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.

Time-restricted feeding: A tool to lose weight and improve cardiometabolic health

Time-restricted feeding: A tool to lose weight and improve cardiometabolic health

OVERVIEW

  • The two most popular forms of time-restricted feeding (intermittent fasting), limiting eating to 4 hours or 6 hours a day, were tested in obese people.
  • Both diets produced the same body weight loss (–3.2%) at the end of the two-month study.
  • Both diets reduced caloric intake by ∼550 kcal/day, without participants having to control the number of calories consumed.
  • Similar reductions in insulin resistance and oxidative stress were observed for both types of diet.

Intermittent fasting has grown in popularity in recent years, as several clinical studies have shown that it can help lose weight and prevent metabolic disease (see also our article: “Intermittent fasting: A new approach to weight loss?”).

There are three different types of diets that are part of intermittent fasting:

  • Alternate-day fasting where you alternate between a day of “fasting” when you consume very few calories (0–800 calories) followed by a day where you eat normally.
  • The 5:2 diet is a modified version of alternate-day fasting that includes two days of fasting per week (<600 calories), followed by five days of normal eating.
  • Time-restricted feeding recommends limiting the period during which food is consumed. The two most popular forms of this diet are the Warrior Diet, where you limit eating to a period of 4 hours a day, and the 18:6 diet, where you fast for 18 hours and eat over a period of 6 hours.

In a randomized controlled study recently published in Cell Metabolism, nutrition researchers wanted to answer the following question: does restricting feeding to a 6-hour window (18:6 diet) produce the same effects on body weight and metabolic risk factors as a 4-hour restriction (Warrior Diet or 20:4 diet)? The researchers hypothesized that compared to a diet limited to a 6-hour period, a diet limited to 4 hours would lead to greater weight loss, a greater drop in blood pressure, better blood glucose control, and more pronounced effects on oxidative stress.

The 58 obese participants (BMI: 30–50 kg/m2) in the 8-week study were divided into three groups:

  • A control group who could eat normally and without time restrictions.
  • A group that had to eat between 3 p.m. and 7 p.m., a restriction over a 4-hour
  • A group that had to eat between 1 p.m. and 7 p.m., a restriction over a 6-hour

There were no restrictions on the amount or type of food consumed and participants were not required to control their calorie intake. During the fasting period, participants were encouraged to drink plenty of water and were allowed to consume calorie-free drinks such as black tea, coffee (without sugar or milk), or diet soda.

After 8 weeks, the two groups that limited their diet to 4-hour and 6-hour periods both lost 3.2% ± 0.4% body weight, while the control group did not significantly lose weight (0.1% ± 0.4%). The 4-hour limited diet therefore did not lead to more weight loss than over a 6-hour period, contrary to the initial hypothesis.

Fasting blood glucose levels were not significantly different between the three groups, eight weeks after the start of the study. In contrast, fasting insulinemia, insulin resistance, and oxidative stress were reduced in both intervention groups, compared to the control group, with no significant difference between the two intervention groups (4 hours vs. 6 hours).

Several parameters, including blood pressure, LDL cholesterol, HDL cholesterol and triglyceride levels were not altered by the time-restricted diet, both for the 4-hour and the 6-hour limitation. These latest results are at odds with previous studies where significant reductions in these parameters were observed. The authors cannot explain these differences, but they suggest that their study may not have had enough participants to be able to observe significant effects on these secondary endpoints of the study.

Summary of key findings from previous studies on intermittent fasting
The effects of alternate-day fasting and the 5:2 diet (2 days of fasting and 5 days of normal eating) on the risk of metabolic disease have been the subject of more than a dozen studies in humans to date. Alternate-day fasting produces 5–7% body weight loss over a short period of time (less than six months). It also provides several metabolic benefits such as reduced blood pressure, LDL cholesterol, triglycerides, fasting insulinemia, insulin resistance, inflammation and oxidative stress. The effects of the 5:2 diet are similar to alternate-day fasting.

Time-restricted feeding has been the subject of fewer studies. There have been six clinical studies in humans to date, and only three of these studies have examined the effects of this diet on body weight loss. According to these few studies, the time-restricted diet produces a loss of body weight of around 2.6 to 3.6% and a reduction in calorie intake of 8 to 20% in 12 to 16 weeks. This type of intermittent fasting has significant effects on metabolic health: marked drop in fasting blood sugar, insulinemia, and insulin resistance. A drop in blood pressure has been observed in several studies, even without loss of body weight. The effects on blood lipid levels are less clear. A few studies of time-restricted feeding report lower triglycerides and LDL cholesterol, but most studies have found no effect on these same lipids.

Conclusion
Although the weight loss seen in this new study is moderate, the authors believe that time-restricted feeding is a promising intervention for those who wish to lose weight. Limiting feeding to a 6-hour period is easier to practice than a 4-hour restriction since someone can, for example, not eat breakfast and have the two meals of the day at relatively normal times (1 p.m. and 6:30 p.m., for example). This study indicates that the 18:6 diet will have as many health benefits as the Warrior Diet (20:4).

Exercise on an empty stomach to burn more fat

Exercise on an empty stomach to burn more fat

OVERVIEW

  • Sedentary men did supervised exercise 3 times a week for 6 weeks after ingesting either a sugary drink or a sugar-free placebo drink.
  • Participants who exercised on an empty stomach “burned” twice as much fat as those who consumed a sugary drink before exercise sessions.
  • Participants who exercised on an empty stomach also saw their insulin sensitivity improve more than those who ingested calories before the exercise sessions.

It is now well established that exercise in all its forms improves overall health. In addition to increasing cardiorespiratory capacity, regular exercise improves insulin sensitivity and reduces insulin secretion after meals. However, each individual’s response to similar exercises is very variable: some people become fitter or lose more weight or stabilize their blood sugar more than others. One of the factors that could be important is the timing of meals and exercise sessions. Muscles use energy in the form of sugars and fats, which can come from the last meal or from reserves in the body when fasting. The accumulation of too much fat in the muscles is problematic for health, because the fat-engorged muscles do not respond well to insulin, a hormone that stimulates the absorption of glucose by muscle, adipose and liver cells. Therefore, excess fat in the muscles can contribute to insulin resistance, hyperglycemia and increased risks of type 2 diabetes and other metabolic imbalances.

In a randomized controlled study, an international team tested the effect of the timing of meals on the metabolic benefits associated with exercise. Thirty sedentary and overweight or obese men were divided into three groups (see figure below): a control group that continued to live normally and two other groups that did supervised exercise in the morning (treadmill running), three times a week for six weeks, without breakfast; the second group ingested a vanilla-flavoured drink containing 20% sugar two hours before each exercise session, whereas the third group ingested a vanilla-flavoured placebo beverage containing water and no calories. After each morning exercise session, participants in both groups drank the beverage they had not received prior to the session. This means that all the runners ingested the same number of calories and did the same amount of exercise, only the timing of calorie consumption differed, i.e. before or after the exercise session.

Figure. Protocol schematic for the training study.  Adapted from Edinburgh et al., 2019.

The study was randomized and controlled, so participants did not know what type of drink they ingested before and after exercising. 83% of participants reported that they could not detect differences between the sugary and placebo drinks or were unable to identify which beverage contained sugar. It should be noted that the sugar used here, maltodextrin (partially hydrolyzed starch), has a very low sweetening power and is therefore difficult to detect.

Blood samples and biopsies of a muscle located in the thigh (vastus lateralis) were taken before and after the intervention in order to measure different metabolites and proteins of interest. Glucose, glycerol, triglycerides, HDL and LDL cholesterol, insulin, C-peptide, and fatty acids were measured in the blood, and phospholipid composition, protein content involved in glucose transport, insulin signalling and lipid metabolism were measured in the vastus lateralis muscle samples.

Not surprisingly, the control group did not improve their physical fitness or insulin sensitivity during these six weeks. On the contrary, the other two groups who exercised saw their fitness improved and their waistline decreased, although only a few of the participants lost weight.

The most striking finding of the study was that participants who exercised on an empty stomach “burned” twice as much fat as those who consumed a sugary drink before the exercise session. Yet participants in both groups who exercised expended the same number of calories.

Participants who ran on an empty stomach also saw their insulin sensitivity improve further and their muscles synthesized greater amounts of certain proteins (AMP-activated protein kinase, an energy sensor, and the glucose transporter GLUT4) involved in the response of muscle cells to insulin and the use of sugars.

Studies on exercise and metabolic health will need to consider the timing of meals in the future. Since it is not possible for everyone to exercise in the morning after the night fasting period, it will be interesting to check if it is possible to obtain the same metabolic benefits after a shorter daytime fasting period, for example, when exercising in the early evening after skipping lunch. However, it should not be forgotten that any physical activity (walking, housework, etc.), performed at any time of the day, is beneficial for health.

Intermittent fasting: A new approach to weight loss?

Intermittent fasting: A new approach to weight loss?

The excessive accumulation of body fat, particularly when concentrated in the abdomen, is an important risk factor for several diseases, including heart diseasetype 2 diabetesdementia as well as several types of cancer. Consequently, for people who are overweight or obese, weight loss is a very important way to reduce the incidence and progression of several of these diseases.

Many studies show that weight loss is indeed associated with a significant improvement of several aspects of the metabolism. For example, an American study showed that among overweight individuals with diabetes, a 5-10% loss of body weight was associated with a notable improvement of several risk factors for heart disease (glycemia, blood pressure, triglycerides, HDL cholesterol) after one year.  These positive effects are even more pronounced when weight loss is more significant, in particular with regard to sugar metabolism, but the key takeaway is that weight loss, even when relatively modest, has a very positive impact on health.

Unfortunately, losing weight is not a “small” matter, since it entails significantly reducing calorie intake for long periods.  However, the results of the CALERIE (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy) study show that it is possible: in this study, conducted over two years, participants successfully reduced their calorie intake by 12%, which translated into a 10% weight loss and a significant improvement of several cardiometabolic risk factors. However, this decrease in calorie intake was well below what researchers wanted (25%), even though participants were closely monitored and could ask for advice from several specialists in the research team.  Significantly reducing food consumption, namely by 500 to 600 calories daily, thus represents a difficult objective to achieve for most people, which explains the well-documented difficulty of adhering, in the long term, to popular weight loss diets developed over the last few years.  Generally, these diets are associated with relatively significant short-term weight loss, but it is very difficult to maintain this loss in the longer term and the majority of people regain the lost pounds (and sometimes even more) after a certain time.  When these diets are repeatedly attempted, they cause what is known as the “yo-yo” effect, which is not only discouraging but can also be harmful to health: in fact, a recent study showed that in patients with a history of cardiovascular events, frequent body-weight fluctuations were associated with a marked increase in the risk of myocardial infarction (117%), stroke (136%), diabetes (78%), and premature death (124%).

Strict but brief restriction
To overcome these limitations, more and more researchers have focused on fasting as a way to take advantage of the benefits associated with caloric restriction.  Instead of consistently reducing the number of calories consumed every day, which seems virtually impossible for the majority of people, this approach involves alternating periods of normal calorie intake with more or less prolonged fasting periods. What we refer to as “intermittent fasting”, for example, consists of fasting or drastically reducing calorie intake (500 calories a day) intermittently, for example, 1 or 2 days a week. These fasting periods can be consecutive, as in the 5:2 diet (5 days of normal diet followed by two days of fasting), or alternating (one out of two days, for example). In both cases, studies show that intermittent fasting is associated with weight loss and an improvement of several cardiometabolic markers, similar to the results obtained following continuous caloric restriction, and could therefore present an interesting alternative.

Nevertheless, an inherent limit to this type of strict fasting is that it remains very difficult for many people to completely deprive themselves of food for 2-3 days. Not to mention that the complete elimination of calories can lead to severe complications in some people, in particular in elderly or frail subjects.

It is in this context that Dr. Valter Longo’s team (University of South California) came up with the idea of developing a diet that reproduces the positive effects of fasting on the body, but without completely forgoing food. Their research conducted on mice showed that a less strict caloric restriction (calories reduced by half), achieved through a plant-based diet high in polyunsaturated fats but low in protein and carbohydrates, could mimic the effects of very strict fasting on several cardiometabolic risk factors and was associated with a significant improvement on health (fewer cancers, reduction in bone-density loss, improvement of cognitive performance) as well as of the life expectancy of the animals. Referred to as the “fasting mimicking diet” (FMD), this new type of caloric restriction could thus represent a new approach to not only lose weight but also improve health in general.

This strategy’s potential is clearly illustrated by the results of a phase 2 clinical study recently published in Science Translational Medicine. The 100 study participants were divided into a control group that followed their usual diet, and a study group that were prescribed the FMD for 5 consecutive days every month, for a period of three months. Afterward, the groups were switched, meaning that the participants from the first control group tested the FMD, whereas the volunteers in the study group reverted to their usually dietary habits.

The results obtained are extremely interesting.  One week following the end of the third caloric restriction cycle using the FMD, participants had lost on average 3 kilos (6.6 lb.), had a smaller waistline (3 cm), and showed an improvement in their blood pressure compared to the control group (- 4 mm Hg). Positive effects of caloric restriction on fasting glucose, the lipid profile (triglycerides, cholesterol), inflammatory protein levels (C-reactive protein), and certain growth factors such as IGF-1 (implicated in the development of cancer) were also observed, in particular in individuals who presented anomalies in these markers at the start of the study. For example, the blood sugar level of participants who were prediabetic at the beginning of the study returned to normal after the intervention.

Caloric restriction using the FMD is still at the experimental stage and further research is necessary to better evaluate its effects in the longer term. In the meantime, one thing is certain: most chronic diseases currently affecting the population are a consequence of the overconsumption of food, and there are only advantages to eating less, even if only a few days a month.