Mechanisms of Disease: Inflammatory Bowel Diseases

Abstract

Inflammatory Bowel Diseases (IBD), represented by Crohn’s Disease (CD) and Ulcerative Colitis (UC), are associated with significant morbidity in western countries and with increasing incidence in the developing world. While analysis of the genome of IBD patients, especially through genome-wide association studies, has unraveled multiple pathways involved in IBD pathogenesis only part of IBD heritability has been explained by genetic studies. This has demonstrated that environmental factors also play a significant role in promoting intestinal inflammation, mostly through their effects in the composition of the microbiome. However, in order for microbial dysbiosis to result in uncontrolled intestinal inflammation, the intestinal barrier formed by intestinal epithelial cells and the innate immune system should also be compromised. Finally, activation of the immune system depends on the working balance between effector and regulatory cells present in the intestinal mucosa, which have also been shown to be dysregulated in this patient population. Therefore, IBD pathogenesis is a result of the interplay of genetic susceptibility, environmental impact on the microbiome that through a weakened intestinal barrier will lead to inappropriate intestinal immune activation. In this review, we will approach the mechanisms proposed to cause IBD from the genetic, environmental, intestinal barrier and the immunologic perspectives.

Relationship(s) between obesity and inflammatory bowel diseases: possible intertwined pathogenic mechanisms

“…The role of the intestinal microflora, the microbiome, has taken a center stage as a co-pathogenic mechanism in many diseases and is discussed later [53][54][55][56][57]. Both temperature and latitude itself have been suggested to alter the microbiome.…”

“…Although mucosal adherent microbiota may be more relevant, at this time most studies of the microbiome are derived from studies on stool. Table 4 outlines comparisons of several phyla, genera and species found in association with obesity and inflammatory bowel diseases, mostly derived from stool samples of patients [53,[91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106]. These are incomplete and there are some discrepancies among studies.…”

“…While the current pathogenic hypothesis includes host genetic predisposition, a dysregulated immune response in conjunction with a disordered intestinal microbiome, the specific interactive causes have not been precisely worked out. Multiple environmental variables are considered to modify risks for IBD [1,2]. These diseases were rare at the beginning of the twentieth century.…”

Rottlerin ameliorates DSS-induced colitis by improving intestinal barrier function via activation of the Epac-2/Rap-1 signaling pathway

“…Western blotting was executed to determine changes in protein levels of bowel as previously described [26] . Primary antibodies as antibodies against Bcl-2, Bax, cleaved caspase-3, p-PI3K, p-Akt, p-mTOR, ZO-1, occludin, PDE-4, Epac-2, Rap-1 and β -actin (Abcam; Cat #: ab182858, ab32503, ab214430, ab182651, ab179463, ab109268, ab216327, 8 ab151549, ab251568, ab14628, ab21238, ab175329 and ab81283, respectively) were used, the dilution ratio is 1:800.…”

“…The epithelial barrier is an integral part of mucosal barrier, which protects against the transmission of macromolecular substances [8] . The function of intestinal barrier is realized through various compositions, containing the epidermis made up of epithelial cells that are plugged through tight junctions (TJs) at the cell boundary seam, mucogel layers, and antimicrobial peptides [9] .…”