Untangling the 2-Way Relationship Between Red Wine Polyphenols and Gut Microbiota

Abstract

See “Red wine consumption associated with increased gut microbiota α-diversity in 3 independent cohorts,” by Le Roy CI, Wells PM, Si J, et al, on page 270. See “Red wine consumption associated with increased gut microbiota α-diversity in 3 independent cohorts,” by Le Roy CI, Wells PM, Si J, et al, on page 270. The production of red wine, a product of the Vitis vinifera L grape and one of the most widely consumed beverages around the world, dates back ≥8000 years, principally originating from the Caucasus region between Europe and Asia. Recent evidence from observational studies demonstrates a role for red wine in the promotion of beneficial gut microbiota.1Le Roy C.I. Wells P.M. Si J. et al.Red wine consumption associated with increased gut microbiota α-diversity in 3 independent cohorts.Gastroenterology. 2020; 158: 270-272Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar In this issue of Gastroenterology, Le Roy et al1Le Roy C.I. Wells P.M. Si J. et al.Red wine consumption associated with increased gut microbiota α-diversity in 3 independent cohorts.Gastroenterology. 2020; 158: 270-272Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar report an association between red wine polyphenols and gut microbiota α-diversity, with only weak associations with white wine and no association with beer, cider, spirits, or all alcohol. The authors propose benefits to gut health even from infrequent red wine consumption and suggest a unique interaction between red wine polyphenols and the modulation of gut microbiota, which poses the question of whether long-term trials are warranted to elucidate potential health-promoting effects of red wine consumption. The red wine polyphenols include flavonoids (anthocyanins and flavan-3-ols), nonflavonoids (stilbenes), gallic acid, oligomeric and polymeric proanthocyanins, catechins, and phenolic acid, and are proposed to exhibit health-promoting effects through reduction of oxidative stress and promotion of beneficial gut bacteria.2Kumar Singh A. Cabral C. Kumar R. et al.Beneficial effects of dietary polyphenols on gut microbiota and strategies to improve delivery efficiency.Nutrients. 2019; 11Crossref PubMed Scopus (218) Google Scholar, 3Nash V. Ranadheera C.S. Georgousopoulou E.N. et al.The effects of grape and red wine polyphenols on gut microbiota - a systematic review.Food Res Int. 2018; 113: 277-287Crossref PubMed Scopus (84) Google Scholar, 4Travica N. D'Cunha N.M. Naumovski N. et al.The effect of blueberry interventions on cognitive performance and mood: a systematic review of randomized controlled trials.Brain Behav Immun. 2019 Apr 15; ([Epub ahead of print])Crossref Scopus (46) Google Scholar Once ingested, relatively small amounts of red wine polyphenols are absorbed in the small intestine (5%–10%), with the remainder reaching the colon as the central location of activity and metabolism by the residential microbiota “producing” polyphenolic conjugates that can enter systemic circulation.5Cueva C. Gil-Sanchez I. Ayuda-Duran B. et al.An integrated view of the effects of wine polyphenols and their relevant metabolites on gut and host health.Molecules. 2017; 22Crossref PubMed Scopus (93) Google Scholar However, interindividual differences in the gut microbiota play an important role in bioavailability of polyphenols and their gut microbiota metabolites.6Bolca S. Van de Wiele T. Possemiers S. Gut metabotypes govern health effects of dietary polyphenols.Curr Opin Biotechnol. 2013; 24: 220-225Crossref PubMed Scopus (154) Google Scholar The anti-inflammatory activity of red wine polyphenols is well-defined, and its influence on gut microbiota diversity cannot be seen as single-sided, but rather a 2-way relationship. The gut microbiota is relatively stable through adulthood, but can be affected by antibiotic medications and changes in food intake, and is pivotal for the onset and development of various metabolic and inflammatory conditions.2Kumar Singh A. Cabral C. Kumar R. et al.Beneficial effects of dietary polyphenols on gut microbiota and strategies to improve delivery efficiency.Nutrients. 2019; 11Crossref PubMed Scopus (218) Google Scholar,5Cueva C. Gil-Sanchez I. Ayuda-Duran B. et al.An integrated view of the effects of wine polyphenols and their relevant metabolites on gut and host health.Molecules. 2017; 22Crossref PubMed Scopus (93) Google Scholar The production of red wine includes the skin of the grapes resulting in nearly a 10-fold higher polyphenolic content than white wine. The consumption of red wine polyphenols is controversially associated with multiple health benefits ranging from reduction in cardiovascular disease risk factors, the metabolic syndrome and depression, improved cognition, and health benefits associated with gut microbiota diversity.7Pavlidou E. Mantzorou M. Fasoulas A. et al.Wine: An aspiring agent in promoting longevity and preventing chronic diseases.Diseases. 2018; 6: 73Crossref Google Scholar,8Moreno-Indias I. Sanchez-Alcoholado L. Perez-Martinez P. et al.Red wine polyphenols modulate fecal microbiota and reduce markers of the metabolic syndrome in obese patients.Food Funct. 2016; 7: 1775-1787Crossref PubMed Google Scholar Red wine polyphenols seem to increase populations of beneficial bacteria1Le Roy C.I. Wells P.M. Si J. et al.Red wine consumption associated with increased gut microbiota α-diversity in 3 independent cohorts.Gastroenterology. 2020; 158: 270-272Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar,9Queipo-Ortuno M.I. Boto-Ordonez M. Murri M. et al.Influence of red wine polyphenols and ethanol on the gut microbiota ecology and biochemical biomarkers.Am J Clin Nutr. 2012; 95: 1323-1334Crossref PubMed Scopus (459) Google Scholar while inhibiting potentially pathogenic bacterial populations.9Queipo-Ortuno M.I. Boto-Ordonez M. Murri M. et al.Influence of red wine polyphenols and ethanol on the gut microbiota ecology and biochemical biomarkers.Am J Clin Nutr. 2012; 95: 1323-1334Crossref PubMed Scopus (459) Google Scholar A systematic review of clinical trials published between 2006 and 2018 examined the effects of red wine polyphenols and grapes on gut microbiota.3Nash V. Ranadheera C.S. Georgousopoulou E.N. et al.The effects of grape and red wine polyphenols on gut microbiota - a systematic review.Food Res Int. 2018; 113: 277-287Crossref PubMed Scopus (84) Google Scholar Only 1 included study lasting 20 days reported changes in gut microbiota composition and participants consumed either 272 mL/d of red wine or dealcoholized red wine.9Queipo-Ortuno M.I. Boto-Ordonez M. Murri M. et al.Influence of red wine polyphenols and ethanol on the gut microbiota ecology and biochemical biomarkers.Am J Clin Nutr. 2012; 95: 1323-1334Crossref PubMed Scopus (459) Google Scholar The findings indicated divergence between groups of several different gut microbiota phyla and species, highlighting complexity surrounding the ethanol content in red wine. The other 6 studies reported increased red wine polyphenols microbial metabolites in feces, urine, plasma, and ileal fluid, representing the modulation of red wine polyphenols by intestinal bacteria and further adding another layer of intricacy to the ‘two-way relationship’. Evidence of gut microbiota modulation from observational studies is also increasing.7Pavlidou E. Mantzorou M. Fasoulas A. et al.Wine: An aspiring agent in promoting longevity and preventing chronic diseases.Diseases. 2018; 6: 73Crossref Google Scholar Across 3 cohorts, Le Roy et al1Le Roy C.I. Wells P.M. Si J. et al.Red wine consumption associated with increased gut microbiota α-diversity in 3 independent cohorts.Gastroenterology. 2020; 158: 270-272Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar found improved α-diversity, particularly barnesiella, in discordant twin analyses, which may be associated with improved cholesterol metabolism and body composition. Results from a Danish study of overall wine intake in 720 adolescents with a 20- or 22-year follow-up, reported an association with less weight gain until midlife, but not for beer and spirits.10Poudel P. Ismailova K. Andersen L.B. et al.Adolescent wine consumption is inversely associated with long-term weight gain: results from follow-up of 20 or 22 years.Nutr J. 2019; 18: 56Crossref PubMed Scopus (4) Google Scholar Wine consumption was also associated with better overall nutrition and lifestyle, whereas moderate wine drinkers exhibited better overall health and quality of life. Moderate intake of red wine is recommended as part of the Mediterranean dietary pattern and is associated with successful aging,11Foscolou A. Koloverou E. Matalas A.-L. et al.Decomposition of Mediterranean dietary pattern on successful aging, among older adults: a combined analysis of two epidemiological studies.J Aging Health. 2018; 31: 1549-1567Crossref PubMed Scopus (6) Google Scholar a J-shaped relationship with all-cause mortality,12Gronbaek M. Becker U. Johansen D. et al.Type of alcohol consumed and mortality from all causes, coronary heart disease, and cancer.Ann Intern Med. 2000; 133: 411-419Crossref PubMed Scopus (442) Google Scholar and is often associated with the “French Paradox” referring to lower cardiovascular disease rates despite high saturated fat consumption in this population.13Renaud S. de Lorgeril M. Wine, alcohol, platelets, and the French paradox for coronary heart disease.Lancet. 1992; 339: 1523-1526Abstract PubMed Scopus (3169) Google Scholar However, it is not possible to derive cause and effect owing to confounding variables in epidemiologic studies such as socioenvironmental factors, healthy user bias, and limitations of self-reported dietary collection methods.7Pavlidou E. Mantzorou M. Fasoulas A. et al.Wine: An aspiring agent in promoting longevity and preventing chronic diseases.Diseases. 2018; 6: 73Crossref Google Scholar The benefits of red over white wine are often attributed to resveratrol. Consumption of this stilbene may protect against fat accumulation through inhibition of lipogenesis and increase insulin-mediated glucose uptake, potentially lowering circulating blood glucose levels.14Weiskirchen S. Weiskirchen R. Resveratrol: how much wine do you have to drink to stay healthy?.Adv Nutr. 2016; 7: 706-718Crossref PubMed Scopus (162) Google Scholar A review of resveratrol trials indicated that its supplementation is not sufficient for the management of obesity despite anti-inflammatory effects.15Christenson J. Whitby S.J. Mellor D. et al.The effects of resveratrol supplementation in overweight and obese humans: a systematic review of randomized trials.Metab Syndr Relat Disord. 2016; 14: 323-333Crossref PubMed Scopus (37) Google Scholar The levels of “pure” resveratrol used in short-term trials, if compared with those found in red wine, indicate consumption of well over 2 L of wine required to reach the equimolar levels, leading to health problems owing to alcohol levels consumed.16El-Serag H.B. Lagergren J. Alcohol drinking and the risk of Barrett's esophagus and esophageal adenocarcinoma.Gastroenterology. 2009; 136: 1155-1157Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar In observational studies, beneficial effects of red wine polyphenols are observed at low and moderate regular wine consumption levels, suggesting benefits are only partially owing to resveratrol.1Le Roy C.I. Wells P.M. Si J. et al.Red wine consumption associated with increased gut microbiota α-diversity in 3 independent cohorts.Gastroenterology. 2020; 158: 270-272Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar,2Kumar Singh A. Cabral C. Kumar R. et al.Beneficial effects of dietary polyphenols on gut microbiota and strategies to improve delivery efficiency.Nutrients. 2019; 11Crossref PubMed Scopus (218) Google Scholar It is without doubt that modifications of the gut microbiota are at the intersection between dietary intake and beneficial health outcomes, and understanding the benefits of red wine polyphenols on gut microbiota remains presented with challenges and controversies. Some of these include the diversity of consumed wines and variation in their polyphenolic content that is influenced by variety of factors (Figure 1).2Kumar Singh A. Cabral C. Kumar R. et al.Beneficial effects of dietary polyphenols on gut microbiota and strategies to improve delivery efficiency.Nutrients. 2019; 11Crossref PubMed Scopus (218) Google Scholar Even with doses that are exceeding physiologically relevant concentrations, evidence of cardiometabolic effects is inconclusive.3Nash V. Ranadheera C.S. Georgousopoulou E.N. et al.The effects of grape and red wine polyphenols on gut microbiota - a systematic review.Food Res Int. 2018; 113: 277-287Crossref PubMed Scopus (84) Google Scholar,15Christenson J. Whitby S.J. Mellor D. et al.The effects of resveratrol supplementation in overweight and obese humans: a systematic review of randomized trials.Metab Syndr Relat Disord. 2016; 14: 323-333Crossref PubMed Scopus (37) Google Scholar Therefore, whether moderate to high dosages will exhibit beneficial health effects without negative implications on gut barrier integrity and gut microbiota remains unknown. This might be further elucidated with technological and research advances in the –omics areas, where red wine polyphenols byproducts might be investigated from the population perspective.2Kumar Singh A. Cabral C. Kumar R. et al.Beneficial effects of dietary polyphenols on gut microbiota and strategies to improve delivery efficiency.Nutrients. 2019; 11Crossref PubMed Scopus (218) Google Scholar The influence of red wine polyphenols on gut microbiota is becoming widely recognized; however, further research of low to moderate consumption of red wine polyphenols over more extended periods is necessary to elucidate the impact of various factors, including overall diet composition.17Garcia-Mantrana I. Selma-Royo M. Alcantara C. et al.Shifts on gut microbiota associated to Mediterranean diet adherence and specific dietary intakes on general adult population.Front Microbiol. 2018; 9 (890–890)Crossref PubMed Scopus (268) Google Scholar Red wine consumption should always be studied in the context of the overall dietary habits of individuals to take into account residual confounding and bias.18Liangpunsakul S. Haber P. McCaughan G.W. Alcoholic liver disease in Asia, Europe, and North America.Gastroenterology. 2016; 150: 1786-1797Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar The majority of observational studies fail to do this adequately; and thus, results from large-scale clinical trials are needed to establish a cause-and-effect relationship between red wine polyphenols and gut microbiota. Because high consumption of alcohol is still associated with multiple adverse health effects,19Sookoian S. Pirola C.J. How safe is moderate alcohol consumption in overweight and obese individuals?.Gastroenterology. 2016; 150: 1698-1703.e2Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar it remains to be seen whether long-term trials of red wine can be safely managed in an ethically responsible manner. Red Wine Consumption Associated With Increased Gut Microbiota α-Diversity in 3 Independent CohortsGastroenterologyVol. 158Issue 1PreviewAlcohol consumption leads to adverse health outcomes.1 However, moderate red wine intake has been shown to exert beneficial effects on metabolic health.2 This is mostly attributed to red wine’s rich and varied polyphenol content.3 Polyphenols have antimicrobial properties that can beneficially affect the gut microbiota (GM), which may have a knock-on effect on host health, as proven by animal studies and clinical trials.4 Surprisingly, the consequences of red wine consumption compared to other type of alcoholic beverages on the GM remain poorly explored in epidemiologic studies. Full-Text PDF