Control of inflammation through diet

Control of inflammation through diet

OVERVIEW

  • Chronic inflammation is actively involved in the formation and progression of plaques that form on the lining of the arteries, which can lead to the development of cardiovascular events such as myocardial infarction and stroke.
  • Two studies show that people whose diet is anti-inflammatory due to a high intake of plants (vegetables, fruits, whole grains), beverages rich in antioxidants (tea, coffee, red wine) or nuts have a significantly lower risk of being affected by cardiovascular disease.
  • This type of anti-inflammatory diet can be easily replicated by adopting the Mediterranean diet, rich in fruits, vegetables, legumes, nuts and whole grains and which has repeatedly been associated with a lower risk of cardiovascular events.

Clinically, the risk of having a coronary event is usually estimated based on age, family history, smoking and physical inactivity as well as a series of measures such as cholesterol levels, blood sugar level and blood pressure. The combination of these factors helps to establish a cardiovascular disease risk “score”, i.e. the likelihood that the patient will develop heart disease over the next ten years. When this score is moderate (10 to 20%) or high (20% and more), one or more specific drugs are generally prescribed in addition to recommending lifestyle changes in order to reduce the risk of cardiovascular events.

These estimates are useful, but they do not take into account other factors known to play an important role in the development of cardiovascular disease. This is especially true for chronic inflammation, a process that actively participates in the formation and progression of plaques that form on the lining of the arteries and can lead to cardiovascular events such as myocardial infarction and stroke.

The clinical significance of this chronic inflammation is well illustrated by studies of patients who have had a heart attack and are treated with a statin to lower their LDL cholesterol levels. Studies show that a high proportion (about 40%) of these people have excessively high blood levels of inflammatory proteins, and it is likely that this residual inflammatory risk contributes to the high rate of cardiovascular mortality (nearly 30%) that affects these patients within two years of starting treatment, despite a significant reduction in LDL cholesterol. In this sense, it is interesting to note that the canakinumab antibody, which neutralizes an inflammatory protein (interleukin-1 β), causes a slight but significant decrease in major cardiovascular events in coronary patients. Statins, used to lower LDL cholesterol levels, are also believed to have an anti-inflammatory effect (reduction in C-reactive protein levels) that would contribute to reducing the risk of cardiovascular events. One of the roles of inflammation is also demonstrated by the work of Dr. Jean-Claude Tardif of the Montreal Heart Institute, which shows that the anti-inflammatory drug colchicine significantly reduces the risk of recurrence of cardiovascular events.

Reducing chronic inflammation is therefore a very promising approach for decreasing the risk of cardiovascular disease, both in people who have already had a heart attack and are at a very high risk of recurrence and in healthy people who are at high risk of cardiovascular disease.

Anti-inflammatory diet
Two studies published in the Journal of the American College of Cardiology suggest that the nature of the diet can greatly influence the degree of chronic inflammation and, in turn, the risk of cardiovascular disease. In the first of these two articles, researchers analyzed the link between diet-induced inflammation and the risk of cardiovascular disease in 166,000 women and 44,000 men followed for 24 to 30 years. The inflammatory potential of the participants’ diet was estimated using an index based on the known effect of various foods on the blood levels of 3 inflammatory markers (interleukin-6, TNFα-R2, and C-reactive protein or CRP). For example, consumption of red meat, deli meats and ultra-processed industrial products is associated with an increase in these markers, while that of vegetables, fruits, whole grains and beverages rich in antioxidants (tea, coffee, red wine) is on the contrary associated with a decrease in their blood levels. People who regularly eat pro-inflammatory foods therefore have a higher inflammatory food index, while those whose diet is rich in anti-inflammatory foods have a lower index.

Using this approach, the researchers observed that a higher dietary inflammatory index was associated with an increased risk of cardiovascular disease, with a 40% increase in risk in those with the highest index (Figure 1). This increased risk associated with inflammation is particularly pronounced for coronary heart disease (acute coronary syndromes including myocardial infarction) with an increased risk of 46%, but seems less pronounced for cerebrovascular accidents (stroke) (28% increase in risk). The study shows that a higher dietary inflammation index was also associated with two risk markers for cardiovascular disease, higher circulating triglyceride levels as well as lower HDL cholesterol. These results therefore indicate that there is a link between the degree of chronic inflammation generated by diet and the risk of long-term cardiovascular disease, in agreement with data from a recent meta-analysis of 14 epidemiological studies that have explored this association.

Figure 1. Change in the risk of cardiovascular disease depending on the inflammatory potential of the diet. From Li et al. (2020). The dotted lines indicate the 95% confidence interval.

Anti-inflammatory nuts
A second study by a group of Spanish researchers investigated the anti-inflammatory potential of walnuts. Several epidemiological studies have reported that regular consumption of nuts is associated with a marked decrease in the risk of cardiovascular disease. For example, a recent meta-analysis of 19 prospective studies shows that people who consume the most nuts (28 g per day) have a lower risk of developing coronary artery disease (18%) or of dying from these diseases (23%). These reductions in the risk of cardiovascular disease may be explained in part by the decrease in LDL cholesterol (4%) and triglyceride (5%) levels observed following the consumption of nuts in intervention studies. However, this decrease remains relatively modest and cannot alone explain the marked reduction in the risk of cardiovascular disease observed in the studies.

The results of the Spanish study strongly suggest that a reduction in inflammation could greatly contribute to the preventative effect of nuts. In this study, 708 people aged 63 to 79 were divided into two groups, a control group whose diet was completely nut free and an intervention group, in which participants consumed about 15% of their calories daily in the form of walnuts (30–60 g/day). After a period of 2 years, the researchers observed large variations in the blood levels of several inflammatory markers between the two groups (Figure 2), in particular for GM-CSF (a cytokine that promotes the production of inflammatory cells) and interleukin-1 β (a highly inflammatory cytokine whose blood levels are correlated with an increased risk of death during a heart attack). This reduction in IL-1 β levels is particularly interesting because, as mentioned earlier, a randomized clinical study (CANTOS) has shown that an antibody neutralizing this cytokine leads to a reduction in the risk of myocardial infarction in coronary heart patients.

Figure 2. Reduction in blood levels of several inflammatory markers by a diet enriched with nuts. From Cofán et al. (2020). GM-CSF: granulocyte-monocyte colony stimulating factor; hs-CRP: high-sensitivity C-reactive protein; IFN: interferon; IL: interleukin; SAA: serum amyloid A; sE-sel: soluble E-selectin; sVCAM: soluble vascular cell adhesion molecule; TNF: tumour necrosis factor.

Taken together, these studies therefore confirm that an anti-inflammatory diet provides concrete benefits in terms of preventing cardiovascular disease. This preventative potential remains largely unexploited, as Canadians consume about half of all their calories in the form of ultra-processed pro-inflammatory foods, while less than a third of the population eats the recommended minimum of five daily servings of fruits and vegetables and less than 5% of the recommended three servings of whole grains. This imbalance causes most people’s diets to be pro-inflammatory, contributes to the development of cardiovascular diseases as well as other chronic diseases, including certain common cancers such as colon cancer, and reduces the life expectancy.

The easiest way to restore this balance and reduce inflammation is to eat a diet rich in plants while reducing the intake of industrial products. The Mediterranean diet, for example, is an exemplary anti-inflammatory diet due to its abundance of fruits, vegetables, legumes, nuts and whole grains, and its positive impact will be all the greater if regular consumption of these foods reduces that of pro-inflammatory foods such as red meat, deli meats and ultra-processed products. Not to mention that this diet is also associated with a high intake of fibre, which allows the production of anti-inflammatory short-chain fatty acids by the intestinal microbiota, and of phytochemicals such as polyphenols, which have antioxidant and anti-inflammatory properties.

In summary, these recent studies demonstrate once again the important role of diet in preventing chronic disease and improving healthy life expectancy.

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!