Gene-environment interactions in inflammatory bowel disease: microbiota and genes

Abstract

A recent research workshop gave an update on the genetics of the inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis. This mini-review summarises the updates of the gene-environmental interactions, especially those outlining the contribution of the gut microbiota to the pathogenesis of IBD.

Figure 1

Proposed mechanisms by which bacteria and fungi induce chronic immune-mediated inflammation and injury of the intestines. (A) Pathogenic bacteria. A traditional pathogen or functional alterations in commensal bacteria, including enhanced epithelial adherence, invasion, resistance to killing by phagocytes or acquisition of virulence factors, can result in increased stimulation of innate and adaptive immune responses. (B) Abnormal microbial composition. Decreased concentrations of bacteria that produce butyrate and other short-chain fatty acids compromise epithelial barrier integrity. Meanwhile, overgrowth of aggressive commensal microbial species increases the number of adjuvants and antigens (Ag) that induce pathogenic immune responses or increase production of toxic metabolites such as hydrogen sulphide (H2S) that block colonocyte utilisation of butyrate and increase mucosal permeability. (C) Defective host containment of commensal bacteria. Increased mucosal permeability can result in overwhelming exposure of bacterial toll-like receptor ligands and antigens that activate pathogenic innate and T cell immune responses. Defective secretion of antimicrobial peptides or secretory immunoglobulin A can lead to mucosal bacterial overgrowth. Defective killing of phagocytosed bacteria can lead to persistent intracellular bacteria and ineffective clearance of bacterial antigens. (D) Defective host immunoregulation. Antigen-presenting cells and epithelial cells overproduce cytokines due to ineffective downregulation, which results in Th1 and Th17 differentiation and inflammation. Dysfunction of regulatory T cells (T-reg) leads to decreased secretion of interleukin (IL)-10 and transforming growth factor (TGF)-b, and loss of immunological tolerance to microbial antigens (an overly aggressive T cell response). Figure reprinted from the Journal of Internal Medicine with permission of the publisher. CpG, unmethylated CpG motifs in bacterial DNA; IFN, interferon; LPS, lipopolysaccharide; PG, peptidoglycan; SCFA, short-chain fatty acids; TNF, tumour necrosis factor.

Figure 2

Inhibition of enteric bacteria and enhancement of barrier function by probiotic bacteria. Schematic representation of the crosstalk between probiotic bacteria and the intestinal mucosa. Antimicrobial activities of probiotics include the (1) production of bacteriocins/defensins, (2) competitive inhibition with pathogenic bacteria, (3) inhibition of bacterial adherence or translocation and (4) reduction of luminal pH. Probiotic bacteria can also enhance intestinal barrier function by (5) increasing mucus production. Reproduced from the Inflammatory Bowel Diseases with permission of the publisher. DC, dendritic cell.