Dietary-Induced Bacterial Metabolites Reduce Inflammation and Inflammation-Associated Cancer via Vitamin D Pathway

• Published in: International journal of molecular sciences Vol. 24; no. 3; p. 1864
• Main Authors: O'Mahony, Caitlin, Clooney, Adam, Clarke, Siobhan F, Aguilera, Mònica, Gavin, Aisling, Simnica, Donjete, Ahern, Mary, Fanning, Aine, Stanley, Maurice, Rubio, Raul Cabrera, Patterson, Elaine, Marques, Tatiana, Wall, Rebecca, Houston, Aileen, Mahmoud, Amr, Bennett, Michael W, Stanton, Catherine, Claesson, Marcus J, Cotter, Paul D, Shanahan, Fergus, Joyce, Susan A, Melgar, Silvia
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 18.01.2023; MDPI
• Subjects: Animals; Bacteria; Bile; Bile acids; Bile Acids and Salts - metabolism; Calciferol; Cancer; Cell proliferation; Colitis; Colitis - metabolism; colitis-associated cancer; Colon - pathology; Colorectal cancer; Combinatorial analysis; Dextran Sulfate - adverse effects; Diet; Diet, High-Fat - adverse effects; Digestive system; Epithelial cells; Epithelium; High fat diet; Immune system; Inflammation; Inflammation - metabolism; Inflammatory bowel disease; Inflammatory bowel diseases; Inflammatory Bowel Diseases - metabolism; Intestinal microflora; Intestine; Lipids; Metabolism; Metabolites; Metastases; Mice; Mice, Inbred C57BL; Microbiota; Microorganisms; Neoplasms - metabolism; Neutrophils; Plasma; proliferation; Risk factors; Signal transduction; Tumors; vitamin D; Vitamin D - metabolism; Vitamin D receptors; colitis; proliferation; bile acids; inflammation; vitamin D; high-fat diet; colitis-associated cancer
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24031864

Environmental factors, including westernised diets and alterations to the gut microbiota, are considered risk factors for inflammatory bowel diseases (IBD). The mechanisms underpinning diet-microbiota-host interactions are poorly understood in IBD. We present evidence that feeding 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 an increase in Firmicutes and cluster 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 the 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 alterations of microbiota-host interactions in IBD/CAC pathophysiology.