Pulmonary, Gastrointestinal and Urogenital Pharmacology
Dietary supplementation of resveratrol attenuates chronic colonic inflammation in mice

https://doi.org/10.1016/j.ejphar.2010.01.025Get rights and content

Abstract

Ulcerative colitis is a nonspecific inflammatory disorder characterized by oxidative and nitrosative stress, leucocyte infiltration and upregulation of inflammatory mediators. Resveratrol is a polyphenolic compound found in grapes and wine, with multiple pharmacological actions, mainly anti-inflammatory, antioxidant, antitumour and immunomodulatory activities. The aim of this study was to investigate the effect of dietary resveratrol on chronic dextran sulphate sodium (DSS)-induced colitis. Six-week-old mice were randomized into two dietary groups: one standard diet and the other enriched with resveratrol at 20 mg/kg of diet. After 30 days, mice were exposed to 3% DSS for 5 days developing acute colitis that progressed to severe chronic inflammation after 21 days of water. Our results demonstrated that resveratrol group significantly attenuated the clinical signs such as loss of body weight, diarrhea and rectal bleeding improving results from disease activity index and inflammatory score. Moreover, the totality of resveratrol-fed animals survived and finished the treatment while animals fed with standard diet showed a mortality of 40%. Three weeks after DSS removal, the polyphenol caused substantial reductions of the rise of pro-inflammatory cytokines, TNF-α and IL-1β and an increase of the anti-inflammatory cytokine IL-10. Also resveratrol reduced prostaglandin E synthase-1 (PGES-1), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) proteins expression, via downregulation of p38, a mitogen-activated protein kinases (MAPK) signal pathway. We conclude that resveratrol diet represents a novel approach to the treatment of chronic intestinal inflammation.

Introduction

Inflammatory bowel disease is a chronic pathology by uncontrolled inflammation of the intestinal mucosa which can affect part of the gastrointestinal tract. Pathophysiological bases of this disease involve genetic factors, immune dysregulation, barrier dysfunction, and a loss of immune tolerance toward the enteric flora (Kucharzik et al., 2006, Sánchez-Muñoz et al., 2008). Increase of inflammatory mediators, including reactive oxygen species such as nitric oxide, prostaglandins and inflammatory cytokines play an important role in immune dysregulation (Kolios et al., 2004, Rojas-Cartagena et al., 2005, Atreya and Neurath, 2005, Ito et al., 2006). Furthermore, reactive oxygen species can activate diverse downstream signalling pathways, for instance mitogen-activated protein kinases (MAPKs) which lead to the activation of transcription factors modulating a number of different steps in the inflammatory cascade. These include production of pro-inflammatory cytokines (tumour necrosis factor alpha (TNF-α), interleukin (IL)-1β, interferon (IFN)-γ, IL-6, IL-12 and IL-17 among others) in different cell-types, degranulation of neutrophils, as well as the expression of important determining parameters namely prostaglandin E2-synthesizing enzymes, including prostaglandin E synthase (PGES)-1 and cyclooxygenase (COX)-2, and inducible nitric oxide synthase (iNOS) (Dubuquoy et al., 2002, Collino et al., 2006, Pecchi et al., 2009).

Resveratrol (trans-3,4,5-trihydroxystilbene), a natural polyphenol, is found in a large number of plant species including some components of the human diet, such as various fruits and vegetables and is abundant in grapes and in red wines. The last years, it has been the focus of numerous in vitro and in vivo studies where its biological attributes have been investigated, which include essentially antioxidant and anti-inflammatory activities, anti-platelet aggregation effect, anti-atherogenic property, oestrogen-like growth promoting effect, growth-inhibiting activity, immunomodulation and chemoprevention (Jang et al., 1997, Bradamante et al., 2004, de la Lastra and Villegas, 2007, Shakibaei et al., 2009). Among the possible mechanisms responsible for its biological activities are downregulation of the inflammatory response through inhibition of synthesis and release of pro-inflammatory mediators, modification of eicosanoid synthesis, inhibition of Kupffer cells and adhesion molecules, inhibition of activated immune cells, or iNOS and COX-2 downregulation via its inhibitory effects on NF-κβ or AP-1 (Jang et al., 1997, Bertelli, 1998, de la Lastra and Villegas, 2005). Moreover, resveratrol has been shown to produce no adverse effects, even when consumed at high concentrations.

Previous studies by our research group have showed the beneficial effect of intragastric resveratrol in an acute and chronic-induced trinitrobenzenesulphonic acid colitis (Martín et al., 2004, Martín et al., 2006); these effects were observed despite extremely low bioavailability and rapid clearance from the circulation (Walle et al., 2004). However, there is no report related to dietary resveratrol on chronic experimental colitis. Thus, the present study was designed to examine the protective/preventive effects of dietary resveratrol intake in a chronic colitis model induced by dextran sulphate sodium (DSS) in C57BL/6 mice, which is useful to identify and validate new therapies for treatment of inflammatory bowel disease (Melgar et al., 2008) by macroscopic and histology parameters and to analyze the mechanisms involved in its effects as inflammatory response such as cytokines production, PGES-1, COX-2, iNOS expression and finally, we studied the role of p38 MAPK signalling pathway in the beneficial effects of resveratrol on chronic colonic inflammation.

Section snippets

Animals and treatment

A total of 50 6-week-old female C57BL/6 mice (Charles River, Tokyo, Japan) were used in this study. They were acclimatized in our Animal Laboratory Center under standard conditions (temperature 24–25.8 °C, humidity 70–75%, lighting regimen of 12L/12D) and were fed pellet diets and water ad libitum. Mice were randomized into two dietary groups: 25 mice were fed with standard diet and the rest were fed with resveratrol-enriched diet at 20 mg/kg of diet (Sigma-Aldrich Company Ltd. Spain) (Table 1)

Therapeutic efficacy of dietary resveratrol for chronic experimental DSS model

Clinical signs on exposure to 3% DSS in the standard diet group for 5 days were loss of body weight, not formed stool or diarrhea and rectal bleeding. The signs were aggravated when disease progressed to the chronic phase. Acute disease did not resolve after DSS removal, instead it progressed to a severe chronic colitis, although paradoxically, diarrhea and weight loss did not correlate with the severity of the inflammation. Significant loss of body weight was observed 1 week after DSS removal in

Discussion

In the present study, results indicate that dietary administration of 3 mg/kg/day of resveratrol reduced the severity and extension of progressive chronic colonic damage induced by a short 5-day exposure of DSS followed by a 3 week rest period in C57BL/6 mice. In control animals, the acute phase (day 5) was characterized by clinical signs, i.e. diarrhea, bloody feces, and body weight loss and the chronic phase (day 21) was characterized by recovered body weight, no/few clinical signs, high

Acknowledgements

This research was supported in part by grants from Ministerio de Ciencia y Tecnología (AGL 2005-05132) and Junta de Andalucía (Spain).

The authors have declared no conflict of interest.

References (54)

  • G.B. Mahady et al.

    Resveratrol and red wine extracts inhibit the growth of CagA+ strains of Helicobacter pylori in vitro

    Am. J. Gastroenterol.

    (2003)
  • J. Martinez et al.

    Effect of resveratrol, a natural polyphenolic compound, on reactive oxygen species and prostaglandin production

    Biochem. Pharmacol.

    (2000)
  • S. Melgar et al.

    Validation of murine dextran sulfate sodium-induced colitis using four therapeutic agents for human inflammatory bowel disease

    Int. Immunopharmacol.

    (2008)
  • E. Pecchi et al.

    Prostaglandins and sickness behavior: old story, new insights

    Physiol. Behav.

    (2009)
  • C. Rojas-Cartagena et al.

    Role of tumor necrosis factor receptors in an animal model of acute colitis

    Cytokine

    (2005)
  • K. Subbaramaiah et al.

    Resveratrol inhibits cyclooxygenase-2 transcription and activity in phorbol ester-treated human mammary epithelial cells

    J. Biol. Chem.

    (1998)
  • K. Subbaramaiah et al.

    Microsomal prostaglandin E synthase-1 is overexpressed in inflammatory bowel disease. Evidence for involvement of the transcription factor Egr-1

    J. Biol. Chem.

    (2004)
  • X. Wang et al.

    Protective effects of 2, 3, 5, 4′-tetrahydroxystilbene-2-O-beta-D-glucoside, an active component of Polygonum multiflorum Thunb, on experimental colitis in mice

    Eur. J. Pharmacol.

    (2008)
  • R. Atreya et al.

    Involvement of IL-6 in the pathogenesis of inflammatory bowel disease and colon cancer

    Clin. Rev. Allergy Immunol.

    (2005)
  • A.A.E. Bertelli

    Modulatory effect of resveratrol, a natural phytoalexin, on endothelial, adhesion molecules and intracellular signal transduction

    Pharm. Biol.

    (1998)
  • S. Bradamante et al.

    Cardiovascular protective effects of resveratrol

    Cardiovasc. Drug Rev.

    (2004)
  • L. Bujanda et al.

    Effect of resveratrol on alcohol-induced mortality and liver lesions in mice

    BMC Gastroenterol.

    (2006)
  • L. Bujanda et al.

    Resveratrol inhibits nonalcoholic fatty liver disease in rats

    BMC Gastroenterol.

    (2008)
  • E. Candelario-Jalil et al.

    Resveratrol potently reduces prostaglandin E2 production and free radical formation in lipopolysaccharide-activated primary rat microglia

    J. Neuroinflammation

    (2007)
  • C.A. de la Lastra et al.

    Resveratrol as an anti-inflammatory and anti-aging agent: mechanisms and clinical implications

    Mol. Nutr. Food Res.

    (2005)
  • C.A. de la Lastra et al.

    Resveratrol as an antioxidant and pro-oxidant agent: mechanisms and clinical implications

    Biochem. Soc. Trans.

    (2007)
  • M. Deniz et al.

    Blood flow alterations in TNBS-induced colitis: role of endothelin receptors

    Inflamm. Res.

    (2004)
  • Cited by (199)

    • Colon delivery of resveratrol for the treatment of inflammatory bowel disease

      2024, Journal of Drug Delivery Science and Technology
    • Natural products in conditions associated with inflammatory bowel diseases: Colorectal cancer, diversion colitis, and obesity

      2023, Natural Plant Products in Inflammatory Bowel Diseases: Preventive and Therapeutic Potential
    View all citing articles on Scopus
    View full text