Alcohol consumption and immunity
Scientific interest in investigating the beneficial health effects of moderate alcohol consumption started in the late 1950 s with the Seven Countries Study Reference Keys1. Since then, numerous epidemiological studies have corroborated the inverse relationship between moderate alcohol intake and cardiovascular risk morbidity and mortality. Regarding the immune system, researchers have long discussed how alcoholic beverages can affect host defence. Alcohol can directly suppress various immune responses, and clinical studies have found alcohol abuse to be associated with an increased incidence of a number of infectious diseasesReference Ahmed2, Reference Szabo3. Although the acute and chronic use of alcohol is deleterious for health and generally viewed as being immunosuppressive, it is not clear that documented alcohol-elicited changes in immune function are of clinical significanceReference MacGregor4. There are several studies supporting an increased incidence of infections among alcoholicsReference Szabo3, Reference Straus and Berenyi5, but these relations are often attributed to concomitant complications of alcoholism, including nutritional deficiencies, gastrointestinal and hepatic conditions and socioeconomic statusReference Watzl and Watson6.
On the other hand, moderate alcohol consumption (up to three to four drinks per day) has been associated with either no riskReference Engs and Aldo-Benson7 or a decreased risk for upper respiratory infectionsReference Cohen, Tyrrell, Russell, Jarvis and Smith8. Since moderate alcohol consumption has been suggested to have a beneficial impact on the immune system compared to alcohol abuse or abstinenceReference Cohen, Tyrrell, Russell, Jarvis and Smith8–Reference Romeo, Warnberg, Díaz, González-Gross and Marcos12, the link between alcohol consumption, immune response, as well as infectious and inflammatory processes remains controversial and not yet completely understood. In reviewing the literature, it is important to realise that other factors, unrelated or indirectly related to immune function, such as drinking pattern, amount of alcohol, beverage type or gender differences, are directly implicated in the relationship between alcohol consumption and the immune systemReference Diaz, Montero, González-Gross, Vallejo, Romeo and Marcos10–Reference Jimenez, Cardinali, Alvarez, Fernandez, Boggio and Esquifino13 (Fig. 1). This review summarises published evidence of how moderate alcohol consumption can play a role in the regulation of the immune response in healthy adults, and the determinants of this modulation (Table 1).
* Amount of alcohol or beverage considered as a moderate consumption of alcohol.
Amount of alcohol
There are several mechanisms by which alcohol can affect immunity. Alcohol seems to impair the ability of white blood cells to migrate to sites of injury and infection, to induce functional abnormalities of T and B lymphocytes, natural killer cells and monocytes/macrophages, and to alter cytokine productionReference Bautista14–Reference Szabo16. However, despite the fact that both cell-mediated and humoral immune responses have been shown to be depleted in high-dose consumers of alcoholReference Budec, Ciric, Koko and Asanin17, Reference Cook18, studies in humans and experimental animals suggest that low-doses of ethanol may enhance the immune responseReference Mendenhall, Theus, Roselle, Grossman and Rouster9, Reference Romeo, Warnberg, Nova, Díaz, González-Gross and Marcos11, Reference Romeo, Warnberg, Díaz, González-Gross and Marcos12. In humans, a moderate intake of alcohol in individuals exposed to rhinoviruses was associated with a decreased risk of developing the common cold, suggesting that moderate consumption of alcohol may enhance the immune response, resulting in a more effective host defenceReference Cohen, Tyrrell, Russell, Jarvis and Smith8. This enhancing effect might depend on the type of beverage (whether it is fermented or distilled), as well as on the amount and duration of ethanol intake.
With regard to cell-mediated immunity, a reduction in CD3+, CD4+, and CD8+ cell numbers has been found after chronic alcohol administration in male ratsReference Boyadjieva, Dokur, Advis, Meadows and Sarkar19. In contrast, in humans an increase in absolute values of the CD3+ lymphocytes has been recently found after 30 days of moderate beer consumptionReference Romeo, Warnberg, Nova, Díaz, González-Gross and Marcos11. Although the first study was made in animals, and the second in humans, the results suggest that the effect of alcohol intake on T lymphocyte subsets may depend on the amount consumed.
Cytokines are signalling proteins produced in response to infection or cell damage. The presence of damaged cells triggers the body's defence responses, including the release of cytokines, resulting in a vicious cycle of inflammation, cell death and scarring. Alcoholic pathology is well known to be associated with a disruption in cytokine balance and functionsReference Deaciuc15, Reference Dominguez-Santalla, Vidal, Vinuela, Perez and Gonzalez-Quintela20, Reference Crews, Bechara and Brown21. Increased serum tumour necrosis factor (TNF)-α and interleukin (IL)-6 concentrations together with decreased IL-10, interferon (IFN)-γ and IL-2 levels have frequently been found in alcoholic patients with liver cirrhosisReference Gonzalez-Quintela, Dominguez-Santalla, Perez, Vidal, Lojo and Barrio22, Reference Daniluk, Szuster-Ciesielska, Drabko and Kandefer-Szerszen23. After an intervention of 30 days of moderate beer consumption in humans, an increased production of IL-2, IL-4, IL-10 and IFN-γ was foundReference Romeo, Warnberg, Nova, Díaz, González-Gross and Marcos11. Similarly, an in vitro study has suggested that some of beneficial health effects of moderate beer intake may relate to its ability to interfere with pro-inflammatory cytokine cascadesReference Winkler, Wirleitner, Schroecksnadel, Schennach and Fuchs24. Moreover, Mandrekar and co-workers have suggested that moderate alcohol consumption (2 ml vodka/kg body weight) has dual anti-inflammatory effects that involve augmentation of IL-10 and attenuation of monocyte inflammatory responsesReference Mandrekar, Catalano, White and Szabo25.
These results could support a role, via an anti-inflammatory mechanism, for moderate alcohol intake in cardiovascular disease (CVD) prevention. This outcome underscores the importance of taking into account the amount of alcohol consumption when evaluating the immune response. Therefore, further studies focused on drinking pattern are necessary to elucidate the effect of moderate alcohol consumption on the immune response.
It is important to highlight other components like polyphenols, antioxidants and vitamins present in beer or wineReference González-Gross, Lebrón and Marcos26, Reference Percival and Sims27, when studying the health effects of these beverages. Ethanol may be detrimental to immune cells due to the generation of free radicals during clearance; however, alcoholic beverages containing antioxidants should be protective against immune cell damageReference Percival and Sims27, Reference Fenech, Stockley and Aitken28. One of the main topics that needs further research, therefore, is the clarification of how different types of alcoholic and non-alcoholic beverages influence specific biological markers, in order to differentiate which effects are due to the alcohol per se and which could be related to other components. In animal models, the consumption of ethanol only led to lower levels of white blood cells; however, the same amount of alcohol consumed as red wine resulted in no suppression of the immune response. This could be due to the action of certain compounds in red wine that could be contributing to prevent suppression of the immune system caused by alcoholReference Percival and Sims27. Similarly, wine intake, especially red wine, has been identified as having a protective effect against the common coldReference Takkouche, Regueira-Mendez, Garcia-Closas, Figueiras, Gestal-Otero and Hernan29. Nevertheless, this remains controversial. Daily moderate consumption of alcohol (500 ml of a 12 % ethanol dilution), and 500 ml of red wine, red grape juice, and dealcoholised red wine for 2 weeks at doses which inversely correlate with CVD risk did not show any effects on human immune cell functionsReference Watzl, Bub, Pretzer, Roser, Barth and Rechkemmer30. However, the design of this study could be questioned since the duration may have been insufficient to affect the immune system; probably it would take up to six weeks to see changes and differences in the immune system.
In the MONICA study, an epidemiological study, moderate consumption of either wine or beer appeared to be associated with lower levels of systemic inflammatory markers in three different European areas (Germany, Scotland, and France). Although the authors have suggested that ethanol itself might be largely responsible for the potential anti-inflammatory effects of these beveragesReference Imhof, Woodward, Doering, Helbecque, Loewel, Amouyel, Lowe and Koenig31, this remains controversial due to the high content of polyphenols and antioxidant vitamins in the these types of fermented alcoholic beverages. After moderate red wine consumption, as compared with gin, a more pronounced decrease in TNF-α-induced adhesion of monocytes to endothelial cells has been observedReference Badía, Sacanella, Fernández-Solá, Nicolás, Antúnez, Rotilio, de Gaetano, Urbano-Márquez and Estruch32. Moreover, Estruch and co-workersReference Estruch, Sacanella, Badia, Antúnez, Nicolás, Fernández-Solá, Rotilio, de Gaetano, Rubin and Urbano-Márquez33 found an additional anti-inflammatory effect by decreasing C-reactive protein (CRP), as well as monocyte and endothelial adhesion molecules, after 28 days of red wine intake compared to gin with the same amount of ethanol (30 g per day).
In fermented alcoholic beverages, apart from alcohol and polyphenols in red wine (quercetin, rutin, catechin, epicatechin and resveratrol), other relevant components (for example, in beer) that could also influence the immune system are total carbohydrate and soluble fiber content, minerals, trace elements and vitamins such as phosphorous, silicon, magnesium, potassium, niacin, riboflavin, piridoxin, folates and vitamin B12Reference González-Gross, Lebrón and Marcos26, Reference Vinson, Mandarano, Hirst, Trevithick and Bose34–Reference Nardini, Natella, Scaccini and Ghiselli36.
Generally, women seem to be more susceptible to autoimmune or inflammatory diseases, although they have a lower risk of infections than men, especially during the pre-menopausal years. This can be attributed to women's high levels of oestrogens that help to stimulate immunity and fight diseaseReference Wilder37–Reference Liu, Loo, Palaszynski, Ashouri, Lubahn and Voskuhl40. One mechanism by which oestrogens could modulate the immune reaction is by regulating cytokine expressionReference Ciesielska39 and reducing pro-inflammatory cytokinesReference Liu, Loo, Palaszynski, Ashouri, Lubahn and Voskuhl40. Several studies have directly examined gender differences in the effects of alcohol on inflammatory and immune responses reporting that females exhibit greater sensitivity to alcohol than malesReference Romeo, Warnberg, Nova, Díaz, González-Gross and Marcos11, Reference Grossman, Nienaber, Mendenhall, Hurtubise, Roselle, Rouster, Weber, Schmitt and Gartside41–Reference Colantoni, Idilman, De Maria, La Paglia, Belmonte, Wezeman, Emanuele, Van Thiel, Kovacs and Emanuele43. Combined differences in pharmacokinetics may increase the vulnerability of women to the effects of ethanol. The mechanisms that may underlie these differences could be gender differences in the physiological processing and metabolic clearance of alcohol and differential sensitivity of the nervous system to alcohol. Some researchers have suggested that differences are mainly due to a lower alcohol-dehydrogenase activity in women, rather than to differences in gastric emptying or in the hepatic oxidation of ethanolReference Baraona, Abittan, Dohmen, Moretti, Pozzato, Chayes, Schaefer and Lieber44. Furthermore, there is also evidence implicating the direct involvement of hormones in the gender differences observed regarding alcohol consumption. Heavy drinking has been suggested to depress oestrogen levels, nullifying oestrogen's beneficial effects on the immune system, and weakening a woman's ability to fight infectionsReference Kovacs and Messingham45 and Colantoni and co workersReference Colantoni, Idilman, De Maria, La Paglia, Belmonte, Wezeman, Emanuele, Van Thiel, Kovacs and Emanuele43 also suggested the role for plasma testosterone levels as liver protector from ethanol-induced oxidative. After one month of moderate beer consumption, women have been found to have increased numbers of leukocytes, neutrophils lymphocyte and CD3+ cells as compared to menReference Romeo, Warnberg, Nova, Díaz, González-Gross and Marcos11. There is clearly a need for a better understanding of the biological mechanisms underlying gender differences in ethanol consumption.
Conclusions and perspectives
There is enough evidence to suggest that there are some compounds in polyphenolic-rich alcoholic beverages such as wine or beer that prevent suppression of the immune system or could trigger a protective effect. In other words, healthy adults who regularly consume a low to moderate amount of beer or red wine could be less prone to infections, and an anti-inflammatory effect could be one explanatory factor of the protective effects of moderate consumption on CVD. Yet some issues remained unresolved and require further research. The effects on the immune system may be due not only to the small amount of alcohol but also to the antioxidants and other components in these types of beverages. Intervention studies might help to elucidate the mechanisms by which moderate alcohol consumption exerts an immunomodulatory effect. However, since interventional endpoint studies in humans are not feasible because of ethical concerns, prospective observational studies are also required to assess the long-term dose-response relationship. Finally, we would like to stress the fact that although the moderate consumption of beer or wine seem to exert some benefits on the immune response in healthy adults, given the serious health risks associated with exceeding two drinks per dayReference LaPorte, Cresanta and Kuller46, increased alcohol consumption cannot be recommended. In addition, it is important to highlight that the messages related to the benefits of moderate consumption of alcohol have always been addressed to adult populations. Children, adolescents, pregnant women and elderly people are recommended not to drink any beverage containing alcohol.
Conflict of interest statement
AM has research funding from Cerveza y Salud Information Centre, the Spanish arm of European Brewers Association, and is a member of the Cerveza y Salud Scientific Committee. JR has had student support and research grants from Cerveza y Salud Information Centre. JW, EN, LED and SG have no conflicts of interest to declare. The review was co-written by all authors.