Inflammatory Bowel Disease: Mechanisms, Redox Considerations, and Therapeutic Targets

Abstract

Oxidative stress is thought to play a key role in the development of intestinal damage in inflammatory bowel disease (IBD), because of its primary involvement in intestinal cells' aberrant immune and inflammatory responses to dietary antigens and to the commensal bacteria. During the active disease phase, activated leukocytes generate not only a wide spectrum of pro-inflammatory cytokines, but also excess oxidative reactions, which markedly alter the redox equilibrium within the gut mucosa, and maintain inflammation by inducing redoxsensitive signaling pathways and transcription factors. Moreover, several inflammatory molecules generate further oxidation products, leading to a self-sustaining and auto-amplifying vicious circle, which eventually impairs the gut barrier. The current treatment of IBD consists of long-term conventional anti-inflammatory therapy and often leads to drug refractoriness or intolerance, limiting patients' quality of life. Immune modulators or anti-tumor necrosis factor a antibodies have recently been used, but all carry the risk of significant side effects and a poor treatment response. Recent developments in molecular medicine point to the possibility of treating the oxidative stress associated with IBD, by designing a proper supplementation of specific lipids to induce local production of anti-inflammatory derivatives, as well as by developing biological therapies that target selective molecules (i.e., nuclear factor-jB, NADPH oxidase, prohibitins, or inflammasomes) involved in redox signaling. The clinical significance of oxidative stress in IBD is now becoming clear, and may soon lead to important new therapeutic options to lessen intestinal damage in this disease.

Increased Expression of DUOX2 Is an Epithelial Response to Mucosal Dysbiosis Required for Immune Homeostasis in Mouse Intestine

“…Since unbalanced production of ROS can exacerbate inflammation 40 , DUOX2 upregulation in IBD is often deemed to be deleterious. Here we demonstrate that loss of DUOX activity not only increases mucosal bacterial uptake, but caused an ileal gene expression profile reminiscent of early CD-associated changes, indicating a distinct paradigm for the role of DUOX2 in early CD pathogenesis.…”

Antioxidant Effect of Natural Table Olives Phenolic Extract Against Oxidative Stress and Membrane Damage in Enterocyte‐Like Cells

“…The protective action of the phenolic extract has a great biological relevance. Changes in membrane fluidity and structure are a key event in the initiation and progression of mucosal barrier dysfunction, correlated to the onset of inflammatory and degenerative intestinal diseases (Biasi and others ). This is especially true in the colon, whose antioxidant capacity is low, in contrast to the high level of oxidizing species (Blau and others ).…”

“…The effect of TBH upon Caco‐2 cells well simulates the damaging action of dietary lipid hydroperoxides on the intestinal mucosa. The redox equilibrium alteration within the intestinal mucosa is deeply related to the onset and progression of the most common degenerative diseases (Biasi and others ). It has been reported that one of the most important sites of olive oil polyphenols action is the intestinal lumen (Halliwell and others ).…”

Redox Regulation of Inflammation: Old Elements, a New Story

“…Recently, the impact of redox modifications on signaling or structural proteins contributing to inflammation has come into focus . Various redox‐sensitive proteins have been reported to be involved in the initiation, progression, and resolution of the inflammatory response.…”