Unraveling the Multifactorial Pathogenesis of Inflammatory Bowel Disease: Systems Biology Insights into Host Genetics, Environmental Exposures, and Gut Dysbiosis

Abstract

Inflammatory Bowel Disease (IBD) is an umbrella term for two separate chronic conditions, Crohn's disease (CD) and ulcerative colitis (UC), which are now a major health problem in the world. This change is similar to the process of urbanization and westernization that is taking place all over the world. In this review, we explore the multifaceted “perfect storm” of factors that influence IBD, all of which interact to cause disease, including genetic predisposition, environmental triggers and an imbalance of gut microbes. Identical twins don't always get the disease, and although genetics are a clear factor, particularly in Crohn's, this means they are not a direct cause. Rather, the current "exposome" seems to require "insults" to the environment as its catalysts. We focus in particular on the dangers of the western diet, including its lack of fiber, which is crucial for delivering important short-chain fatty acids to the gut, and the role that common food additives may have in damaging the gut lining. The review also discusses the "IBD paradox" on smoking and the "hygiene hypothesis" which states that a too sterile early-life environment could lead to an under-trained immune system. The root of this imbalance is the gut microbiome. A reduction in the diversity of microorganisms, the loss of protective bacteria such as Faecalibacterium prausnitzii, and the presence of "pathobionts", such as Adherent-Invasive E. coli, are features of IBD that are always observed. These changes cause a weakened intestinal barrier and inability of the body's innate immune system to remove threats, creating a constant, self-perpetuating immune response against the gut. We explore these interactions in the context of epigenetics and demonstrate how the DNA of our bodies is physically ‘marked’ by our environment. In conclusion, we suggest that the next generation of patients with IBD should be treated in a precision medicine fashion and thus restore a unique ecological and immune balance in each patient.