Modulation of the gut microbiota by dietary interventions to prevent cardiometabolic diseases

Modulation of the gut microbiota by dietary interventions to prevent cardiometabolic diseases

OVERVIEW

  • In a study of 307 participants, the Mediterranean-style diet was associated with a composition of the gut microbiota conducive to good cardiometabolic health.
  • In another study, intermittent fasting altered the gut microbiota and prevented the development of hypertension in rats that spontaneously became hypertensive as they aged.
  • The metabolism of bile acids modulated by the microbiota has been identified as a regulator of blood pressure.
  • Dietary interventions aimed at modifying the gut microbiota could be a viable non-pharmacological approach to prevent and treat high blood pressure and other conditions.

Cardiometabolic diseases including type 2 diabetes and cardiovascular disease are on the rise in Canada and around the world. These diseases, which reduce the quality of life and life expectancy of those affected and generate significant costs for society, can be prevented by maintaining good lifestyle habits, including a healthy diet and regular exercise.

Recent studies have linked microbial metabolism and immune interactions in the gut and the risk of cardiometabolic disease (see our articles on the subject herehere and here). Two new studies show that the type of diet and the frequency of meals have effects on the risk of metabolic disease, which are in part due to alterations in the gut microbiota. The results of these new studies suggest that modulation of the gut microbiota by dietary interventions could be a new preventive and therapeutic approach.

US researchers analyzed the microbiome data of 307 male participants in the Health Professionals Follow-up Study as well as their eating habits and biomarkers of blood glucose regulation, lipid metabolism and inflammation. The Mediterranean-style diet (consisting mainly of vegetables, legumes, fruits, nuts, olive oil, and some wine and red meat) was associated with a composition of the gut microbiota conducive to good cardiometabolic health. The positive association between the Mediterranean-style diet and a lower risk of cardiometabolic disease was particularly strong among participants whose microbiota contained little Prevotella copri bacteria. Researchers do not yet understand why the Mediterranean diet is less effective in people whose microbiota contains the bacterium Prevotella copri, however, they make several hypotheses that will need to be verified in future studies. In any case, it can be envisaged that prevention approaches may one day be personalized according to the intestinal microbial profile of each person.

Benefits of intermittent fasting for hypertension
Intermittent fasting involves compressing the time during which one eats over a short period (6-8 h) and “fasting” the rest of the day (16-18 h). Intermittent fasting has positive effects on weight and body fat loss, chronic inflammation, metabolism, and cardiovascular health (see our articles on the subject here and here). The main metabolic benefits of intermittent fasting are reduced blood LDL cholesterol levels, increased insulin sensitivity and better blood glucose control in diabetics, reduced oxidative stress and inflammation. On the one hand, we know that an imbalance in the intestinal microbiota (intestinal dysbiosis) contributes to the development of hypertension. On the other hand, studies in recent years have shown that fasting and caloric restriction significantly reduce blood pressure, both in animal models and in hypertensive patients.

A recent study shows that the beneficial effects of intermittent fasting on blood pressure are attributable, at least in part, to the modulation of the gut microbiota. The researchers used an animal model commonly used in hypertension research: spontaneously hypertensive stroke-prone (SHRSP) rats, a unique genetic model of severe hypertension and stroke. Hypertensive SHRSP rats and normotensive Wistar-Kyoto (WKY) rats were subjected for 8 weeks to one or the other of the following diets: 1) ad libitum throughout the study (control groups) or 2) a diet alternating a day with food at will and a day without access to food (intermittent fasting). Hypertensive (SHRSP) and normotensive (WKY) rats in the control groups ingested the same amount of food. In contrast, the rats subjected to intermittent fasting ate more on days with food at will than those in the control groups, presumably to compensate for the fasting day. Despite this, the total amount of food ingested during the study was significantly lower in hypertensive (-27%) and normotensive (-35%) rats subjected to intermittent fasting, compared to animals in the respective control groups that had access to food at will. Despite a similar food intake, the hypertensive rats in the control group gained significantly less weight than the normotensive rats.

As expected, the blood pressure of hypertensive rats measured weekly was significantly higher than that of normotensive rats. In contrast, intermittent fasting significantly reduced blood pressure in hypertensive rats by an average of about 40 mmHg by the end of the study, compared to hypertensive rats who had access to food at will. This significant decrease brought the blood pressure of hypertensive rats to levels comparable to those of normotensive rats.

Role of the gut microbiota in the regulation of blood pressure
Animal models allow experiments on the role of the gut microbiota that could not be done in humans. In order to find out whether the gut microbiota plays a role in the effect of intermittent fasting, the researchers continued their studies by “transplanting” the microbiota from hypertensive and normotensive rats into “germ-free” rats, i.e. rats reproduced under special conditions in such a way that they do not contain any microorganisms.

Germ-free rats that received microbiota from hypertensive rats had significantly higher blood pressure than those that received microbiota from normotensive rats when subjected to the control diet (ad libitum). In contrast, intermittent fasting reduced the blood pressure of germ-free rats that received microbiota from hypertensive rats to levels comparable to those of rats that received microbiota from normotensive rats. These results demonstrate that the alterations in the microbiota of hypertensive rats caused by intermittent fasting are sufficient to cause a reduction in blood pressure. Analysis of the microbiota by whole-genome shotgun sequencing has enabled researchers to identify bile acid metabolism as a potential mediator of blood pressure regulation. Subsequent analyses revealed that the blood levels of 11 bile acids (out of 18) in hypertensive SHRSP rats were significantly lower than those in normotensive rats. In support of the hypothesis, the addition of cholic acid (a precursor of bile acids) in the food or the activation of the bile acid receptor (TGR5) significantly reduced the blood pressure (by 18 mmHg) of hypertensive rats.

In summary, the quality of food and frequency with which we eat has a significant impact on the microorganisms in our microbiota, cardiometabolic risk factors and, ultimately, our overall health. By changing the diet and the frequency of meals, it may be possible to significantly improve the condition of people with chronic diseases.

Insufficient dietary fibre intake harms the gut microbiota and the immune system’s balance

Insufficient dietary fibre intake harms the gut microbiota and the immune system’s balance

OVERVIEW

  • The typical diet in Western countries does not contain enough fibre.
  • This insufficient fibre intake adversely affects the bacteria in the gut microbiota and therefore the immunity and health of the host.
  • An abundant and varied consumption of dietary fibre helps maintain a diverse and healthy microbiota, which produces metabolites that contribute to human physiology and health.

Dietary fibre is made up of complex sugars that cannot be digested by human digestive enzymes, but is an important source of energy for gut bacteria, which have the ability to break it down. This fibre comes mainly from plants, but is also found in animal tissues (meat, offal), fungi (mushrooms, yeasts, moulds), and foodborne microorganisms. The main fibres are cellulose, lignins, pectin, inulin, starches and dextrins resistant to amylases, chitins, beta-glucans and other oligosaccharides. However, not all dietary fibre can be used by the intestinal microbiota (cellulose for example), so researchers are more particularly interested in “microbiota-accessible carbohydrates” or MAC, which are found in legumes, wheat and oats, for example.

Resurgence of allergies and inflammatory and autoimmune diseases
Non-communicable diseases, such as allergies and inflammatory and autoimmune diseases have been on the rise in Western countries over the past century. Although we do not know all the causes of these increases, it is quite plausible that they have an environmental component. The transition from the traditional diet to the Western diet that occurred after the Industrial Revolution is often called into question. The typical Western diet consists primarily of processed foods high in sugar and fat, but low in minerals, vitamins, and fibre. The recommended daily intake of dietary fibre is at least 30 grams (1 ounce), while followers of the Western diet consume only 15 grams on average. In addition, people living in traditional societies consume up to 50–120 g/day of fibre and have a much more diverse gut microbiota than Westerners. A diverse microbiota is associated with good health in general, while a poorly diversified microbiota has been associated with chronic diseases common in Western countries, such as type 2 diabetes, obesity, inflammatory bowel disease (ulcerative colitis, Crohn’s disease), colorectal cancer, rheumatoid arthritis and asthma.

Metabolites of the gut microbiota
The gut microbiota contributes to human physiology by producing a multitude of metabolites. The most studied are short-chain fatty acids (SCFAs), which are organic compounds such as acetate, propionate and butyrate that together constitute ≥95% of SCFAs. These metabolites are absorbed and find their way into the bloodstream via the portal vein and act on the liver and then, via the peripheral blood circulation, on other organs of the human body. SCFAs play key roles in the regulation of human metabolism, the immune system, and cell proliferation. SCFAs are metabolites produced by microorganisms in the intestinal microbiota from dietary fibres, which are complex sugars. The microbiota produces other metabolites from amino acids derived from dietary protein, including indole and its derivatives, tryptamine, serotonin, histamine, dopamine, p-cresol, phenylacetylglutamine, and phenylacetylglycine.

A lack of dietary fibre leads to the generation of toxic metabolites by the microbiota
Insufficient fibre intake not only leads to reduced microbiota diversity and a reduction in the amount of SCFAs produced, but also causes a shift in the metabolism of microorganisms towards the use of substrates less favourable for human health. Among these alternative substrates, amino acids from food proteins are fermented by the microbiota into branched-chain fatty acids, ammonia, amines, N-nitroso compounds, phenolic compounds such as p-cresol, sulphides, and indole compounds. These metabolites are either cytotoxic and/or pro-inflammatory and they contribute to the development of chronic diseases, particularly colorectal cancer.

Effects on mucus production that protects the intestinal lining
The main substrates used by the microbiota when fibre intake is low are mucins, glycoproteins contained in the mucus that cover and protect the epithelium of the intestinal lining. Maintaining this layer of mucus is very important to prevent infections; however, a diet low in fibre alters the composition of the gut microbiota and leads to a significant deterioration of the mucus layer, which can increase the susceptibility to infections and chronic inflammatory diseases (see figure, below). Transcriptomic analyses have revealed that when there is a lack of MAC-type fibres, the enzymes that break down the mucus are expressed in greater quantities in the microorganisms of the microbiota. The consequences of the deterioration and thinning of the mucus layer are a dysfunction of the intestinal barrier, i.e. increased permeability, which increases susceptibility to infection by pathogenic bacteria. A diet rich in fibre has the opposite effect: the microbiota is diverse and the abundant production of SCFA metabolites stimulates the production and secretion of mucus by specialized epithelial cells, known as goblet cells.

Figure. Effect of a high- or low-fibre diet on the composition and diversity of the gut microbiota and the impact on human physiology. MAC: microbiota-accessible carbohydrates. From Makki et al., 2018.

Immune system
A healthy gut microbiota contributes to the maturation and development of the immune system (see this review article). For example, short-chain fatty acids (SCFAs) produced by the microbiota stimulate the production of regulatory T-cells. SCFAs have many effects on the function and hematopoiesis of dendritic cells as well as on neutrophils, which are the first leukocytes to be mobilized by the immune system in the presence of a pathogen.

Inflammation and colon cancer
The incidence of inflammatory bowel disease has increased dramatically in the West over the past few decades. A diet low in fibre has been correlated with an increased incidence of Crohn’s disease. On the contrary, a sufficient intake of dietary fibre seems to protect against the development of ulcerative colitis, an effect which has been associated with a decrease in SCFAs produced by the microbiota, butyrate in particular, which has anti-inflammatory properties. Inflammatory bowel disease can lead to the development of colon cancer. Additionally, reduced dietary fibre intake has been linked to an increased incidence of colorectal cancer.

Dietary fibre plays a much more complex role than was believed a short time ago, when it was thought that it had a purely mechanical role in intestinal transit, by an increase in the volume of the alimentary bolus and by its emollient properties. Adequate dietary fibre intake helps maintain a diverse and healthy gut microbiota, which can prevent the development of allergies as well as inflammatory and autoimmune diseases. The gut microbiota is the subject of intense research efforts, as evidenced by the numerous scientific articles published each month, and it certainly has not revealed all of its secrets!

Plant-based meat substitutes reduce certain cardiovascular risk factors

Plant-based meat substitutes reduce certain cardiovascular risk factors

OVERVIEW

  • Participants in a study were divided into two groups, for eight weeks, one consumed two daily servings of plant-based meat substitutes (Beyond Meat products: burger, mock beef, sausage, mock chicken), while the other group ate the same amount of real meat (beef, pork, chicken).
  • Participants who ate plant-based meat substitutes lost some weight and had significantly lower blood levels of trimethylamine oxide (TMAO) and LDL cholesterol than those who consumed meat during the same period.
  • Plant-based meat substitutes appear to be beneficial for health compared to meat since high levels of TMAO and LDL cholesterol are two risk factors for cardiovascular disease.

In an article published in these pages in 2019, we discussed the merits and drawbacks of new food products that mimic the taste and texture of meat, such as Beyond Meat and Impossible Burger. These products are certainly more environmentally friendly than red meat (beef and pork in particular), which requires a lot of resources that tax the global environment. On the other hand, they are ultra-processed products that contain significant amounts of saturated fat and salt.

To determine whether plant-based meat substitutes could be healthier than meat, the Beyond Meat company funded Dr. Christopher D. Gardner, an independent and renowned researcher at Stanford University School of Medicine in California, to conduct a randomized controlled study. One must be extremely careful with studies funded by the food industry, since publishing only the results that will support the sale of their products is to their advantage. On the other hand, in the case of this study, all precautions seem to have been taken so that there is no influence on the results: study design (randomized and controlled with a crossover design), statistical analyses conducted by a third party who was not involved in the design of the study and data collection. Beyond Meat was not involved in the design of the study, the conduct of the study, or the analysis of the data. In addition, Dr. Gardner stated that he has already completed six food industry-sponsored studies with null findings from the original hypothesis.

The 36 study participants were randomly divided into two groups. During the first eight weeks, one group of participants were assigned to eat two servings/day of plant-based meat substitutes (Beyond Meat products: burger, mock beef, sausages, mock chicken), while the other group consumed two servings/day of meat (beef, pork, chicken). The two groups then switched their diet for the next eight weeks (crossover study design). Fasting levels of lipids, glucose, insulin, and trimethylamine oxide (TMAO) were measured before the start of the study and every two weeks during both phases of the study.

The main endpoint of the study was the blood level of TMAO, an emerging risk factor associated with atherosclerosis and other cardiovascular diseases. The group that consumed meat during the first eight weeks had a significantly higher TMAO mean level than the group that consumed plant-based meat substitutes (4.7 vs. 2.7 µM), as well as a higher LDL cholesterol (the “bad cholesterol”) mean level (121 vs. 110 mg/dL), while the mean HDL cholesterol (the “good cholesterol”) level was not significantly different.

A surprise awaited the researchers: Participants who first consumed plant-based products during the first eight weeks did not see their TMAO levels increase when they ate meat during the second part of the study. Researchers were unable to identify any changes in the microbiome (gut flora) that could have explained this difference. However, it appears that making the participants “vegetarian” for eight weeks caused them to lose the ability to produce TMAO from meat. This effect of a vegetarian diet on the microbiome has already been demonstrated by Dr. Stanley L. Hazen’s team at the Cleveland Clinic. After a few weeks of returning to a carnivorous diet, the microbiome begins to produce TMAO again from red meat and eggs.

TMAO is a metabolite produced by the gut microbiome from carnitine and choline, two compounds found in large quantities in red meat such as beef and pork. High concentrations of TMAO can promote atherosclerosis and thrombosis. Indeed, numerous observational studies and animal models have shown that there is an association between TMAO and cardiovascular risk, and that it is beneficial to reduce the levels of TMAO. It should be noted, however, that a causal link between TMAO and cardiovascular disease has not been established and that it is possible that it is a marker rather than a causal agent of these diseases.

In addition to the favourable effect on TMAO, participants who ate plant-based meat substitutes lost weight (1 kg on average) and had significantly lower LDL-cholesterol levels than those who ate meat (110 vs. 121 mg/dL). These differences were observed regardless of the order in which participants followed the two diets.

Beyond Meat probably hopes that these results will allow them to respond to criticisms about their products, which areultra-processed and contain a lot of salt and almost as much saturated fat as meat. Many people want to reduce their consumption of red meat, but do not like classic vegetarian dishes. It seems to us that if these meat substitutes appeal to consumers concerned about maintaining good health and allow them to reduce their meat consumption, this will be beneficial for them and may encourage them to cook veggie burgers and other plant-based meat substitutes themselves. Who knows, maybe these products will lead to significant changes in diet in the future. Considerably reducing our meat consumption can only be beneficial to our health and that of the planet.

 

A new metabolite derived from the microbiota linked to cardiovascular disease

A new metabolite derived from the microbiota linked to cardiovascular disease

OVERVIEW

  • Metabolomic screening has identified a new metabolite associated with cardiovascular disease in the blood of people with type 2 diabetes.
  • This metabolite, phenylacetylglutamine (PAGln), is produced by the intestinal microbiota and the liver, from the amino acid phenylalanine from dietary proteins.
  • PAGln binds to adrenergic receptors expressed on the surface of blood platelets, which results in making them hyper-responsive.
  • A beta blocker drug widely used in clinical practice (Carvedilol) blocks the prothrombotic effect of PAGln.

A research group from the Cleveland Clinic in the United States recently identified a new metabolite of the microbiota that is clinically and mechanistically linked to cardiovascular disease (CVD). This discovery was made possible by the use of a metabolomic approach (i.e. the study of metabolites in a given organism or tissue), a powerful and unbiased method that identified, among other things, trimethylamine oxide (TMAO) as a metabolite promoting atherosclerosis and branched-chain amino acids (BCAAs) as markers of obesity.

The new metabolomic screening has identified several compounds associated with one or more of these criteria in the blood of people with type 2 diabetes: 1) association with major adverse cardiovascular events (MACE: myocardial infarction, stroke or death) in the past 3 years; 2) heightened levels of type 2 diabetes; 3) poor correlation with indices of glycemic control. Of these compounds, five were already known: two which are derived from the intestinal microbiota (TMAO and trimethyllysine) and three others that are diacylglycerophospholipids. Among the unknown compounds, the one that was most strongly associated with MACE was identified by mass spectrometry as phenylacetylglutamine (PAGln).

In summary, here is how PAGln is generated (see the left side of Figure 1):

  • The amino acid phenylalanine from dietary proteins (animal and plant origin) is mostly absorbed in the small intestine, but a portion that is not absorbed ends up in the large intestine.
  • In the large intestine, phenylalanine is first transformed into phenylpyruvic acid by the intestinal microbiota, then into phenylacetic acid by certain bacteria, particularly those expressing the porA
  • Phenylacetic acid is absorbed and transported to the liver via the portal vein where it is rapidly metabolized into phenylacetylglutamine or PAGln.

Figure 1. Schematic summary of the involvement of PAGln in the increase in platelet aggregation, athero-thrombosis and major adverse cardiovascular events. From Nemet et al., 2020.

Researchers have shown that PAGln increases the effects associated with platelet activation and the potential for thrombosis in whole blood, on isolated platelets and in animal models of arterial damage.

PAGln binds to cell sites in a saturable manner, suggesting specific binding to membrane receptors. The researchers then demonstrated that PAGln binds to G-protein coupled adrenergic receptors, expressed on the surface of the platelet cell membrane. The stimulation of these receptors by PAGln causes the hyperstimulation of the platelets, which then become hyper-responsive and accelerate the platelet aggregation and the thrombosis process.

Finally, in a mouse thrombus model, it has been shown that a beta blocker drug widely used in clinical practice (Carvedilol) blocks the prothrombotic effect of PAGln. This result is particularly interesting because it suggests that the beneficial effects of beta blockers may be partly caused by reversing the effects of high PAGln levels. The identification of PAGln could lead to the development of new targeted and personalized strategies for the treatment of cardiovascular diseases.

Effectiveness of exercise to prevent and mitigate diabetes: An important role of the gut microbiota

Effectiveness of exercise to prevent and mitigate diabetes: An important role of the gut microbiota

OVERVIEW

  • In overweight, prediabetic and sedentary men, exercise induced changes in the gut microbiota that are correlated with improvements in blood sugar control and insulin sensitivity.
  • The microbiota of the participants who are “responders” to exercise had a greater ability to produce short chain fatty acids (SCFAs) and to eliminate branched-chain amino acids (BCAAs). Conversely, the microbiota of non-responders was characterized by an increased production of metabolically harmful compounds.
  • Transplantation of the fecal microbiota of responders into obese mice produced roughly the same beneficial effects of exercise on insulin resistance. Such effects were not observed after transplanting the microbiota of non-responders.
Regular exercise has beneficial effects on blood glucose control and insulin sensitivity, and is therefore an interesting strategy to prevent and mitigate type 2 diabetes. Unfortunately, in some people, exercise does not cause a favourable metabolic response, a phenomenon called “exercise resistance”. The causes of this phenomenon have not been clearly established, although some researchers have suggested that genetic predispositions and epigenetic changes may contribute to this.

A growing body of data indicates that an imbalance in the gut microbiota (dysbiosis) plays an important role in the development of insulin resistance and type 2 diabetes. Several different mechanisms are involved, including an increase in intestinal permeability and increased endotoxemia, changes in the production of certain short chain fatty acids and branched-chain amino acids, and disturbances in bile acid metabolism. Changes in the composition and function of the gut microbiota have been observed in people with type 2 diabetes and prediabetics. One study also showed that transplanting a healthy person’s microbiota into the intestines of people with metabolic syndrome results in increased microbial diversity and improved blood sugar control as well as sensitivity to insulin.

The intestinal microbiota (formerly intestinal flora) is a complex ecosystem of bacteria, archaea (small microorganisms without nuclei), eukaryotic microorganisms (fungi, protists) and viruses, which has evolved with human beings for several thousands of years. A human gut microbiota, which can weigh up to 2 kg, is absolutely necessary for digestion, metabolic function, and resistance to infection. The human gut microbiota has an enormous metabolic capacity, with more than 1,000 different species of bacteria and 3 million unique genes (the microbiome).

Recent data indicate that exercise modulates the gut microbiota in humans as well as in other species of animals. For example, it has been found that the gut microbiota of professional athletes is more diverse and has a healthier metabolic capacity than the microbiota of sedentary people. However, it is still unclear how these exercise-induced changes in the microbiota are involved in the metabolic benefits (see figure below).

Figure. Changes in the gut microbiota and intestinal epithelium through exercise and health benefits. BDNF: Brain-derived neurotrophic factor (growth factor). From: Mailing et al., 2019.

A study published in Cell Metabolism tried to answer this question by performing an intervention in overweight, prediabetic and sedentary men. Study participants were randomly assigned to a control group (sedentary) or to a 12-week supervised training program. Blood and fecal samples were collected before and after the procedure. After the 12 weeks, modest but significant weight loss and fat loss were observed in people who exercised, with improvements in several metabolic parameters, such as insulin sensitivity, favourable lipid profiles, improved cardiorespiratory capacity and levels of adipokines (signalling molecules secreted by adipose tissues) which are functionally associated with insulin sensitivity. The researchers observed that there was a high interpersonal variability in the results. After classifying the participants as “non-responders” and “responders”, according to their insulin sensitivity score, the researchers analyzed the composition of each participant’s microbiota.

Among responders, exercise altered the concentration of more than 6 species of bacteria belonging to the genera Firmicutes, Bacteroidetes, and Probacteria. Among these bacteria, those belonging to the genus Bacteroidetes are involved in the metabolism of short chain fatty acids (SCFAs). Among the most striking differences between the microbiota of responders and non-responders, the researchers noted a 3.5-fold increase in the number of Lanchospiraceae bacterium, a butyrate producer (a SCFA), which is an indicator of intestinal health. The bacterium Alistipes shahii, which has already been associated with inflammation and is present in higher amounts in obese people, decreased by 43% in responders, while it increased 3.88 times in non-responders. The Prevotella copri bacteria proliferated at a reduced rate in the responders; it is one of the main bacteria responsible for the production of branched-chain amino acids (BCAAs) in the gut and contributes to insulin resistance.

The researchers then transplanted the fecal microbiota of responders and non-responders into obese mice. The fecal microbiota transplantation (FMT) of the responders had the effect in mice of reducing blood sugar and insulin as well as improving insulin sensitivity, while such favourable effects were not observed in mice that received a FMT from non-responders.

Mice saw their blood levels of SCFAs increase significantly, while the levels of BCAAs (leucine, isoleucine, valine) and aromatic amino acids (phenylalanine, tryptophan) decreased after receiving the microbiota from responders. In contrast, mice that received the microbiota from non-responders saw opposite changes in the levels of these same metabolites. BCAA supplementation attenuated the beneficial effects of FMT from responders on blood sugar regulation and insulin sensitivity, while SCFA supplementation in mice that received the microbiota of non-responders partially corrected the defect in blood glucose regulation and insulin sensitivity.

Taken together, these results suggest that the gut microbiota and its metabolites are involved in the beneficial metabolic effects caused by exercise. In addition, this study indicates that poor adaptation of the gut microbiota is partly responsible for the lack of a favourable metabolic response in people who do not respond to exercise.

Eggs: To consume with moderation

Eggs: To consume with moderation

The old debate over whether egg consumption is detrimental to cardiovascular health has been revived since the recent publication of a study that finds a significant, albeit modest, association between egg or dietary cholesterol consumption and the incidence of cardiovascular disease (CVD) and all-cause mortality. Eggs are an important food source of cholesterol: a large egg (≈50 g) contains approximately 186 mg of cholesterol. The effect of eggs and dietary cholesterol on health has been the subject of much research over the last five decades, but recently it has been assumed that this effect is less important than previously thought. For example, the guidelines of medical and public health organizations have in recent years minimized the association between dietary cholesterol and CVD (see the 2013 AHA/ACC Lifestyle Guidelines and the 2015–2020 Dietary Guidelines for Americans). In 2010, the American guidelines recommended consuming less than 300 mg of cholesterol per day; however, the most recent recommendations (2014–2015) do not specify a daily limit. This change stems from the fact that cholesterol intake from eggs or other foods has not been shown to increase blood levels of LDL-cholesterol or the risk of CVD, as opposed to the dietary intake of saturated fat that significantly increases LDL cholesterol levels, a significant risk of CVD.

Some studies have reported that dietary cholesterol increases the risk of CVD, while others reported a decrease in risk or no effect with high cholesterol consumption. In 2015, a systematic review and meta-analysis of prospective studies was unable to draw conclusions about the risk of CVD associated with dietary cholesterol, mainly because of heterogeneity and lack of methodological rigour in the studies. The authors suggested that new carefully adjusted and rigorously conducted cohort studies would be useful in assessing the relative effects of dietary cholesterol on the risk of CVD.

What distinguishes the study recently published in JAMA from those published previously is its great methodological rigour, in particular a more rigorous categorization of the components of the diet, which makes it possible to isolateindependent relationships between the consumption of eggs or cholesterol from other sources and the incidence of CVD. The cohorts were also carefully harmonized, and several fine analyses were performed. The data came from six U.S. cohorts with a total of 29,615 participants who were followed for an average of 17.5 years.

The main finding of the study is that greater consumption of eggs or dietary cholesterol (including eggs and meat) is significantly associated with a higher risk of CVD and premature mortality. This association has a dose-response relationship: for every additional 300 mg of cholesterol consumed daily, the risk of CVD increases by 17% and that of all-cause mortality increases by 18%. Each serving of ½ egg consumed daily is associated with an increased risk of CVD of 6% and an increased risk of all-cause mortality of 8%. On average, an American consumes 295 mg of cholesterol every day, including 3 to 4 eggs per week. The model used to achieve these results took into account the following factors: age, gender, race/ethnicity, educational attainment, daily energy intake, smoking, alcohol consumption, level of physical activity, use of hormone therapy. These adjustments are very important when you consider that egg consumption is commonly associated with unhealthy behaviours such as smoking, physical inactivity and unhealthy eating. These associations remain significant after additional adjustments to account for CVD risk factors (e.g. body mass index, diabetes, blood pressure, lipidemia), consumption of fat, animal protein, fibre and sodium.

A review of this study suggests that the association between cholesterol and the incidence of CVD and mortality may be due in part to residual confounding factors. The authors of this review believe that health-conscious people reported eating fewer eggs and cholesterol-containing foods than they actually did. Future studies should include “falsification tests” to determine whether a “health consciousness” factor is the cause of the apparent association between dietary cholesterol and CVD risk.

Eggs, TMAO and atherosclerosis
A few years ago, a metabolomic approach identified a compound in the blood, trimethylamine-N-oxide (TMAO), which is associated with increased cardiovascular risks. TMAO is formed from molecules from the diet: choline, phosphatidylcholine (lecithin) and carnitine. Bacteria present in the intestinal flora convert these molecules into trimethylamine (TMA), then the TMA is oxidized to TMAO by liver enzymes called flavin monooxygenases. The main dietary sources of choline and carnitine are red meat, poultry, fish, dairy products and eggs (yolks). Eggs are an important source of choline (147 mg/large egg), an essential nutrient for the liver, muscles and normal foetal development, among others.

A prospective study indicated that elevated plasma concentrations of TMAO were associated with a risk of major cardiac events (myocardial infarction, stroke, death), independent of traditional risk factors for cardiovascular disease, markers of inflammation, and renal function. It has been proposed that TMAO promotes atherosclerosis by increasing the number of macrophage scavenger receptors, which carry oxidized LDL (LDLox) to be degraded within the cell, and by stimulating macrophage foam cells (i.e. filled with LDLox fat droplets), which would lead to increased inflammation and oxidation of cholesterol that is deposited on the atheroma plaques. A randomized controlled study indicates that the consumption of 2 or more eggs significantly increases the TMAO in blood and urine, with a choline conversion rate to TMAO of approximately 14%. However, this study found no difference in the blood levels of two markers of inflammation, LDLox and C-reactive protein (hsCRP).

Not all experts are convinced that TMAO contributes to the development of CVD. A major criticism is focused on fish and seafood, foods that may contain significant amounts of TMAO, but are associated with better cardiovascular health. For example, muscle tissue in cod contains 45–50 mmol TMAO/kg. For comparison, the levels of choline, a precursor of TMAO, are 24 mmol/kg in eggs and 10 mmol/kg in red meat. The only sources of choline that are equivalent to that in TMAO in marine species are beef and chicken liver. TMAO contained in fish and seafood is therefore significantly more important quantitatively than TMAO that can be generated by the intestinal flora from choline and carnitine from red meat and eggs. This was also measured: plasma levels of TMAO are much higher in people who have a fish-based diet (> 5000 μmol / L) than in people who eat mostly meat and eggs (139 μmol / L). In their response to this criticism, the authors of the article point out that not all fish contain the same amounts of TMAO and that many (e.g. sea bass, trout, catfish, walleye) do not contain any. Fish that contain a lot of TMAO are mainly deep-sea varieties (cod, haddock, halibut). The TMAO content of other fish, including salmon, depends on the environment and when they are caught.

Other experts believe this could be a case of reverse causality: the reduction in renal function associated with atherosclerosis could lead to an accumulation of TMAO, which would mean that this metabolite is a marker and not the cause of atherosclerosis. To which the authors of the hypothesis counter that the high concentration of TMAO is associated with a higher risk of cardiovascular events even when people have completely normal kidney function.

Diabetes and insulin resistance
People who are overweight (BMI> 25) and obese (BMI> 50) are at higher risk of becoming insulin resistant and having type 2 diabetes and metabolic syndrome, conditions that can, independently or in combination, lead to the development of cardiovascular disease. There is evidence that dietary cholesterol may be more harmful to diabetics. Intestinal absorption of cholesterol is impaired in diabetics, i.e. it is increased. However, in a randomized controlled trial, when diabetic patients consumed 2 eggs per day, 6 times per week, their lipid profile was not altered when their diet contained mono- and polyunsaturated fatty acids. Other studies (mostly subsidized by the egg industry) suggest that eggs are safe for diabetics.

Dr. J. David Spence of the Stroke Prevention & Atherosclerosis Research Center believes that people at risk for CVD, including diabetics, should avoid eating eggs (see also this more detailed article). This expert in prevention argues that it is the effects of lipids after a meal that matter, not fasting lipid levels. Four hours after a meal high in fat and cholesterol, harmful phenomena such as endothelial dysfunction, vascular inflammation and oxidative stress are observed. While egg whites are unquestionably a source of high-quality protein, egg yolks should not be eaten by people with cardiovascular risks or genetic predispositions to heart disease.

The association between the consumption of eggs or foods containing cholesterol and the risk of CVD is modest. But since this risk increases with the amount consumed, people who eat a lot of eggs or foods containing cholesterol have a significant risk of harming their cardiovascular health. For example, according to the study published in JAMA, people who consume two eggs per day instead of 3 or 4 per week have a 27% higher risk of CVD and a 34% higher risk of premature mortality. It is therefore prudent to minimize the consumption of eggs (less than 3 or 4 eggs per week) and meat in order to limit the high intake of cholesterol and choline and avoid promoting atherosclerosis.