2 research outputs found
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Protein fermentation, gut microbiota and colorectal cancer
The purpose of this project was to determine the interaction between dietary protein and the
gut microbiome in the production of genotoxic metabolites, with a particular focus on the
poorly characterised metabolite 4-cresol.
The thesis describes, in the first instance, data from a large human observation study (n=205
healthy Omani adults). In which dietary records and urinary nitrogen excretion were used to
estimate protein consumption in relation to urinary 4-cresol excretion. The study observed
positive correlations between excreted 4 cresol and protein intake and then sought to explain
the inter-individual variance in this by evaluating the influence of the colonic microbiota.
Then the study focused on predicting 4-cresol exposures in the colon using in vitro gut
fermentation models. The microbiota composition and metabolic profiles from these models
are evaluated against different substrates, including comparisons of animal and plant proteins.
We show that the total production of 4-cresol is dependent both on the host microbiota and also
upon the dietary nitrogen source. The metabolite profiles of these fermentations may be used
to predict DNA damage, with 4-cresol emerging as the greatest correlate of fermentation
supernatant mediated genotoxicity.
Finally, the study explored whether specific tumour isolates of F. nucleatum produce 4-cresol,
or other genotoxins, that could drive intestinal carcinogenesis. At this stage the study is unable
to conclude whether or not these isolates are passengers or drivers of intestinal disease. This
work suggests the need for better models of the effects of the tumour environment on microbial
growth.
The most significant aspect of this thesis is that it evidences both the potential genotoxic
contribution of 4-cresol in the colonic milieu, but also that urinary 4-cresol sulfate may be used
as a biomarker of genotoxic colonic fermentation and thus, may be of use as a cancer risk
endpoint in future dietary intervention study
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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