The pros and cons of alcohol

The pros and cons of alcohol

Cardiologue et Directeur de la prévention, Institut de Cardiologie de Montréal. Professeur titulaire de clinique, Faculté de médecine de l'Université de Montréal. / Cardiologist and Director of Prevention, Montreal Heart Institute. Clinical Professor, Faculty of Medicine, University of Montreal.30 January 2023

This is an updated version of an article originally published in 2018

Even though alcohol has been a daily part of human existence for millennia, the substance is far from innocuous and in fact has very complex effects on health. This complexity is well illustrated by the J-shaped relationship between the quantity of alcohol consumed and the risk of premature death observed in a large number of epidemiological studies. One large-scale study, carried out among more than 300,000 people followed for nearly 10 years, shows that moderate alcohol consumption (3 to 14 glasses per week for men and 3 to 7 glasses for women) is associated with an approximately 20% lower risk of all-cause mortality compared to non-drinkers (Figure 1). This protective window is very narrow, however, with a rapid increase in mortality risk observed at higher quantities.

Figure 1. Relationship between alcohol consumption and the risk of premature death. The maximum risk reduction observed in the study (– 0.1 log) corresponds to a reduction of approximately 20% in risk. Adapted from Xi et al. (2017).

As a reminder, what is commonly considered a “glass” or a “standard drink” refers to the quantity of alcoholic drink that leads to the absorption of approximately 12 to 15 grams of pure alcohol (Table 1). The size of a glass therefore directly depends on the alcohol content of the drink consumed.

Table 1. Alcohol content of the main types of alcoholic beverages. Adapted from Educ’alcool.

Type of alcoholic beverageOne standard drink equals:
Beer (5% alc/vol)340 mL (12 oz.)
Wine (12% alc/vol)140 mL (5 oz.)
Fortified wine (e.g. Port) (20% alc/vol)85 mL (3 oz.)
Spirits (40% alc/vol) 45 mL (1.5 oz.)

However, the protective effect of low doses of alcohol on mortality has been called into question by a major study recently published in The Lancet. In this study, which analyzed the alcohol consumption habits of about 600,000 drinkers, the authors did not observe a decrease in mortality, even at low amounts of alcohol, but rather a significant increase in the risk of premature death starting at 100 g of alcohol per week, which only equals one drink per day (Figure 2A). In contrast, analysis of the same data revealed a lower risk of cardiovascular mortality, consistent with hundreds of studies that have observed a cardioprotective effect resulting from moderate alcohol consumption (Figure 2B). Nevertheless, the authors suggest that the amounts of alcohol that are currently recommended (1 drink daily for women, two for men) are too high and that these limits should be lowered. Another study, also published in The Lancet, draws similar conclusions, specifically that intake as low as only one glass per day is associated with an increased risk of developing one of the 23 pathologies associated with alcohol consumption, and, according to the authors, that there does not appear to be a safe level of alcohol consumption. Yet, as some experts have pointed out, this approach is a bit “absolutist”, since the increased risk observed at low amounts of alcohol was extremely low, going from 0.914 percent in non-drinkers to 0.918 in those who consumed one glass a day and to 0.977 for those who drank two glasses a day. Therefore, for moderate drinkers, the actual risk associated with alcohol consumption is for all intents and purposes negligible.

Figure 2. Relationship between alcohol consumption (in g per week) and the risk of premature all-cause mortality (A) or cardiovascular mortality (B) calculated from a synthesis of 83 epidemiological studies involving 600,000 participants. Adapted from Wood et al. (2018).

At this stage, it is difficult to say whether these recent studies are superior to previous ones and if moderate alcohol consumption is indeed devoid of any beneficial effects on mortality (see box). Each epidemiological study has its strengths and weaknesses, and the only true method to resolve this ambiguity would be to conduct a randomized clinical study where the health of moderate drinkers could be compared to that of non-drinkers, but such a study is not feasible due to ethical considerations. In any event, a cautious interpretation of all these studies is to state that the negative effects of alcohol should certainly not be trivialized, and that it is important to drink very moderately to take advantage of its potential benefits while avoiding its well-documented harmful effects (Table 2). Historically, the maximum amounts of alcohol considered to be associated with health benefits are 1-3 glasses per day for men and 1-2 glasses per day for women. At these low levels, alcohol increases HDL cholesterol levels, improves glycemic control, and has anticoagulant and anti-inflammatory properties, all of which contributes to reducing the risk of cardiovascular events, notably myocardial infarction. In light of the results of the two studies published in The Lancet, it would seem advisable to slightly lower these limits to 2 glasses a day for men and 1 glass a day for women.

Cardioprotection by alcohol is not a myth

In recent years, a fairly radical current of thought has emerged claiming that the cardiovascular benefits of alcohol are a “myth” and that there is no safe level of consumption. This message, conveyed by organizations such as the WHO and the Canadian Centre on Substance Use and Addiction (CCSA), is, however, based on a rather limited reading of research; for example, in the recent CCSA report, the analysts selected only 16 studies out of more than 5,000 publications available, which necessarily increases the risk of bias. But even under these conditions, the report clearly shows a reduced risk of ischemic heart disease at low levels of alcohol consumption, in agreement with hundreds of major studies that have focused on this issue, including the study published in The Lancet mentioned earlier (Figure 2B). The CCSA’s conclusion that there is no health benefit associated with moderate alcohol consumption therefore contradicts their own findings and the body of evidence accumulated over the past 30 years, particularly with regard to reducing the risk of ischemic heart disease such as myocardial infarction, the leading cause of cardiovascular mortality. A similar dissonance is found in a recent article, in which the authors claim that alcohol cardioprotection is a “myth”, while at the same time presenting data showing a strong decrease in the risk of ischemic heart disease. In other words, the research findings on the positive impact of low-dose alcohol on cardiovascular mortality do not justify the conclusion that there is no safe threshold for alcohol consumption. In our opinion, the recommendations of very serious organizations such as the Harvard School of Public Health and the National Institute on Alcohol Abuse and Alcoholism NIAAA), i.e., a daily consumption of 2 glasses for men and 1 drink for women, remain the most relevant.

Above these levels, however, consumption is clearly abusive, since it is associated with an increased risk of several cancers, in particular oral, laryngeal, esophageal, colon, liver and breast cancer. Chronic consumption of large quantities of alcohol is also associated with several cardiovascular diseases, including atherosclerosis, hypertension, some cardiomyopathies as well as arrhythmias, which considerably increase the risk of cardiovascular mortality. It should also be noted that binge drinking, where large amounts of alcohol can be consumed in a short amount of time, is also associated with several harmful effects, in particular a much higher risk of stroke.

Table 2. The different types of alcohol consumption. Adapted from Fernández-Solà (2015).

Type of consumptionPure alcohol (g)Standard drinksEffect on health
Light
< 20 g per day (men)
< 10 g per day (women)		1 glass
¾ glass
Positive
Moderate20-45 g per day (men)
10-30 g per day (women)
1-3 glasses
1-2 glasses
Controversial, could depend on the type of alcohol
Abusive
> 45 g per day (men)
> 30 g per day (women)		More than 3 glasses
More than 2 glasses
Negative
Binge drinking
> 60 g in one sitting4 glasses or moreNegative

Alcohol is thus a formidable double-edged sword, and it is important to limit daily alcohol consumption to low levels, ideally a maximum of 2 glasses per day for men and 1 glass for women, and most likely a bit less.

Opt for red wine
Red wine is a complex beverage containing several milligrams of phenolic compounds (specifically resveratrol), which are extracted from grape skin during the fermentation process. These molecules have antioxidant, anti-inflammatory, antiplatelet, and vasodilator properties, which suggests that red wine could have more significant positive effects than those associated simply with the presence of alcohol.

One of the foremost examples of these benefits is the famous “French paradox”, where regularly drinking red wine would be responsible for the low incidence of coronary heart disease observed in France compared to other Western countries, despite a diet high in saturated fats. This beneficial effect is supported by a Danish study, which showed that the risk of premature death was three times lower in moderate red wine drinkers than in those who drink beer or spirits, and also by the results of other studies conducted in Northern California and in Eastern France.

Another argument in favour of choosing red wine is its lower impact on the risk of cancer, possibly due to its resveratrol content. In laboratories, this molecule has one of the most powerful anticancer effects in the plant world and could thus counteract the carcinogenic effect of alcohol. For example, a study showed that whereas the moderate consumption of alcoholic beverages other than wine increases the risk of oral cancer by 38%, this increased risk lowers to only 7% in red wine drinkers. A similar phenomenon is observed for lung cancer, where moderate wine consumption is associated with a reduced risk of this cancer, whereas consumption of beer and spirits increases the risk. It would therefore appear that the greatest decrease in mortality associated with red wine consumption observed in several studies is not only associated with a more pronounced protective effect on the risk of heart disease but also with a less harmful effect on the risk of cancer than other types of alcohol. This phenomenon was also observed in the study published in The Lancet mentioned above. When the authors examined mortality according to the type of alcohol consumed, they observed an enormous difference in risk between wine and other types of alcohol, with red wine consumption (up to 300 g per week) being associated with a slight 10% increase in mortality, which is much lower than that observed in beer and spirit drinkers (Figure 3).


Figure 3. Relationship between the type of alcohol consumed (in grams per week) and the risk of premature death. Adapted from Wood et al. (2018).

The superiority of red wine over other types of alcohol is also suggested by a recent study on the association between alcohol consumption and the risk of atrial fibrillation (AF), an arrhythmia that significantly increases the risk of stroke. In this study, the researchers observed that moderate alcohol consumption in general (7 glasses per week or less) was associated with a small decrease in the risk of AF, but that this risk increased significantly at higher amounts (14 glasses and more per week). However, when the same analysis was carried out taking into account the type of alcohol consumed, it was observed that the risk of AF did not increase in people who drank up to 14 glasses of red wine per week (Figure 4). White wine also seems to minimize the risk of AF, but to a lesser degree (increased risk starting at 10 glasses per week), while beer and spirits increase this risk very quickly, starting from about 3 glasses per week.


Figure 4. Relationship between the type of alcohol consumed (in standard drinks per week) and the risk of atrial fibrillation. Note that one drink is the British standard unit of 8 g (10 mL) of alcohol. The gray areas represent the 95% confidence intervals. Adapted from Tu et al. (2021).

Overall, these observations confirm the results of the INTERHEART study and those of the Åkesson group, which show that moderate consumption of alcohol represents one of the lifestyle factors that can contribute to a lower risk of coronary heart disease and early death. A recent study demonstrates to what extent the impact of lifestyle habits can be extraordinary: 50-year-olds who don’t smoke, have a healthy diet, do 30 minutes or more of daily physical activity, maintain a healthy weight (BMI between 19 and 25), and drink moderately (5-15 g/day for women, 5-30 g/day for men) have 82% less risk of dying from heart disease and 65% less risk of dying of cancer. In practice, this translates to a 14-year increase in life expectancy for women and 12 years for men! Thus, to truly be beneficial, alcohol consumption should be part of an overall healthy lifestyle, including a diet high in plant-based foods, regular physical activity, maintaining a normal body weight, and, of course, not smoking.

 

 

 

 

Gut microorganisms boost motivation to exercise

Gut microorganisms boost motivation to exercise

Cardiologue et Directeur de la prévention, Institut de Cardiologie de Montréal. Professeur titulaire de clinique, Faculté de médecine de l'Université de Montréal. / Cardiologist and Director of Prevention, Montreal Heart Institute. Clinical Professor, Faculty of Medicine, University of Montreal.25 January 2023

OVERVIEW

  • The composition of the intestinal microbiota has a significant effect on the motivation of laboratory mice to exercise, according to a recently published study.
  • Two intestinal bacteria are particularly associated with better performance during exercise: Eubacterium rectaleand Coprococcus eutactus.
  • These bacteria produce metabolites, fatty acid amides (FAA), which bind to the type-1 cannabinoid receptor (CB1), located in the sensory nerves in the intestine, and are connected to the brain via the spinal cord.
  • Stimulation of the CB1 receptor causes an increase in dopamine levels during exercise in a specific region of the brain called the ventral striatum where the reward circuits are located.

It is well established that physical exercise, practised on a regular basis, decreases the risk of developing chronic diseases, improves cognitive function, and decreases the risk of dying prematurely. To be able to take full advantage of these many benefits, it is necessary to exercise regularly and preferably over long periods of time. Yet many people have a sedentary lifestyle, and motivation to exercise is low or non-existent. Motivation to exercise is regulated in the central nervous system and requires signals initiated by dopamine, a neurotransmitter involved in a host of functions including motor control, attention, memory, cognition, sleep, pleasure and motivation. Neurons that produce dopamine are found in regions of the brain called the ventral tegmental area and the substancia nigra. Dopaminergic neurons extend into other parts of the brain to regulate cognitive, emotional, and motivational aspects related to reward-associated behaviours.

Does the motivation to exercise depend solely on our brain and our state of mind regarding this activity? It seems not, according to a recent study carried out on mice which shows that motivation is partly attributable to bacteria present in the intestine. A surprising discovery that is the result of the combined efforts of several teams of researchers.

In order to identify new regulators of exercise performance, the researchers used a cohort of 199 mice with high genetic diversity. The cohort of mice was subjected to extensive genome, metabolome, microbiome analyses, and their exercise performance was evaluated (treadmill, exercise wheel). Genomic analyses suggest that genes contribute very little to the observed differences between the exercise performance of different mice.

Since previous work (see here, here, here, and here) suggested that the microbiome would have a potential role on performance during exercise, the researchers wanted to test whether the variability in the performance of different mice could be attributed to the microbiome, by performing “loss of function” (depletion of the microbiome) and “gain of function” (transplantation of the microbiome) experiments. Complete depletion of the microbiome with broad-spectrum antibiotics caused a decrease in the mice’s exercise performance by approximately 50%. On the contrary, transplantation of the microbiome from exercise-performing mice to “germ-free” mice (raised under sterile conditions and containing no microorganisms) increased the exercise performance of the recipient mice. In addition, the exercise performance of the recipient mice correlated with that of the donor mice. When the broad-spectrum antibiotic treatments were stopped, the exercise performance of the mice returned to normal, as did that of the germ-free mice when they were no longer kept under sterile conditions. Taken together, the results of these experiments suggest that the microbiome strongly contributes to the ability to exercise in mice.

In order to identify the class of microorganisms and more precisely which bacteria contribute to the increase in exercise performance, the mice were treated with narrower-spectrum antibiotics, and the intestines of germ-free mice were colonized with a single microorganism. Among the bacteria tested, those of the genera Eubacterium and Coprococcusimproved the exercise performance of mice, to levels comparable to those observed for mice that received a whole microbiome transplant.

At the mechanistic level, the researchers first tested whether the improvement in exercise performance by the microbiome was not caused by a favourable effect on muscle function. However, the results of several tests indicate that the microbiome has no significant effect on muscle physiology. The researchers’ attention then turned to motivation, one of the important factors contributing to exercise performance, along with musculoskeletal function.

One region of the brain that is particularly involved in motivation control is the striatum. As expected, levels of the main neurotransmitter involved in motivation/reward neural signals in the striatum, dopamine, increased after the mice exercised. However, this increase was much less significant in mice whose microbiome was depleted, indicating a role of the microbiome in the release of dopamine after exercise. Levels of two other important neurotransmitters in the striatum, namely glutamate and acetylcholine, did not change following exercise or microbiome depletion.

How can bacteria that colonize the gut boost dopamine levels in the brain? There are two possible pathways: 1) through circulating factors, i.e., metabolites produced by bacteria or 2) through afferent neural circuits. Proteomic analyses of blood samples did not identify any metabolites significantly associated with exercise performance that are related to the microbiome. The researchers therefore focused on the sensory neurons that innervate the intestine.

The researchers used a line of mice (Trpv1DTA) in which a large part of the afferent vagus and spinal nerves that express the vanilloid receptor are absent. The exercise performance of Trpv1DTA mice is low, comparable to that of normal mice whose microbiome has been depleted by antibiotics. Microbiome depletion in Trpv1DTA mice did not alter exercise performance.

How can gut bacteria activate sensory nerves in the gut? The researchers showed that, in vitro, isolated spinal nerve neurons are activated by fecal extracts from normal mice, but much less by extracts from mice without microbiome. This result suggests that a metabolite from the microbiome is involved in the activation of sensory nerves. Metabolomics analyses identified candidates, several of the most potent of which were fatty acid amides (FAAs), such as N-oleoylethanolamide (OEA).

In order to prove that these compounds alone can boost exercise performance, the researchers introduced supplements of five FAAs to the diets of mice whose microbiome had been depleted by antibiotics. This supplementation restored signals generated by sensory nerves, increased levels of dopamine in the brain, and exercise performance. Then, the clever researchers transformed E. coli bacteria that normally do not produce FAA by introducing the genes responsible for the production of these metabolites. The intestines of germ-free mice were colonized with this bacterium modified to produce FAAs or with the parental line which does not produce FAAs. Exercise performance was improved by colonization with the FAA-producing bacteria, but not by colonization with the parent bacteria. Finally, the researchers showed that the effect of FAAs is mediated by cannabinoid type 1 (CB1) receptors, located in the sensory nerves in the intestine and which are connected to the brain via the spinal cord.

Studies done on mice don’t always translate to humans, but both have a similar endocannabinoid system connected to the ventral striatum. The results of this study suggest possible diet-based interventions to increase people’s motivation to exercise and optimize performance in elite athletes.

A diet rich in flavonols is associated with slower cognitive decline

A diet rich in flavonols is associated with slower cognitive decline

Professeur titulaire au Département de Médecine de l’Université de Montréal. Directeur du Centre ÉPIC de l’Institut de cardiologie de Montréal.4 January 2023

OVERVIEW

  • Participants in a study who had a high dietary intake of flavonols had slower cognitive decline than those who had a lower intake.
  • Higher total flavonol intake was associated with a significantly slower decline in episodic memory, semantic memory, perceptual speed and working memory.
  • Among the flavonols, kaempferol and quercetin were associated with slower cognitive decline, but not myricetin and isorhamnetin.

Flavonoids are polyphenolic compounds found in plants and in large quantities in fruits and vegetables in particular. These compounds are best known for their anti-inflammatory and antioxidant properties. Flavonoids have been associated in several previous studies with slowing age-related cognitive decline and dementia. However, few studies have attempted to identify which flavonoid subclasses and individual molecules are most active in protecting brain health. A recently published American study provides some answers by evaluating the effect of the intake of total flavonols and individual flavonols (kaempferol, quercetin, myricetin, isorhamnetin) on the cognitive performance of the elderly.

The study was conducted among 961 participants from the city of Chicago in the United States, aged 60 to 100, who were part of the Rush Memory and Aging Project cohort, and who were followed for 6.9 years on average. The participants, whose average age was 81 at the start of the study, were mostly female (75%), Caucasian (98%), and had an average of 15 years of schooling. Participants’ diet was assessed using a validated semi-quantitative questionnaire, and dietary flavonol intake was inferred from the collected data. The participants’ cognitive performance was assessed annually with a battery of 19 standardized tests.

A higher dietary intake of total flavonols and individual flavonols was associated with a lower rate of overall cognitive decline and several cognitive domains. A higher intake of total flavonols was associated with a slower decline in episodic memory (memories of personal events), semantic memory (memory of facts and concepts), perceptual speed, and working memory (short-term memory), but had no effect on visuospatial construction ability (understanding and representation of space in 2 and 3 dimensions).

Analysis of individual flavonols indicates that higher intakes of kaempferol and quercetin are associated with slower cognitive decline. In contrast, myricetin and isorhamnetin were not associated with an effect on global cognitive decline. Kale, beans, tea, spinach and broccoli were the foods highest in kaempferol among those consumed in this study. Tomatoes, kale, apples and tea were the foods highest in quercetin in this study.

The mechanisms underlying this favourable association are not yet well understood. The study authors suggest that the anti-inflammatory properties of flavonols may decrease the amplitude or duration of neuroinflammation. In addition, the antioxidant properties of flavonols could reduce or even prevent cell damage caused by oxidative stress, which generates reactive oxygen derivatives (free radicals, oxygenated ions, peroxides).

An earlier study by the same group of researchers reported that green leafy vegetables (spinach, kale, collard greens, lettuce) and certain constituents including kaempferol were associated with slowing overall cognitive decline. The authors concluded that “eating about one serving per day of green leafy vegetables and foods high in phylloquinone, lutein, nitrate, folate, α-tocopherol, and kaempferol may help slow cognitive decline with age.”

The protective role of certain flavonols on cognition has been demonstrated in animal models. Thus, quercetin supplementation improves memory and learning in transgenic mice used as an animal model of Alzheimer’s disease. In another study, kaempferol and myricetin improved memory and learning and reduced oxidative stress in mice used as a model of Alzheimer’s disease.

The prospective design of the American study does not make it possible to establish a causal link between dietary flavonol intake and cognition. Randomized clinical trials would confirm the role of flavonols on cognitive performance and, in the longer term, the prevention of cognitive decline associated with age. This type of study would also make it possible to clarify the dose-response relationship for optimal brain health. In any case, the study also has several strong points: a large number of participants, duration of the study, robust measurement of cognition by the 19 cognitive tests, validated questionnaires. The results were adjusted to minimize residual confounders, since it is possible that a higher dietary intake of flavonols is an indirect effect of a healthier diet. Among the limitations of this study are: self-reported food intake is subject to recall bias; because of their advanced age, participants are at risk of mild cognitive impairment that could cause errors when answering food questionnaires; there remains a possibility of reverse causation (cognitive decline may have altered participants’ eating habits). According to the authors, additional analyses (sensitivity analyses), however, indicate that reverse causation is unlikely.

The results of this study suggest that the consumption of fruits and vegetables (especially green leafy vegetables) in the elderly may not only help them maintain good health in general, but also delay or prevent cognitive decline. However, more studies are needed to confirm and better understand how flavonols slow cognitive and memory decline.