Oxidative stress, hormones, and effects of natural antioxidants on intestinal inflammation in inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) is a chronic, relapsing gastrointestinal (GI) disorder characterized by intestinal inflammation. The etiology of IBD is multifactorial and results from a complex interplay between mucosal immunity, environmental factors, and host genetics. Future therapeutics for GI disorders, including IBD, that are driven by oxidative stress require a greater understanding of the cellular and molecular mechanisms mediated by reactive oxygen species (ROS). In the GI tract, oxidative stressors include infections and pro-inflammatory responses, which boost ROS generation by promoting the production of pro-inflammatory cytokines. Nuclear factor kappa B (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2) represent two important signaling pathways in intestinal immune cells that regulate numerous physiological processes, including anti-inflammatory and antioxidant activities. Natural antioxidant compounds exhibit ROS scavenging and increase antioxidant defense capacity to inhibit pro-oxidative enzymes, which may be useful in IBD treatment. In this review, we discuss various polyphenolic substances (such as resveratrol, curcumin, quercetin, green tea flavonoids, caffeic acid phenethyl ester, luteolin, xanthohumol, genistein, alpinetin, proanthocyanidins, anthocyanins, silymarin), phenolic compounds including thymol, alkaloids such as berberine, storage polysaccharides such as tamarind xyloglucan, and other phytochemicals represented by isothiocyanate sulforaphane and food/spices (such as ginger, flaxseed oil), as well as antioxidant hormones like melatonin that target cellular signaling pathways to reduce intestinal inflammation occurring with IBD.

Keywords: Crohn’s disease; IBD; antioxidants; flavonoids; hormones; oxidative stress; polyphenols; ulcerative colitis.

Figure 1

Antioxidant and anti-inflammatory effects of phytochemicals and hormones. Anti-inflammatory mechanisms involve the modulation of nuclear factor-kappa B (NF-κB) pathways, such as the downstream pro-inflammatory effects mediated by Toll-like receptor (TLR) activation. Activation (release of IκB inhibition) and nuclear translocation of NF-κB inhibition, which result in the transcription of several pro-inflammatory genes, can be inhibited by several phytochemicals and hormones (left panel). Kelch-like ECH-associated protein-1 (Keap1)-induced activation and nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), resulting in an increased expression of antioxidant enzymes (AOEs), can also be inhibited by phytochemicals and hormones (right panel). In the presence of OS, Keap1 relinquishes its binding to Nrf2, thereby enabling the translocation of Nrf2 into the nucleus. Subsequently, Nrf2 forms a complex with small Maf (sMaf) proteins, resulting in the formation of Nrf2/sMaf heterodimer, which then binds to the Antioxidant Response Element (ARE) located on different stress-related gene targets. The figure was produced with BioRender (www.biorender.com; accessed on 17^th July 2023). Resveratrol (RSV); Curcumin (CUR); Quercetin (QCT); Ginger (GIN); Flavonoids (FLA); Caffeic acid phenethyl ester (CAPE); Luteolin; (LUT); Xanthohumol (XN); Genistein (GEN); Berberine (BER); Flaxseed oil (α-linolenic acid) (FSO); Sulforaphane (SUL); Tamarind xyloglucan (TXG); Alpinetin (ALP); Proanthocyanidins (PA); Anthocyanins (ANTH); Silymarin (SIL); Thymol (THY); Melatonin (MEL); ubiquitin (Ub); phosphorylation (P); IκB kinase (Iκκ); Mammalian NF-κB family members: NF-κB1 (p50), c-Rel and RelA (p65).

Figure 2

Overview of cellular reactive oxygen species (ROS) generation and their scavenging by antioxidant defense system (AODS). Supplemental antioxidants can help lower oxidative stress by scavenging free radicals, blocking enzymes that produce ROS, or stimulating AODS enzymes and molecules. The figure was produced with BioRender (www.biorender.com; accessed on 17^th July 2023). Superoxide dismutase (SOD); catalase (CAT); glutathione peroxidases (GPx); glutathione reductase (GR); reduced glutathione (GSH); oxidized glutathione (GSSG); glucose-6-phosphate dehydrogenase (G6PD).

Figure 3

Immune responses in IBD and anti-inflammatory effects of phytochemicals and hormones. Whereas the physiologic state of the gastrointestinal (GI) immune system is dominated by immune tolerance, which maintains homeostatic balance, disturbances with IBD are associated with an exaggerated (i.e., pro-inflammatory) immune response, intestinal dysbiosis, and compromised intestinal barrier function. Pro-inflammatory mediators can perpetuate and exacerbate these dysregulated immune responses, while several phytochemicals and hormones can shift this imbalance toward homeostasis. The figure was produced with BioRender (www.biorender.com; accessed on 17^th July 2023). Resveratrol (RSV); Curcumin (CUR); Quercetin (QCT); Ginger (GIN); Flavonoids (FLA); Caffeic acid phenethyl ester (CAPE); Luteolin; (LUT); Xanthohumol (XN); Genistein (GEN); Berberine (BER); Flaxseed oil (α-linolenic acid) (FSO); Sulforaphane (SUL); Tamarind xyloglucan (TXG); Alpinetin (ALP); Proanthocyanidins (PA); Anthocyanins (ANTH); Silymarin (SIL); Thymol (THY); Melatonin (MEL); interferon-gamma (IFNγ); tumor necrosis factor-alpha (TNF-α); transforming growth factor β (TGF-β); interleukin (IL). Naive CD4 T cells differentiated Th1, Th17, Tfh (follicular T helper), and Treg (T regulatory) subsets.