Dietary induced bacterial metabolites reduce inflammation and inflammation-associated cancer via Vitamin D pathway

Abstract: Environmental factors, including westernized diets and alterations to the gut microbiota are considered risk factors for inflammatory bowel diseases (IBD). Mechanisms underpinning diet-microbiota-host interactions are poorly understood in IBD. We present evidence that feeding of a lard-based high fat (HF)-diet can protect mice from developing DSS-induced acute and chronic colitis and colitis-associated cancer (CAC), by significantly reducing tumour burden/incidence, immune cell infiltration, cytokine profile and cell proliferation. We show that HF-protection was associated with increased gut microbial diversity and a significant reduction in Proteobacteria and increase in Firmicutes and Clostridium XIVa abundance. Microbial functionality was modulated in terms of signalling fatty acids and bile acids (BA). Faecal secondary BAs were significantly induced to include moieties that can activate Vitamin D receptor (VDR), a nuclear receptor richly represented in the intestine and colon. Indeed, colonic VDR downstream target genes were upregulated in HF-fed mice and in combinatorial lipid-BAs-treated intestinal HT29 epithelial cells. Collectively, our data indicate that HF-diet protects against colitis and CAC risk through gut microbiota and BA metabolites modulating Vitamin D targeting pathways. Our data highlights the complex relationship between dietary fat-induced alteration of microbiota-host interactions in IBD/CAC pathophysiology.