microbial activity being implicated in increased susceptibility to neoplastic transformation.[2]
Low tyrosine medium induced no significant bacteriological changes whilst high tyrosine medium led to an increase in total bacteria after 4h fermentation compared with baseline
The addition of FOS to low tyrosine medium resulted in significant increases in bifidobacteria at 4h and of total bacteria and C. histolyticum group at 8 h when compared to baseline
Summary
The colon is the most common site for intestinal tumours[1] with microbial activity being implicated in increased susceptibility to neoplastic transformation.[2] Environmental factors, diet, modulate the composition and metabolic activity of the colonic microbiota with implications for cancer risk.[3,4] Current mechanistic models implicating diet in CRC risk propose that dietary fibre favourably improves the balance of the microbiota, increasing the abundance of saccharolytic species relative to proteolytic microbes The latter are associated with increased production of an assortment of genotoxic metabolites from meat based or endogenous substrates.[4,5,6] Epidemiological studies implicate red and processed meat in particular in increasing risk of CRC. 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 diet, making it a potential modifiable biomarker of genotoxicity in the colon
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