Antioxidant therapy for treatment of inflammatory bowel disease: Does it work?

Abstract

Oxidative stress (OS) is considered as one of the etiologic factors involved in several signals and symptoms of inflammatory bowel diseases (IBD) that include diarrhea, toxic megacolon and abdominal pain. This systematic review discusses approaches, challenges and perspectives into the use of nontraditional antioxidant therapy on IBD, including natural and synthetic compounds in both human and animal models. One hundred and thirty four papers were identified, of which only four were evaluated in humans. Some of the challenges identified in this review can shed light on this fact: lack of standardization of OS biomarkers, absence of safety data and clinical trials for the chemicals and biological molecules, as well as the fact that most of the compounds were not repeatedly tested in several situations, including acute and chronic colitis. This review hopes to stimulate researchers to become more involved in this fruitful area, to warrant investigation of novel, alternative and efficacious antioxidant-based therapies.

Keywords: Antioxidant therapy; Biomarkers; Complementary and alternative medicine; Crohn's disease; Inflammatory bowel diseases; Nutraceuticals; Oxidative stress; Ulcerative colitis.

Graphical abstract

Fig. 1

Important risk factors associated with inflammatory bowel diseases and immunological changes.

Fig. 2

Main substances used/tested in inflammatory bowel disease therapy (articles published from 2009–2015/06).

Fig. 3

Main results from the database search.

Fig. 4

Oxidative stress and its association with the physiopathological process of IBD. Legend description: reactive oxygen species (ROS) are produced through several metabolic pathways. (1) In mitochondria, during the respiratory process, the electron transport chain normally transforms 2–3% of O₂ to O₂^•– (complex I and III). Then, this reactive species undergoes dismutation by Mn-SOD and generates (2) H₂O₂. In the cytosol, O₂^•– can be generated by (3) xanthine oxidase (XO), (4) cyclooxygenase 2 (COX2) and (5) NADPH oxidase (NOX) and generates (6) advanced glycation end-products (AGE) that are involved with the inflammatory process, or can form (7) H₂O₂ by CuZn–SOD. Hydrogen peroxide can be also produced by (8) immune cells: monocytes, lymphocytes and (A) neutrophils (principally), coming from leukocyte infiltration that is characteristic of IBD. The reactive molecule H₂O₂, unlike the O₂^•–, is long lived and highly biomembrane permeable, facilitated by the (9) aquaporin-8 channel. In the cytosol, together with metals such as Fe²⁺, Cu²⁺, Co²⁺ and Cr²⁺, and by (10) the Fenton and Haber-Weiss reactions, H₂O₂ forms the hydroxyl radical (HO^·) which is highly toxic and can directly cause (11) lipid peroxidation (LP). Other actions by HO^• are: (12) DNA fragmentation, (13) inactivation of mitochondrial pyruvate dehydrogenase (PDH), (14) mucin depolarization and (15) destruction of (B) apical intercellular junctions. These damaging actions cause (11) tissue disruption and cellular death and then ulcerations in the mucosa, typical IBD damage; (12) mutagenesis and cancer; (13) increased mitochondrial O₂^•– generation and OS, which has a direct relationship to the severity of the disease; (14) decreased formation of the mucous layer and promotion of (15) bacterial translocation, which stimulates macrophages and neutrophil recruit, as well as increased intestinal permeability; and facilitates (16) leukocytes and neutrophil infiltration, causing inflammation. Another enzyme present in the cytosol, lipoxygenase (LPO) also causes LP via (17) lipoperoxide (LOOH) formation. All reactive nitrogen species (RNS) are formed from nitric oxide (NO^•), produced by (18) inducible nitric oxide synthase (iNOS) that converts l-arginine to l-citruline. The NO^• reacts with O₂^•– to furnish (19) the peroxynitrite anion (ONOO^–), which then becomes (20) peroxynitrous acid (ONOOH). The latter then generates the new species (21) of nitrogen dioxide (NO₂^•) that causes LP. ONOO^– is highly reactive and can cause (12) DNA fragmentation and RNS/ROS stimulation (10) of LP. Nitric oxide has dangerous actions on enterocytes. This gas stimulates (22) chloride secretion to the mucosa with a consequent (23) water release into the intestinal lumen causing osmotic diarrhea, the most frequent symptom of IBD. RNS are chemotactic mediators of macrophages and neutrophils that (24) stimulate ferrous release from defense cells (25) into the intracellular environment. Nitric oxide, despite having a half-life of ≅ 3 s, can (26) diffuse to the muscle layer (smooth muscle) and causes no-cholinergic and no-adrenergic relaxing and consequently toxic megacolon, a common clinical complication of IBD. Because of disrupted permeability, antigens derived from food digestion and from commensal or pathogenic bacteria can overcome the unprotected mucosal barrier and provoke a continuous intestinal immune response that then causes tissue damage. The inflammatory response often results in continued epithelial injury, which causes erosions and ulcerations leading to an increased exposure to intestinal microbiota and amplification of the inflammatory response. Antioxidant cell defenses involve enzymes and non-enzymes present in peroxisomes. In this organelle, H₂O₂ can be transformed into water (H₂O) by (27) catalase (CAT), principally in the inflammatory process, and (28) by glutathione peroxidase (GPx). For peroxisomes to obtain GPx there is a need to convert reduced glutathione (GSH) to its oxidized form (GSSH). For regeneration of GSH, the presence of (29) glutathione reductase (GR) – glutathione cycle is necessary. Adapted from Refs. , , . A – Disruption of intercellular junctions The intercellular junctions of the intestinal epithelium are constituted of tight junctions (TJ), adherent junctions (AJ), and desmosomes. The epithelial tight junctions form a barrier to the entry of allergens, toxins and pathogens across the epithelium into the interstitial tissue. ROS and RNS can promote disruption of both, TJs and AJs. NO^· and ONOOH cause nitration of actin present in the cell cytosol. Concomitant to RNS, H₂O₂^• and HO^• can cause dephosphorylation (serin/thyrosin) or phosphorylation (thyrosin) of occludin – connected to actin by ZO (Zonula occludens) (1, 2 or 3) proteins – and phosphorylation (tyrosine) of β-catenin – which connect E-cadherin with α-catenin and this to actin. Both, actin rearrangement (caused by nitration) and (de)phosphorylation of adherent/linker proteins, promote disruption of intercellular junctions, barrier dysfunction and consequent increase of intestinal permeability to neutrophil and bacterial/toxin infiltration and hence the inflammatory processes. B – Neutrophils and OS Neutrophils are the principal ROS and RNS sources during the inflammatory process. These cells produce O₂•^– from NOX and NO^• from iNOS. H₂O₂ and Cl^- are produced by the myeloperoxidase (MPO) enzyme, which leads to the production of hypochlorus acid (HOCl). Both MPO and HOCl cause LP and tissue damage. Adapted from Refs. , .