Oxidative Stress in the Pathogenesis of Crohn's Disease and the Interconnection with Immunological Response, Microbiota, External Environmental Factors, and Epigenetics

Abstract

Inflammatory bowel disease (IBD) is a complex multifactorial disorder in which external and environmental factors have a large influence on its onset and development, especially in genetically susceptible individuals. Crohn's disease (CD), one of the two types of IBD, is characterized by transmural inflammation, which is most frequently located in the region of the terminal ileum. Oxidative stress, caused by an overabundance of reactive oxygen species, is present locally and systemically in patients with CD and appears to be associated with the well-described imbalanced immune response and dysbiosis in the disease. Oxidative stress could also underlie some of the environmental risk factors proposed for CD. Although the exact etiopathology of CD remains unknown, the key role of oxidative stress in the pathogenesis of CD is extensively recognized. Epigenetics can provide a link between environmental factors and genetics, and numerous epigenetic changes associated with certain environmental risk factors, microbiota, and inflammation are reported in CD. Further attention needs to be focused on whether these epigenetic changes also have a primary role in the pathogenesis of CD, along with oxidative stress.

Keywords: Crohn’s disease; antioxidants; dysbiosis; environmental factors; epigenetics; inflammation; microbiota; oxidative stress; pathogenesis.

Figure 1

Intracellular antioxidant enzymes responsible for the detoxification of mitochondrial-generated reactive oxygen species. Note that there are two forms of intracellular superoxide dismutase in humans—mitochondrial (Mn-SOD) and cytosolic (Cu/Zn-SOD). These enzymes catalyze the dismutation of the highly reactive superoxide anion (O₂⁻) to oxygen and hydrogen peroxide (H₂O₂). In turn, H₂O₂ serves as a substrate for both glutathione peroxidase (GPx) and catalase, which catalyze its reduction to water (figure modified from Moret I [5]).

Figure 2

Factors linked to the etiopathogenesis of Crohn’s disease and oxidative stress as a key effector mechanism underlying the pathogenesis. Immunological factors associated with CD comprise both impaired innate response (infiltration of activated neutrophils and macrophages into the affected gut mucosa) and adaptive response (accumulation of CD4⁺ T cells in the lamina propria with a Th1/Th17 immune response). Environmental factors, especially diet, tobacco smoking, and the microbiota (the “in-vironment”), have an outstanding influence on the course and development of CD that appears to outweigh the influence of genetic factors (i.e., genetic susceptibility to the disease). Epigenetics provides a link between genetics and environmental factors and might constitute, at least to some extent, the mechanism through which some environmental factors mediate their impact on CD. Oxidative stress plays a central role in CD pathogenesis and was associated with the aforementioned factors.