Advertisement

Effect of Resveratrol Supplementation on Inflammatory Markers: A Systematic Review and Meta-analysis of Randomized Controlled Trials

      Abstract

      Purpose

      The evidence has suggested that resveratrol has anti-inflammatory effect; however, the results are inconsistent and inconclusive. The aim of this study was to assess the effect of resveratrol supplementation on the levels of inflammatory markers through a systematic review and meta-analysis of available randomized controlled trials (RCTs).

      Methods

      A search strategy was completed using Medline, ISI Web of Science, Directory of Open Access Journal, SID, ProQuest, Cochrane Library, Scopus, and EMBASE up to May 2017, to identify placebo-controlled RCTs that assessed resveratrol effects on circulating (serum and plasma) inflammatory markers (interleukin [IL]-6, tumor necrosis factor–α [TNF-α], and high-sensitivity C-reactive protein [hs-CRP]) among adult participants aged 17 years and older in 17 RCTs with a total of 736 subjects. The evaluation of study quality was performed using the Jadad scale. Weighted mean difference (WMD) was calculated for evaluating the changes in the inflammatory markers using fixed-effects or random-effects models. We performed subgroup and sensitivity analyses to evaluate the heterogeneity of the studies.

      Findings

      Seventeen RCTs, including 736 subjects, fulfilled the eligibility criteria and were selected for analyses. The results of meta-analysis found significant reductions in the level of TNF-α (WMD, –0.44; 95% CI, –0.71 to –0.164; P = 0.002; Q statistic = 21.60; I2 = 49.1%; P = 0.02) and hs-CRP (WMD, –0.27; 95% CI, –0.5 to –0.02; P = 0.033; Q statistic = 26.95; I2 = 51.8%; P = 0.013) after supplementation with resveratrol. Resveratrol supplementation had no significant effect on the level of IL-6 (WMD, –0.16; 95% CI, –0.53 to 0.20; P = 0.38; Q statistic = 36.0; I2 = 72.3%; P = 0.001). Statistically significant heterogeneity was observed for the type of sample in IL-6 and study duration in inflammatory markers IL-6, TNF-α, and hs-CRP.

      Implications

      Available evidence from RCTs suggests that resveratrol supplementation significantly reduced TNF-α and hs-CRP levels. Significant improvement in inflammatory markers support resveratrol as an adjunct to pharmacologic management of metabolic diseases.

      Graphical abstract

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Clinical Therapeutics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Meshkani R
        • Vakili S
        Tissue resident macrophages: Key players in the pathogenesis of type 2 diabetes and its complications.
        Clinica Chimica Acta. 2016; 462: 77-89
        • Khodabandehloo H
        • Gorgani-Firuzjaee S
        • Panahi G
        • Meshkani R
        Molecular and cellular mechanisms linking inflammation to insulin resistance and β-cell dysfunction.
        Translational Research. 2016; 167: 228-256
        • Su H
        • Liu R
        • Chang M
        • Huang J
        • Jin Q
        • Wang X
        Effect of dietary alpha-linolenic acid on blood inflammatory markers: a systematic review and meta-analysis of randomized controlled trials.
        European Journal of Nutrition. 2017; : 1-15
        • Collaboration ERF.
        C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis.
        The Lancet. 2010; 375: 132-140
        • Kasperska-Zajac A
        • Grzanka A
        • Damasiewicz-Bodzek A
        • et al.
        Elevated plasma il-8 concentration is related to severity of systemic inflammation in chronic spontaneous urticaria.
        Journal of biological regulators and homeostatic agents. 2017; 31: 957-961
        • Lujan HL
        • DiCarlo SE
        Physical activity, by enhancing parasympathetic tone and activating the cholinergic anti-inflammatory pathway, is a therapeutic strategy to restrain chronic inflammation and prevent many chronic diseases.
        Medical hypotheses. 2013; 80: 548-552
        • Sahebkar A
        • Serban C
        • Ursoniu S
        • et al.
        Lack of efficacy of resveratrol on C-reactive protein and selected cardiovascular risk factors—Results from a systematic review and meta-analysis of randomized controlled trials.
        International journal of cardiology. 2015; 189: 47-55
        • Csiszar A.
        Anti‐inflammatory effects of resveratrol: possible role in prevention of age‐related cardiovascular disease.
        Annals of the New York Academy of Sciences. 2011; 1215: 117-122
        • Smoliga JM
        • Baur JA
        • Hausenblas HA
        Resveratrol and health–a comprehensive review of human clinical trials.
        Molecular nutrition & food research. 2011; 55: 1129-1141
        • Leporini L
        • Giampietro L
        • Amoroso R
        • et al.
        In vitro protective effects of resveratrol and stilbene alkanoic derivatives on induced oxidative stress on C2C12 and MCF7 cells.
        Journal of biological regulators and homeostatic agents. 2017; 31: 589-601
        • Liu F-C
        • Tsai Y-F
        • Tsai H-I
        • Yu H-P
        Anti-inflammatory and organ-protective effects of resveratrol in trauma-hemorrhagic injury.
        Mediators of inflammation. 2015; 2015
        • Ghanim H
        • Sia CL
        • Korzeniewski K
        • et al.
        A resveratrol and polyphenol preparation suppresses oxidative and inflammatory stress response to a high-fat, high-carbohydrate meal.
        The Journal of Clinical Endocrinology & Metabolism. 2011; 96: 1409-1414
        • Tomé-Carneiro J
        • Larrosa M
        • Yánez-Gascón MJ
        • et al.
        One-year supplementation with a grape extract containing resveratrol modulates inflammatory-related microRNAs and cytokines expression in peripheral blood mononuclear cells of type 2 diabetes and hypertensive patients with coronary artery disease.
        Pharmacological research. 2013; 72: 69-82
        • Moher D
        • Liberati A
        • Tetzlaff J
        • Altman DG
        • Group P
        Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
        PLoS medicine. 2009; 6e1000097
        • Tomé-Carneiro J
        • Gonzálvez M
        • Larrosa M
        • et al.
        Grape resveratrol increases serum adiponectin and downregulates inflammatory genes in peripheral blood mononuclear cells: a triple-blind, placebo-controlled, one-year clinical trial in patients with stable coronary artery disease.
        Cardiovascular Drugs and Therapy. 2013; 27: 37-48
        • Tomé-Carneiro J
        • Gonzálvez M
        • Larrosa M
        • et al.
        One-year consumption of a grape nutraceutical containing resveratrol improves the inflammatory and fibrinolytic status of patients in primary prevention of cardiovascular disease.
        American Journal of Cardiology. 2012; 110: 356-363
        • Agarwal B
        • Campen MJ
        • Channell MM
        • et al.
        Resveratrol for primary prevention of atherosclerosis: clinical trial evidence for improved gene expression in vascular endothelium.
        International journal of cardiology. 2013; 166: 246-248
        • Brasnyó P
        • Molnár GA
        • Mohás M
        • et al.
        Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients.
        British Journal of Nutrition. 2011; 106: 383-389
        • Faghihzadeh F
        • Adibi P
        • Rafiei R
        • Hekmatdoost A
        Resveratrol supplementation improves inflammatory biomarkers in patients with nonalcoholic fatty liver disease.
        Nutrition research. 2014; 34: 837-843
        • Zahedi HS
        • Jazayeri S
        • Ghiasvand R
        • Djalali M
        • Eshraghian MR
        Effects of polygonum cuspidatum containing resveratrol on inflammation in male professional basketball players.
        International journal of preventive medicine. 2013; 4: S1
        • Ghanim H
        • Sia CL
        • Abuaysheh S
        • et al.
        An antiinflammatory and reactive oxygen species suppressive effects of an extract of Polygonum cuspidatum containing resveratrol.
        The Journal of Clinical Endocrinology & Metabolism. 2010; 95: E1-E8
        • Militaru C
        • Donoiu I
        • Craciun A
        • Scorei ID
        • Bulearca AM
        • Scorei RI
        Oral resveratrol and calcium fructoborate supplementation in subjects with stable angina pectoris: effects on lipid profiles, inflammation markers, and quality of life.
        Nutrition. 2013; 29: 178-183
        • Bo S
        • Ciccone G
        • Castiglione A
        • et al.
        Anti-inflammatory and antioxidant effects of resveratrol in healthy smokers a randomized, double-blind, placebo-controlled, cross-over trial.
        Current medicinal chemistry. 2013; 20: 1323-1331
        • Bo S
        • Ponzo V
        • Ciccone G
        • et al.
        Six months of resveratrol supplementation has no measurable effect in type 2 diabetic patients. A randomized, double blind, placebo-controlled trial.
        Pharmacological research. 2016; 111: 896-905
        • Samsami-kor M
        • Daryani NE
        • Asl PR
        • Hekmatdoost A
        Anti-inflammatory effects of resveratrol in patients with ulcerative colitis: a randomized, double-blind, placebo-controlled pilot study.
        Archives of medical research. 2015; 46: 280-285
        • Chen S
        • Zhao X
        • Ran L
        • et al.
        Resveratrol improves insulin resistance, glucose and lipid metabolism in patients with non-alcoholic fatty liver disease: a randomized controlled trial.
        Digestive and Liver Disease. 2015; 47: 226-232
        • Yoshino J
        • Conte C
        • Fontana L
        • et al.
        Resveratrol supplementation does not improve metabolic function in nonobese women with normal glucose tolerance.
        Cell metabolism. 2012; 16: 658-664
        • Poulsen MM
        • Vestergaard PF
        • Clasen BF
        • et al.
        High-dose resveratrol supplementation in obese men: an investigator-initiated, randomized, placebo-controlled clinical trial of substrate metabolism, insulin sensitivity, and body composition.
        Diabetes. 2013; 62: 1186-1195
        • Timmers S
        • Konings E
        • Bilet L
        • et al.
        Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans.
        Cell metabolism. 2011; 14: 612-622
        • Khodabandehloo H
        • Seyyedebrahimi S
        • Esfahani EN
        • Razi F
        • Meshkani R
        Resveratrol supplementation decreases blood glucose without changing the circulating CD14+ CD16+ monocytes and inflammatory cytokines in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study.
        Nutrition Research. 2018; 54: 40-51
        • Jadad AR
        • Moore RA
        • Carroll D
        • et al.
        Assessing the quality of reports of randomized clinical trials: is blinding necessary?.
        Controlled clinical trials. 1996; 17: 1-12
        • R Neves A
        • Lucio M
        • LC Lima J
        • Reis S
        Resveratrol in medicinal chemistry: a critical review of its pharmacokinetics, drug-delivery, and membrane interactions.
        Current medicinal chemistry. 2012; 19: 1663-1681
        • de Ligt M
        • Timmers S
        • Schrauwen P
        Resveratrol and obesity: can resveratrol relieve metabolic disturbances?.
        Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 2015; 1852: 1137-1144
        • Szkudelski T
        • Szkudelska K
        Anti‐diabetic effects of resveratrol.
        Annals of the New York Academy of Sciences. 2011; 1215: 34-39
        • Liu K
        • Zhou R
        • Wang B
        • Mi MT
        Effect of resveratrol on glucose control and insulin sensitivity: a meta-analysis of 11 randomized controlled trials.
        The American journal of clinical nutrition. 2014; 99: 1510-1519
        • Liu K
        • Zhou R
        • Wang B
        • Mi M-T
        Effect of resveratrol on glucose control and insulin sensitivity: a meta-analysis of 11 randomized controlled trials.
        The American journal of clinical nutrition. 2014; 99: 1510-1519
      1. Zhao Y, Chen B, Shen J, Wan L, Zhu Y, Yi T. The Beneficial Effects of Quercetin, Curcumin, and Resveratrol in Obesity. 2017;2017:1459497.

        • Jeon BT
        • Jeong EA
        • Shin HJ
        • et al.
        Resveratrol attenuates obesity-associated peripheral and central inflammation and improves memory deficit in mice fed a high-fat diet.
        Diabetes. 2012; 61: 1444-1454
        • Jimenez-Gomez Y
        • Mattison JA
        • Pearson KJ
        • et al.
        Resveratrol improves adipose insulin signaling and reduces the inflammatory response in adipose tissue of rhesus monkeys on high-fat, high-sugar diet.
        Cell metabolism. 2013; 18: 533-545
        • Kim S
        • Jin Y
        • Choi Y
        • Park T
        Resveratrol exerts anti-obesity effects via me chanisms involving down-regulation of adipogenic and inflammatory processes in mice.
        Biochemical pharmacology. 2011; 81: 1343-1351
        • Lee S-M
        • Yang H
        • Tartar D
        • et al.
        Prevention and treatment of diabetes with resveratrol in a non-obese mouse model of type 1 diabetes.
        Diabetologia. 2011; 54: 1136-1146
        • Kim M
        • Lim J
        • Youn H
        • et al.
        Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK–SIRT1–PGC1α axis in db/db mice.
        Diabetologia. 2013; 56: 204-217
        • Li Z
        • Diehl A
        Innate immunity in the liver.
        Current opinion in gastroenterology. 2003; 19: 565-571
        • Hotamisligil GS
        • Shargill NS
        • Spiegelman BM
        Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance.
        Science. 1993; 259: 87-91
        • Lesmana CRA
        • Hasan I
        • Budihusodo U
        • et al.
        Diagnostic value of a group of biochemical markers of liver fibrosis in patients with non‐alcoholic steatohepatitis.
        Journal of digestive diseases. 2009; 10: 201-206
        • Li Z
        • Yang S
        • Lin H
        • et al.
        Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease.
        Hepatology. 2003; 37: 343-350
        • Yang SJ
        • Lim Y
        Resveratrol ameliorates hepatic metaflammation and inhibits NLRP3 inflammasome activation.
        Metabolism. 2014; 63: 693-701
        • Libby P
        • Ridker PM
        • Maseri A
        Inflammation and atherosclerosis.
        Circulation. 2002; 105: 1135-1143
        • Li J
        • Xie C
        • Zhuang J
        • et al.
        Resveratrol attenuates inflammation in the rat heart subjected to ischemia-reperfusion: Role of the TLR4/NF-κB signaling pathway.
        Molecular medicine reports. 2015; 11: 1120-1126
        • Wakabayashi I
        • Takeda Y
        Inhibitory effects of resveratrol on MCP-1, IL-6, and IL-8 production in human coronary artery smooth muscle cells.
        Naunyn-Schmiedeberg's archives of pharmacology. 2013; 386: 835-839
        • Song R
        • Li WQ
        • Dou JL
        • et al.
        [Resveratrol reduces inflammatory cytokines via inhibiting nuclear factor-kappaB and mitogen-activated protein kinase signal pathway in a rabbit atherosclerosis model].
        Zhonghua xin xue guan bing za zhi. 2013; 41: 866-869
        • Deng YH
        • Alex D
        • Huang HQ
        • et al.
        Inhibition of TNF‐α‐mediated endothelial cell–monocyte cell adhesion and adhesion molecules expression by the resveratrol derivative, trans208;3, 5, 4′‐trimethoxystilbene.
        Phytotherapy research. 2011; 25: 451-457
        • Dong W
        • Yang R
        • Yang J
        • et al.
        Resveratrol pretreatment protects rat hearts from ischemia/reperfusion injury partly via a NALP3 inflammasome pathway.
        International journal of clinical and experimental pathology. 2015; 8: 8731
        • Cong X
        • Li Y
        • Lu N
        • et al.
        Resveratrol attenuates the inflammatory reaction induced by ischemia/reperfusion in the rat heart.
        Molecular medicine reports. 2014; 9: 2528-2532
        • Cheng L
        • Jin Z
        • Zhao R
        • Ren K
        • Deng C
        • Yu S
        Resveratrol attenuates inflammation and oxidative stress induced by myocardial ischemia-reperfusion injury: role of Nrf2/ARE pathway.
        International journal of clinical and experimental medicine. 2015; 8: 10420
        • Ren Z
        • Wang L
        • Cui J
        • et al.
        Resveratrol inhibits NF-kB signaling through suppression of p65 and IkappaB kinase activities.
        Die Pharmazie. 2013; 68: 689-694