Critique 234: Effects of red wine consumption on gut microbiota that affect health and disease – 14 November 2019

Le Roy CI, Wells PM, Si J, Raes J, Bell JT, Spector TD.  Red wine consumption associated with increased gut microbiota ɑ-diversity in 3 independent cohorts.  Gastroenterology 2019.  In press, doi.org/10.1053/j.gastro.2019.08.024

 Authors’ Comments from Paper

 “Moderate red wine intake has been shown to exert beneficial effects on metabolic health, mostly attributed to red wine’s rich and varied polyphenol content.  We aimed to investigate and compare the effect of various alcoholic drinks on the gut microbiota (GM) and subsequent health outcomes in large population-based cohorts.

“We used a discovery cohort of 916 UK female individuals (TwinsUK) using a linear mixed effect model adjusted for age, BMI, Healthy Eating Index, education, and family structure.  Alcohol consumption was derived from food frequency questionnaires.  Alcohol patterns associated with ɑ-diversity were evaluated on GM beta-diversity using permutational multi-variate analysis of variance on Bray-Curtis dissimilarity matrix, and their association with 85 genera present in at least 10% of the population, when ɑ-diversity was considered as a mediator of the association between alcohol consumption and BMI or blood fasting glucose, insulin, total cholesterol, chylomicron, LDL, and HDL levels.  Replications were sought using the Flemish Gut Flora Project (FGFP, n=1,104) and the American Gut Project (n=904), as well as in discordant twin analysis in the discovery cohort.”

In Results, the authors report: “Red wine consumption was positively associated in a frequency-dependent manner with ɑ-diversity, but even rare consumption showed an effect.  White wine also displayed a lesser but suggestive positive association with ɑ-diversity, while we saw no association with other alcohol categories.”

The authors summarize their findings: “Red wine consumption was associated with an increase in gut microbial ɑ-diversity, potentially mediating host BMI reduction in 2 cohorts.  This was not observed in response to any of the other alcohols studied.  These results could be due to the high polyphenol content of red wine, contributing to the global debate about its potential health benefits and further our understanding of gut microbiota mechanisms.”

Forum Comments 

This brief paper supports earlier research relating wine consumption to gut microbiota, and the relation of the latter to obesity and to cardiovascular and other diseases.  Reviewer Finkel states that “These results are in line with the burgeoning studies of the influences of what are living in our guts — just a beginning.  There are other papers in the pipeline on similar matters – for example, the recently released pre-publication paper by Naumovski et al states: “It is without doubt that modifications of 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 a variety of factors (Kumar Singh et al).”  These authors state further: “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 (Poudel et al).”

Naumovski et al also note: “Wine consumption was also associated with better overall nutrition and lifestyle, while 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 (Foscolou et al), a J-shaped relationship with all-cause mortality(Gronbaek et al), and is often associated with the “French Paradox” referring to lower CVD rates despite high saturated fat consumption in the population (Renaud, De Lorgeril).

“However, it is not possible to derive cause and effect due to confounding variables in epidemiological studies such as socio-environmental factors, healthy user bias, and limitations of self-reported dietary collection methods.  Some of these include the diversity of consumed wines and variation in their polyphenolic content that is influenced by variety of factors: even with doses that are exceeding physiologically relevant concentrations, evidence of cardiometabolic effects is inconclusive (Nash et al, Christenson et al).  Therefore, whether moderate to high dosages will exhibit beneficial health effects without negative implications on gut barrier integrity and gut microbiota is still unknown.  This might be further elucidated with technological and research advances in the ‘-omics’ areas where red wine polyphenols by-products might be investigated from the population perspective (Kumar Singh et al).”

Reviewer de Gaetano wrote: “I agree that this is an interesting study combining epidemiology and mechanisms.  I would have appreciated a better definition of spirits.  Some (many…) years ago we compared red wine and gin consumption (Estruch et al).  The latter beverage did not virtually contain any measurable polyphenols.  But other spirits do.  A direct comparison between groups consuming either an alcoholic beverage containing no polyphenol or red wine would have better supported the role of polyphenols, as suggested by the authors.”

Forum member Waterhouse commented: “This is a very interesting study.  The authors control for all sorts of issues, but seem to have forgotten to control for other dietary sources of polyphenols, if that is their hypothesis.  In addition, the major phenolics in red wine are the proanthocyanidins, not resveratrol or gallic acid, the ones discussed in this paper.  The proanthocyanidins are also the major constituents of chocolate, with lesser amounts in apples and a few other foods, with related compounds in tea.  So, it would have been very interesting to try and control for intake of these compounds.

“In addition, there are a number of studies showing a relationship between alcohol consumption and BMI that they seem to have overlooked.  These include Arif & Rohrer, Dumesnil et al, and Barry et al.  So, the relationship between regular alcohol consumption and reduced BMI has already been well documented.”  Reviewer Teissedre noted: “I fully agree with the comments of Waterhouse, and add that we should not forget that red wine also contains sulfur dioxide that should influence the microbiota in the gut.”

Forum member van Velden wrote: “In the 21st century we are confronted with an increase in the incidence of chronic and degenerative diseases due to ageing.  This is due to the effective management of acute diseases with effective antibiotics, etc.  However, the inappropriate use of broad spectrum antibiotics resulted in the destruction of the gut microbiome.  The non-pathological bacteria in the gut have an important function in the immune function by breaking down fibres and other food ingredients and releasing micronutrients that stimulate the body’s immunity.  Probiotics are standard practice to help restore the gut microbiome.

“Higher socio-economic groups with a responsible lifestyle use lifestyle-related interventions such as weight control, no smoking, exercise and a Mediterranean diet rich in fruit and vegetables.  This includes moderate red wine consumption and low consumption of refined carbohydrates.  The anti-oxidant components in red wine have an important role to play in this regard to reduce oxidative stress.  The sugar in the grape juice has been fermented to ethanol.  Nutri-genetics is also an emerging contributing factor in disease expression that has to be taken into consideration.  However, we must be careful to consider mono-interventions in disease causation and prevention, and health promotion.”

Reviewer Djoussé added comments: “This paper helps explain potential biologic effects of red wine on health.  Modulation of gut flora is one step closer to understanding the biologic pathways of red wine.  Unfortunately, the authors were not able to relate alpha diversity with bioactive compounds such as TMAO (produced by gut bacteria) that is known to affect CVD risk.  Nonetheless, a crossover trial of the effects of red wine intervention and TMAO (a choline metabolite derived by gut bacteria known to adversely affect CVD risk and prognosis in CHF) is listed on Clinical trial.gov, but no findings yet (unless I missed them).  Furthermore, resveratrol has been reported to reduce TMA production (Chen et al).  Definitely an interesting study.”

Reviewer Puddey noted: “I am in agreement with the commentary (and caveats) that accompany the forum critique of this article.  I would also note that authors of this paper have previously documented other aspects of the gut microbiome as a potential determinant of human health using TwinsUK data that warrant further consideration.  Firstly, Bowyer et al reported on how socio-economic status may influence gut micro-biota, a very relevant confounder if examining associations with alcohol intake, where patterns of drinking and choice of alcoholic beverage may have large socio-economic determinants.  Secondly, Visconti et al have highlighted the importance of not focusing on the taxonomy of the fecal microbiome alone but also its interaction with both the fecal and the systemic metabolic host environment. This will be another major consideration given the wide genetic and gender diversity in alcohol and polyphenol metabolism. This is clearly an interesting area with potential emerging implications for the effects of alcohol and red wine in health and disease.”

References noted in Forum critique:

Arif AA, Rohrer JE.  Patterns of alcohol drinking and its association with obesity: data from the third national health and nutrition examination survey, 1988–1994.  BMC Public Health 2005;5;126. doi:10.1186/1471-2458-5-126

Barry AE, Anna K Piazza-Gardner AK, Holton MK.  Assessing the alcohol–BMI relationship in a US national sample of college students.  Health Education J 2014;74:496-504.  https://doi.org/10.1177/0017896914547289

Bowyer RCE, Jackson MA, Le Roy CI, et al.  Socioeconomic status and the gut microbiome: A TwinsUK Cohort Study. Microorganisms 2019;7

Chen M-L, Yi L, Zhang Y, Zhou X, Ran L, Yang J, Zhu J-D, Zhang QY, Mi M-T, Rey F.  Resveratrol Attenuates Trimethylamine-N-Oxide (TMAO)-Induced Atherosclerosis by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut Microbiota.  mBio 2018;7:e02210-15. doi:10.1128/mBio.02210-15

Christenson J, Whitby SJ, 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;14:323-333

Dumesnil C1, Dauchet L, Ruidavets JB, Bingham A, Arveiler D, Ferrières J, et al.  Alcohol consumption patterns and body weight.  Ann Nutr Metab 2013;62:91-97. doi: 10.1159/000342839

Estruch R1, 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

Foscolou 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;31:1549-1567

Gronbaek 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;133:411-419

Kumar Singh A, Cabral C, Kumar R, et al.  Beneficial Effects of Dietary Polyphenols on Gut Microbiota and Strategies to Improve Delivery Efficiency. Nutrients 2019;11

Liangpunsakul S, Haber P, McCaughan GW. Alcoholic Liver Disease in Asia, Europe, and North America.  Gastroenterology 2016;150:1786-1797

Nash V, Ranadheera CS, Georgousopoulou EN, et al. The effects of grape and red wine polyphenols on gut microbiota – A systematic review. Food Res Int 2018;113:277-287

Naumovski N, Panagiotakos DB, D’Cunha NM.  Untangling the two-way relationship between red wine polyphenols and gut microbiota.  Gastroenterology 2019:pre-publication.  doi: https:// doi.org/10.1053/j.gastro.2019.10.015

Poudel P, Ismailova K, Andersen LB, 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;18:56

Renaud S, de Lorgeril M.  Wine, alcohol, platelets, and the French paradox for coronary heart disease.  Lancet 1992;339:1523-1526

Visconti A, Le Roy CI, Rosa F, et al.  Interplay between the human gut microbiome and host metabolism.  Nat Commun 2019;10:4505

Forum Summary

This brief paper supports earlier research relating wine consumption to gut microbiota, and the relation of the latter to obesity and to cardiovascular and other diseases.  The authors report that “Red wine consumption was positively associated in a frequency-dependent manner with ɑ-diversity, but even rare consumption showed an effect.  White wine also displayed a lesser but suggestive positive association with ɑ-diversity, while we saw no association with other alcohol categories.”  They suggested that these effects of red wine on gut microbiota may play a role in the reduced risk of obesity, cardiovascular disease, and reduced total mortality associated with red wine intake that have been demonstrated in many cohort studies.

An increasing number of studies point to beneficial effects of wine, especially red wine, which may not be present for other types of beverages containing alcohol.  However, we agree with the conclusions of the authors: “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.  The majority of observational studies fail to do this adequately; and thus, results from large scale clinical trials are needed in order to establish a cause and effect relationship between red wine polyphenols and gut microbiota.”

Forum members consider that the present analyses support a beneficial health effect of regular and moderate red wine, but also agree that much further research will be required to work out the complex relation between the consumption of red wine and gut microbiota and the effects on health

*                  *                  *                     *                  *                 *               *                 *              *                *

This critique by the International Scientific Forum on Alcohol Research has been prepared with contributions from the following members:

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

Ian Puddey, MD, Emeritus Professor, Faculty of Health & Medical Sciences, University of Western Australia, Nedlands, Australia

Luc Djoussé, MD, DSc, Dept. of Medicine, Division of Aging, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA, USA

Pierre-Louis Teissedre, PhD, Faculty of Oenology–ISVV, University Victor Segalen Bordeaux 2, Bordeaux, France

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

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

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

Professor Andrzej Pająk, Epidemiology and Population Studies, Jagiellonian University Medical College, Kraków, Poland

Creina Stockley, PhD, MSc Clinical Pharmacology, MBA; Adjunct Senior Lecturer at the University of Adelaide, Australia

Ian Puddey, MD, Emeritus Professor, Faculty of Health & Medical Sciences, University of Western Australia, Nedlands, Australia

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

Ramon Estruch, MD, PhD, Hospital Clinic, IDIBAPS, Associate Professor of Medicine, University of Barcelona, Spain