Critique 212: Is it the alcohol or other substances in wine that lead to its beneficial health effects? — 15 March 2018

Fragopoulou E, Cholevaa M, Antonopoulou S, Demopoulos CA.   Wine and its metabolic effects. A comprehensive review of clinical trials.  Metabolism Clinical and Experimental 2018;83:102-119.

 Authors’ Abstract

The introduction of the term “French Paradox” motivated an extensive and in-depth research into health benefits of moderate wine consumption. The superiority of wine is thought to be attributed to its micro-constituents and consequent effort was made to isolate and identify these bioactive compounds as well as to elucidate the mechanisms of their action.

Controlled trials offer more concrete answers to several raised questions than observational studies. Under this perspective, clinical trials have been implemented, mainly in healthy volunteers and rarely in patients, in order to investigate the acute or chronic effect of wine consumption on metabolism and physio-pathological systems, which are mainly associated with cardiovascular diseases.

The aim of this review is to update the knowledge about the acute and long term effect of wine consumption on lipid and glucose/insulin metabolism as well as on the inflammatory and haemostatic systems, based on the reported data of controlled clinical trials. In conclusion, the most repeated result of wine consumption is on lipid metabolism, attributed mainly to ethanol, while wine micro-constituents seem to have an important role mainly in haemostatic and inflammatory/endothelial systems.

Forum Comments

Forum members agreed that this was an excellent paper, summarizing potential differences between health effects associated with wine in comparison with those related just to the alcohol in wine and other alcoholic beverages. Among the effects on lipids, data suggest that it is the alcohol in wine that primarily affects HDL-cholesterol, as essentially all studies show that this lipid is increased among consumers of all types of alcoholic beverage.

For the effects on glucose metabolism, a number of studies report that effects specific to wine are found especially in older or diabetic subjects; some suggest that it may occur only among subjects with slow ethanol metabolism. Such effects are probably related to both alcohol and the polyphenols present in wine.

For hemostatic system effects, Forum members agree with the authors’ conclusion that both red and white wines have more favorable effects on platelet aggregation, and on many other coagulation factors, than alcohol itself. A number of studies suggest separate beneficial effects of both alcohol (Booyse et al, 1999) and certain wine polyphenols on fibrinolysis, a critical factor for the development of cardiovascular disease.  As stated by Booyse et al in 2007, “Our research has identified and defined a molecular mechanism by which moderate levels of alcohol or individual wine components (i.e., principal red wine polyphenols, catechins, and quercetin) induce increased t-PA expression, resulting in increased endothelial cell-induced fibrinolysis.  However, the authors of the present paper concluded that it is alcohol, and not other wine constituents, that has the primary effect.  As for inflammatory markers, the authors consider that CRP is lowered by both alcohol and wine, but certain other factors (e.g., adhesion molecules) appear to be better reduced by wine.

The authors also report on post-prandial, short-term effects from intervention studies, but it appears that the small numbers of subjects studied, and differences in study design, make it difficult to make firm conclusions. As stated, HDL effects are mainly from alcohol, but studies often do not clearly separate wine effects from alcohol effects.  For adiponectin, inflammation, and endothelial function, however, it appears that wine has definite advantages over alcohol alone.  (It is appreciated that in observational studies it is often difficult to separate the effects of the multiple constituents of wine in comparison with the effects only of alcohol, as alcohol may enhance the absorption or physiologic effects of the various constituents.)

Specific comments by Forum members: Forum member Finkel found the paper “very attractive,” but commented: “The protective effect of wine was reported long before 1979, as stated by the authors.  Nevertheless, this paper can be an important resource, a stepping stone to further our understanding in a still embryonic field.”

Reviewer Waterhouse referred to a quotation from a paper by Klatsky for a much earlier reference to wine and cardiovascular disease and the “French Paradox.” According to Klatsky et al, “In 1819 Dr. Samuel Black, an Irish physician interested in angina pectoris was perceptive about epidemiologic aspects of wine and disease.  Noting much angina in Ireland but observing little discussion in  the  writings  of  French  physicians,  his  explanation of the presumed disparity was due to ‘the French habits and modes of living, coinciding with the benignity of their climate  and  the  peculiar  character  of  their  moral  affections.’”  Forum member de Gaetano suggests that the first observation that moderate wine consumption can have beneficial health effects is much earlier: “It is reported in Homer’s Odyssey that when Odysseus (Ulysses) escaped the cavern of Polyphemus, it was thanks to an important difference between the two – Odysseus was able to drink wine in moderation, while Polyphemus was not and passed out from drunkenness.”  (And was subsequently blinded by Odysseus.)

Reviewer Goldfinger wrote: “I too like this paper a lot. It addresses, but certainly doesn’t answer the question of, mechanistic differences between wine and other alcoholic beverages. The authors approach the topic honestly, concluding, ‘It is difficult to distinguish the action of ethanol from the one of wine micro-constituents.’  I also like their touching on the subject of trials comparing wine to dealcoholized wine, raising concern of likely different pattern of absorption of non-alcohol components.

“It has been my understanding that important polyphenolic compounds have enhanced absorption in combination with ethanol. This publication lends credibility to the presumption that wine in the better alcoholic beverage for health, although teasing this out has always been a difficult task, as ethanol itself is robust.  I believe it was Serge Renaud who published the observation that alcohol reduced ischemic strokes, but increased hemorrhagic strokes, and, reduced heart attack risk (a thrombogenic event), but not necessarily angina pectoris (an endothelial/supply-demand event) identifying specific mechanisms attributed to alcohol.  The present paper has no definitive answers, but excellent intellectual discussion.”

Waterhouse noted: “I think we can say that since fruit consumption is related to reduced cardiovascular disease, and fruit is the major dietary source of phenolics (wine is made from grapes), then it is reasonable to infer that those same substances in wine will have a similar health benefit (Zhao et al). Further, wine is high in glycerol, approaching 1%, and the impact of wine on lipid metabolism might be related to its presence as well as that of ethanol (Xue et al).”

Forum member Mattivi wrote: “This review is a dense, comprehensive compendium of present knowledge on the effect of wine consumption on several clinical parameters or accepted proxies. It is lacking insight on the mechanistic aspects, in particular for those associated with so-called wine micro-constituents.  As the authors correctly state in their conclusion, ‘Future research should be directed towards the identification of wine micro-constituents’ catabolites.’  I would emphasize that this latter aspect is absolutely due, since virtually none of the wine micro-constituents circulates in the human biofluids in their native form.

“Some vascular effects are a clear example of that. Wine’s micro-constituents other than ethanol seem to be responsible for the endothelial function improvement and this effect closely mirrors the demonstrated (and accepted from EFSA) effect of the metabolites of cocoa procyanidins, which are also in the pool of the main microbial catabolites of wine, proanthocyanidins.  Some of the common effects of wine and our plant food are likely mediated by the same pool of (mostly microbial) metabolites.”

Forum member Van Velden stated: “These results resonate with our research on the cardioprotective effects of wine on cardiovascular disease and diabetes. We agree that the effect on lipid metabolism is due to ethanol that raises the HDL-C fraction.  In wine the glucose (sucrose) is fermented into alcohol, hence the beneficial effects for diabetic patients.  With the emphasis on the low carb / high fat diet, wine does not increase the triglycerides as much as grape juice does.  It is in tune with the recommendation to limit the intake of refined sugars in the diet, and to allow moderate amounts of saturated fat (butter and animal fat) in the prudent diet.

“The polyphenolic compounds such as resveratrol and quercetin are responsible for the anti-coagulant effects of wine. The important thing about the Mediterranean diet, is that it is a lifestyle incorporating wine with more fruit and vegetables, less meat, more fish with omega-3 fatty acids, and exercise.  Our research comparing wine and brandy confirmed the findings of this study; wine is better!”

Forum member de Gaetano also stated that their own studies strongly support the findings in this review article: “We found that wine (30 g/daily for 30 days) was anti-inflammatory and inhibited inflammatory cell adhesion and function in healthy volunteers, while gin (30 g/daily) did not. Both beverages however, similarly reduced lipid parameters (Badia et al; Estruch et al).  Further, in animal experiments and in vitro studies, wine and de-alcoholated wine stimulated the production of nitric oxide (NO) — a potent vasodilator and platelet aggregation inhibitor, and the basis of the drug, Viagra — by endothelial cells (Wollny et al; Gresele et al).”

References from Forum review

Badía E, Sacanella E, Fernández-Solá J, Nicolás JM, Antúnez E, Rotilio D, de Gaetano G, Urbano-Márquez A, Estruch R. Decreased tumor necrosis factor-induced adhesion of human monocytes to endothelial cells after moderate alcohol consumption.  Am J Clin Nutr 2004;80:225-30.

Black, S. Clinical and pathological reports. 1819.  Alex Wilkinson, Newry, England: 1–47.

Booyse FM, Aikens ML, Grenett HE. Endothelial Cell Fibrinolysis: Transcriptional Regulation of Fibrinolytic Protein Gene Expression (t-PA, u-PA, and PAI-1) by Low Alcohol.  Alcoholism: Clinical & Experimental Research 1999; 23:1119–1124.  DOI: 10.1111/j.1530-0277.1999.tb04235.x

Booyse FM, Pan W, Grenett HE, Parks DA, Darley-Usmar VM, Bradley KM, Tabengwa EH. Mechanism by which Alcohol and Wine Polyphenols Affect Coronary Heart Disease Risk.  Ann Epidemiol 2007;17:S24–S31.

Estruch R, Sacanella E, Badia E, Antúnez E, Nicolás JM, Fernández-Solá J, Rotilio D, de Gaetano G, Rubin E, Urbano-Márquez A. Different effects of red wine and gin consumption on inflammatory biomarkers of atherosclerosis: a prospective randomized crossover trial. Effects of wine on inflammatory markers.  Atherosclerosis 2004;175:117-123.

Gresele P1, Cerletti C, Guglielmini G, Pignatelli P, de Gaetano G, Violi F. Effects of resveratrol and other wine polyphenols on vascular function: an update.  J Nutr Biochem 2011;22:201-211. doi: 10.1016/j.jnutbio.2010.07.004

Klatsky A. Alcohol and Cardiovascular Health. Intergr Comp Biol 2004;44:324-328.

Wollny T, Aiello L, Di Tommaso D, Bellavia V, Rotilio D, Donati MB, de Gaetano G, Iacoviello L. Modulation of haemostatic function and prevention of experimental thrombosis by red wine in rats: a role for increased nitric oxide production.  Br J Pharmacol 1999;127:747-755.

Xue LL, Chen HH, Jiang, JG. Implications of glycerol metabolism for lipid production.  Progress in Lipid Research 2017;68:12-25.  DOI: 10.1016/j.plipres.2017.07.002

Zhao CN, Meng X, Li Y, Li S, Liu Q, Tang GY, Li HB. Fruits for prevention and treatment of cardiovascular diseases.  Nutrients 2017;9:29.

Forum Summary

While epidemiologists have long noted that consumers of wine tend to have better health outcomes than consumers of other alcoholic beverages, it has always been of concern that we were comparing drinkers, and not the drink itself. In recent years, many basic scientists have evaluated the non-alcoholic constituents in wine, and most studies show beneficial health effects from polyphenols and other components in wine as well as beneficial health effects from the alcohol in wine.

The present study provides an excellent review of clinical trials that compared the effects of wine versus no intervention or versus the effects of other alcoholic beverages. The specified outcomes related to effects on lipids, glucose/insulin metabolism, hemostatic mechanisms, and inflammatory/endothelial systems. The authors conclude that “The most repeated result of wine consumption is on lipid metabolism, attributed mainly to ethanol, while wine micro-constituents seem to have an important role mainly in haemostatic and inflammatory/endothelial systems.”  Forum members cite several other important effects of wine micro-constituents, including demonstrated effects of such components at the cellular, molecular, and gene levels to sustain increased fibrinolytic activity, which is closely related to the development of cardiovascular disease.

Forum members were unanimous is considering that this was an excellent review of human clinical trials on the topic; the paper does not, however, comment on the mechanisms by which micro-constituents may operate to improve health.   Given that since virtually none of the wine micro-constituents circulates in the human biofluids in their native form, it is especially important that the catabolites of wine micro-constituents be better defined and evaluated.

Overall, current data indicate that wine may be especially effective in lowering the risk of cardiovascular disease not only through the alcohol it contains, but also from a number of its key polyphenols. Forum members also point out that, for beneficial health effects of any type of alcoholic beverage, the pattern of drinking is especially important: the consumption of small or moderate amounts on a regular basis, and preferably with food.

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The following members provided input for this critique by the International Scientific Forum on Alcohol Research:

Andrew L. Waterhouse, PhD, Department of Viticulture and Enology, University of California, Davis, USA

David Van Velden, MD, Dept. of Pathology, Stellenbosch University, Stellenbosch, South Africa

David Vauzour, PhD, Senior Research Associate, Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, UK

Fulvio Ursini, MD.  Dept. of Biological Chemistry, University of Padova, Padova, Italy 

Creina Stockley, PhD, MSc Clinical Pharmacology, MBA; Health and Regulatory Information Manager, Australian Wine Research Institute, Glen Osmond, South Australia, Australia

Fulvio Mattivi, MSc, CAFE – Center Agriculture Food Environment, University of Trento, via E. Mach 1, San Michele all’Adige, Italy

Tedd Goldfinger, DO, FACC, Desert Cardiology of Tucson Heart Center, University of Arizona School of Medicine, Tucson, AZ, USA

Harvey Finkel, MD, Hematology/Oncology, Retired (Formerly, Clinical Professor of Medicine, Boston University Medical Center, Boston, MA, USA)

R. Curtis Ellison, MD, Professor of Medicine, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA

Giovanni de Gaetano, MD, PhD, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo NEUROMED, Pozzilli, Italy