Effects of Resveratrol on Inflammatory Bowel Disease : A Review

The Center for Disease Control and Prevention (CDC) estimates 1.4 million diagnosed cases of inflammatory bowel disease (IBD) in the United States costing the health care industry between $1.7 and $5.2 billion each year [1,2]. IBD accounts for more than 700,000 physician visits, 100,000 hospitalizations, and disability in 119,000 patients annually in the United States [1]. IBD, which includes Ulcerative Colitis (UC) and Crohn’s disease (CD), is an autoimmune disease and poses pained digestion and malnutrition risk due to a compromised gastrointestinal tract. The etiology of this disease remains unknown, but is thought to be a combination of immune responses, environmental factors and genetic dynamics [3]. Although IBD alone is not fatal, those with UC and CD have a six times increased risk of developing colon cancer [4]. Current drugs and surgeries used to treat the symptoms of IBD can cause negative side effects [1,5]. For these reasons, it is important to find a treatment that is able to reduce the development of IBD with little side effects.


Introduction
The Center for Disease Control and Prevention (CDC) estimates 1.4 million diagnosed cases of inflammatory bowel disease (IBD) in the United States costing the health care industry between $1.7 and $5.2 billion each year [1,2].IBD accounts for more than 700,000 physician visits, 100,000 hospitalizations, and disability in 119,000 patients annually in the United States [1].IBD, which includes Ulcerative Colitis (UC) and Crohn's disease (CD), is an autoimmune disease and poses pained digestion and malnutrition risk due to a compromised gastrointestinal tract.The etiology of this disease remains unknown, but is thought to be a combination of immune responses, environmental factors and genetic dynamics [3].Although IBD alone is not fatal, those with UC and CD have a six times increased risk of developing colon cancer [4].Current drugs and surgeries used to treat the symptoms of IBD can cause negative side effects [1,5].For these reasons, it is important to find a treatment that is able to reduce the development of IBD with little side effects.
Resveratrol, 3,5,40 -trihydroxy-trans-stilbene, is a natural phenol and phytoalexin that can be found in red wine, grapes, peanuts, and Japanese knotweed.It has been widely researched for its antioxidant properties, most specifically in cancer and cardiovascular diseases [6][7][8][9].In some human studies, resveratrol can decrease signs of inflammation with virtually no side effects [8,10].No human studies, however, exist to show anti-inflammatory effects of resveratrol in IBD.The objective of this review is to discuss the effects of resveratrol on inflammatory signaling pathways, inflammatory biomarkers, intestinal microflora and clinical symptoms in animal models of experimental IBD.To our knowledge, this is the first review assessing the effect of resveratrol on IBD.pathways.P38 MAPK, one of four, general MAPK signaling systems in mammals, has been recognized as a critical part in the pathogenesis of CD [11,12].Activation of p38 MAPK, by the proinflammatory cytokine tumor necrosis factor (TNF)-α, is down regulated with resveratrol administration [11,13].

Reduced proinflammatory mediators
Excess nitric oxide (NO) has been associated with the etiology and progression of IBD [26,27].Inducible nitric oxide synthase (iNOS), which initiates NO production, is up regulated in a state of chronic intestinal inflammation [27].Resveratrol generally diminishes iNOS protein expression [13,16,28] and NO production [29,30].One study dissimilarly found resveratrol to raise NO levels above baseline values [21].Since constitutive NO is also involved in gut homeostasis, [27] restoring NO after resveratrol supplementation may be beneficial for gastrointestinal maintenance of equilibrium, however, prolonged large quantity of NO would be harmful.
IBD comprises excess CD 3+ and CD3 4+ T-cells; [34] however, as a result of resveratrol they are decreased to normal levels [18,23,28].Forkhead box P3 cells are typically reduced in IBD, [35] but increase with Resveratrol [23] signifying decreased natural T regulatory cells and reduced severity of IBD [36].CD11b + and Gr-1 + were increased during resveratrol supplementation leading to decreased effector T-cell function and a decline in clinical symptoms [33].

Modification of intestinal microflora
Rise in colonic permeability in IBD allows interaction between microbiota and immune responses [30,42].Resveratrol administration reduces Escherichia coli; Enterococci, and total bacteria load in the intestine 1.0 -3.0 orders of magnitude [23,30,37].Resveratrol simultaneously increases Lactobacilli and Bifidobacteria 1.0 order of magnitude, peaking after 20 days of administration [23,30].Resveratrol is not only able to reduce bacteria overgrowth, but also limit bacteria translocation into sub-epithelial tissues, [23] which can be a crucial factor in disease progression.

Effects of Resveratrol on Inflammatory Bowel Disease: A Review
Copyright: © 2014 Hong et al.

Discussion
Based on current research, 1 to 100 mg/kg/day of resveratrol appears to improve clinical symptoms of experimentallyinduced IBD in animals by beneficially modulating inflammatory signaling pathways, oxidative stress, COX-2, acute phase proteins, leukocytes, cytokines, and intestinal microflora.Positive results such as these indicate a potential role for resveratrol in actual cases of IBD.
Anti-inflammatory drugs currently used in the treatment of IBD can induce headache, nausea, pain, diarrhea, sleep disturbance, glucose intolerance, hepatotoxicity, pneumonitis, and tremor [5].These drugs are used to moderate cytokines, COX-2, and ROS, [5] which, based on current literature, can also be accomplished with resveratrol.In one animal study, 10 mg/ kg/day of resveratrol was equally effective to 300 mg/kg of sulphasalazine in reducing signs of IBD [21].Although few studies have directly compared the effects of resveratrol to current medical treatments, resveratrol appears to have characteristics that match such treatments.Studies in both animals with IBD and humans without IBD, have determined no adverse effects of Resveratrol [10,43,44].Its supplementation and effects have not yet been determined for patients with IBD.Although experimental induced IBD is a well-established animal model, the reviewed studies are limited by the controlled living conditions and diet, which do not mimic the varying stress factors of free-living conditions that can affect intestinal inflammation [45][46][47].Additionally, although many studies contained significance values of findings, they did not report exact values, which hindered quantitative synthesis of data.All studies, however, measured both physical and biological markers of IBD, confirming the results and the true progression of the disease.The strength and significance seen in these studies encourages the continuation of research on resveratrol supplementation on IBD.
Resveratrol appears to improve many attributes of IBD in experimental animal models, suggesting resveratrol as a promising complimentary therapy for IBD.Further research is needed to confirm if such attributes remain effective in humans while refining optimal dosage, discovering pro-drug administration and standardizing measures including instillation of resveratrol, supplementation duration and histological scores.

Table 1 :
Studies Examining the Effect of Resveratrol on Experimental IBD.
Notes.This table summarizes the results of studies examining the effects of resveratrol in experimental models of IBD, in comparison to groups not supplementing resveratrol.a , p<0.05; b , p<0.01; c , p<0.001; ~, average ad lib dosage; ∄ no significant difference; *, mg/kg/every other day.(Doses in mg/kg/day).