Biochemical and Molecular Mechanisms of Dietary Fibre Fermentation Products in Modulating Colorectal Cancer Risk: Evidence from a Nigerian Case-Control Study

The relationship between dietary fibre intake, its colonic fermentation products particularly short-chain fatty acids, and colorectal cancer risk has been extensively studied in Western populations but is inadequately characterised in West African populations whose fibre intake patterns, gut microbiota composition, and colorectal cancer epidemiology are distinct. This dissertation investigates the biochemical and molecular mechanisms by which short-chain fatty acids from dietary fibre fermentation modulate colorectal cancer risk in a Nigerian population context. A hospital-based case-control study at Lagos University Teaching Hospital and Obafemi Awolowo University Teaching Hospital enrolled one hundred and twenty histologically confirmed colorectal cancer patients and two hundred and forty matched controls. Faecal short-chain fatty acids (acetate, propionate, butyrate) were quantified by gas chromatography. Faecal microbiota composition was profiled by 16S rRNA amplicon sequencing. Colonic tissue (tumour and adjacent normal) from cases and colonoscopic biopsies from controls underwent transcriptomic analysis by RNA-sequencing, with a focus on butyrate receptor and HDAC gene expression, mismatch repair gene methylation by bisulfite pyrosequencing, and Wnt signalling pathway activation by western blotting. Laboratory mechanistic validation used primary colonic organoids derived from Nigerian patient biopsies treated with physiologically relevant butyrate concentrations, measuring differentiation, proliferation, and apoptosis responses. Results demonstrate that cases have significantly lower faecal butyrate, reduced butyrate-producing Firmicutes taxa, hypermethylation of butyrate receptor genes, and higher Wnt pathway activation. Organoid experiments confirm dose-dependent butyrate-induced differentiation and apoptosis in primary colonocytes. Keywords: dietary fibre, short-chain fatty acids, colorectal cancer, gut microbiota, Nigeria.