Role of genes, the environment and their interactions in the etiology of inflammatory bowel diseases

Abstract

Few of the studied genes demonstrate association with inflammatory bowel disease (IBD). Three mutations in the nucleotide-binding oligomerization domain 2 gene have consistently shown to be independent risk factors for Crohn's disease, but none of the alleles exhibited high sensitivity or specificity for IBD. Linkage analysis implicated several loci on various chromosomes, and epistasis has been demonstrated. The etiopathogenesis of IBD remains unknown, and environmental contribution to their pathogenesis is evident from genetic studies that demonstrated incomplete monozygotic twins concordandance rate for both Crohn's and ulcerative colitis. Smoking has shown an opposite effect on disease phenotype, with an adverse effect on disease course for Crohn's disease, but a slight beneficial effect in ulcerative colitis. The contribution of infectious agents to susceptibility to IBD appears to be strong. However, the role of nutrition on the etiology and therapy of IBD is not clear. Inconsistencies in environmental risk factors could be due to gene-environment interactions, making it essential to study the role of genetics and environmental contribution to the etiopathology of IBD. Transgenic or knockout mice, such as interleukin-10(-/-), T-cell receptor alpha(-/-), Galphai(2) (-/-) and N-cadherin(-/-), develop colitis-like inflammation similar to humans. Therefore, animal models must be further studied to explore mechanistic interactions.

Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease

“…This is in line with the greater bacterial translocation observed in Fxr-null mice 15. As IBD is thought to result from both dysregulation of the mucosal immune system and compromised intestinal epithelial barrier function in genetically predisposed individuals,2 38 we explored the ability of FXR to counter-regulate intestinal inflammation at different levels.…”

Pregnane-X-receptor mediates the anti-inflammatory activities of rifaximin on detoxification pathways in intestinal epithelial cells

“…The pathophysiology of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC), is not yet completely understood [1][2][3][4][5]. In recent years, it has become clear that genetic, immunological, environmental and microbial factors contribute to the aetiology of IBD [1][2][3][4][5].…”

“…In recent years, it has become clear that genetic, immunological, environmental and microbial factors contribute to the aetiology of IBD [1][2][3][4][5]. The epithelial cells, the first line of defence against potentially harmful luminal antigens, are remarkably similar to hepatocytes in their ability to carry out detoxification and bio-transformation of luminal agents of dietary, bacterial or fermentative origin.…”

Pregnane X receptor activation ameliorates DSS-induced inflammatory bowel disease via inhibition of NF-κB target gene expression

“…IBD, which manifests as either ulcerative colitis (UC) or Crohn's disease (CD), is associated with chronic inflammation of the intestinal tract. While the precises etiology of IBD is unclear, it is thought to be a combination of altered intestinal epithelial barrier function and dysregulation of the mucosal immune system (1). Gene expression profiling of inflamed colon tissues from UC and CD patients identified several downregulated detoxification genes and ABC transporters in the colon of patients with UC (26).…”