The emerging role of oxidative stress in inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) is a chronic immune-mediated condition that affects the digestive system and includes Crohn's disease (CD) and ulcerative colitis (UC). Although the exact etiology of IBD remains uncertain, dysfunctional immunoregulation of the gut is believed to be the main culprit. Amongst the immunoregulatory factors, reactive oxygen species (ROS) and reactive nitrogen species (RNS), components of the oxidative stress event, are produced at abnormally high levels in IBD. Their destructive effects may contribute to the disease's initiation and propagation, as they damage the gut lining and activate inflammatory signaling pathways, further exacerbating the inflammation. Oxidative stress markers, such as malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and serum-free thiols (R-SH), can be measured in the blood and stool of patients with IBD. These markers are elevated in patients with IBD, and their levels correlate with the severity of the disease. Thus, oxidative stress markers can be used not only in IBD diagnosis but also in monitoring the response to treatment. It can also be targeted in IBD treatment through the use of antioxidants, including vitamin C, vitamin E, glutathione, and N-acetylcysteine. In this review, we summarize the role of oxidative stress in the pathophysiology of IBD, its diagnostic targets, and the potential application of antioxidant therapies to manage and treat IBD.

Keywords: IBD treatment; antioxidant therapy; inflammatory bowel disease; oxidative stress; oxidative stress markers.

Figure 1

Components of the oxidative stress mechanism in IBD. The alteration of mitochondrial dysfunction, overproduction of ROS, damage to biomolecules, immune cell recruitment, and impaired antioxidant system participate in the mechanism of oxidative stress condition in IBD. Oxidative stress also triggers NF-κB activation and enhances inflammatory responses, a vital pathological component of IBD. Additionally, Nrf2 increases a variety of genes, allowing renal cells to act as antioxidants and reducing the production of cytokines and adhesion molecules that promote inflammations.

Figure 2

Nrf2-Mediated signaling in response to oxidative stress in IBD. (1) Upon sensing oxidative stress, cells phosphorylate Nrf2, which is normally sequestered in the cytoplasm by kelch-like ECH-associated protein 1 (Keap1). (2) The antioxidant response element (ARE) of the antioxidant genes is then bound by Nrf2 when it translocates into the nucleus. (3) HO-1 and GSTs are examples of antioxidant genes whose transcription is stimulated by Nrf2. (4) The antioxidant genes are then expressed, which prevents oxidative stress and keeps cells’ redox balance.

Figure 3

The NF-κB pathway as one of the mechanisms by which ROS can contribute to the pathogenesis of IBD. Radiation, mitochondria, NADPH oxidase, and Endoplasmic reticulum are the main sources of ROS.ROS activates the IKK complex. The IKK phosphorylates IkBA, which leads to its degradation.NF-κB is activated and translocated into the nucleus. NF-κB binds to particular DNA sequences and triggers the transcription of many different genes, including those that produce adhesion molecules, pro-inflammatory cytokines, and other inflammatory mediators (e.g., TNF-α, IL-6, and IL-1).The transcription of pro-inflammatory genes leads to the production of inflammatory cytokines and other molecules that contribute to the inflammatory response in the intestinal mucosa. Immune cells like neutrophils and macrophages are drawn to the area of gut tissue inflammation by these inflammatory signals. The influx of immune cells and the ongoing inflammation can result in tissue damage, ulceration, and the chronic inflammation that characterizes IBD.

Figure 4

The influence of ROS and cytokines on signaling pathways in intestinal epithelial cells. NOX enzymes generate superoxide anion, elevating advanced glycation end product (AGE) in epithelial cell membranes. SOD3 converts superoxide to hydrogen peroxide, enhancing AGE content. Concurrently, NF-κB is activated by AGE, NOX, and pro-inflammatory cytokines (IL-6, TNF-α), triggering increased expression of caspase 3, ICAM, TNF-α, and IL-6 genes. Meanwhile, MAPK activation boosts AP-1 signaling and iNOS production. AGE advanced glycation end products, AP-1 activator protein 1, ICAM intracellular adhesion molecule, IL-6 interleukin 6, IL-6R interleukin 6 receptor, iNOS inducible nitric oxide synthase, NF-κB nuclear factor-kappa B, NOX NADPH oxidase, MAPK mitogen-activated protein kinases, OCl − hypochlorite ion, SOD3 extracellular superoxide dismutase, TNF-α tumor necrosis factor-alpha, TNFR tumor necrosis factor receptor.