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Eating behavior has changed dramatically in recent decades. The traditional breakfast-lunch-dinner pattern has been replaced by frequent snacking, large meals at night, and skipping breakfast. At the same time, the level of cardiometabolic diseases increased, including cardiovascular diseases and type 2 diabetes (DM2).

Irregular eating increases the risk of obesity, insulin resistance, and hyperglycemia, contributing to the development of type 2 diabetes. Conversely, a diet that maintains the timing and frequency of meals improves the quality of life and protects against the development of type 2 diabetes and cardiovascular disease.

Intermittent fasting improves insulin sensitivity

Intermittent fasting is a predetermined pause in food intake.

There are several modes of intermittent fasting:

  • Fasting every other day.
  • 5/2 – two days of fasting per week.
  • Fasting-mimicking diet – several consecutive days of low-calorie intake, then a normal eating cycle. Calorie restriction days are held every one to four months or every two weeks. Most of the diet on calorie restriction days is plant-based.
  • 12/12, 14/10, 16/8, and other modes – daily fasting for 12-16 hours.

Eating during the daytime is essential for fasting 12-16 hours daily. This regimen improves cardiometabolic health by increasing insulin sensitivity, normalizing blood pressure, and reducing oxidative stress. So, in a study on mice with obesity, one group of mice was starving at night, and the other had free access to food at any time. Night fasting in the first group of mice led to a decrease in body weight and fat mass, improved glycemic control, reduced hepatic steatosis, and better endurance during running.

How Intermittent Fasting Acts

Intermittent fasting works like a metabolic switch:

  • Fasting causes the body to use fatty acids and ketone bodies as fuel instead of glucose. During fasting, cells activate signaling pathways that enhance protection against oxidative and metabolic stress and remove or repair damaged molecules.
  • The resumption of food intake leads to increased levels of the peptide hormones GLP-1 and insulin. GLP-1 reduces food intake and has neuroprotective attributes. Insulin enhances glucose uptake and promotes tissue growth and neuroplasticity.

Intermittent Fasting Improves Gut Microbiota

Gut microbiota are microorganisms that inhabit the intestines. The microbiota regulates metabolism, digestion, immunity and affects liver disease, cancer, and neurodegenerative disorders.

The microbiota of obese people is less diverse than that of lean people. In addition, the microbiota of people with cardiometabolic disorders differs from that of healthy people. When microbiota-deprived mice were transplanted with microbiota from humans or rodents with cardiometabolic conditions, the mice also developed obesity, insulin resistance, and hypertension.

Intermittent fasting:

  • increases the bacterial diversity of the intestinal microbiota;
  • increases the number of Bacteroidetes and the production of short-chain fatty acids, which is associated with lower weight and improved cardiovascular health;
  • increases the number of Akkermansia and Lactobacillus, which help to reduce the number of opportunistic microorganisms.

Gut Microbiota Associated with Circadian Rhythms

Circadian rhythms regulate the sleep-wake cycle, cardiovascular activity, liver metabolism, endocrine function, meal times, and microbiota composition. Diurnal fluctuations in the gut microbiota composition are necessary to regulate metabolism and nutrient absorption, energy expenditure, waste excretion, and immune function.

In rodent studies, diurnal fluctuations in microbiota composition were attenuated by:

  • a diet high in fat;
  • change of time zones;
  • deficiency of genes necessary for maintaining circadian rhythms.

Under any of these conditions, the mice also became prone to metabolic disorders.

A human study has shown that disruption of the daily fluctuations in the microbiota composition increases the risk of type 2 diabetes. Intermittent fasting restructures the microbiota in diabetes, preventing diabetic retinopathy.

Intermittent Fasting in Cardiometabolic Disorders

Obesity and lipid metabolism

Obesity poses a severe risk to cardiovascular health. Research supports the benefits of intermittent fasting for weight loss in obese people:

  • In a study of mice fed with a high-fat diet, fasting for 16 hours a day reduced body weight and fat mass regardless of total calorie intake and without any change in physical activity.
  • A meta-analysis of randomized controlled trials in overweight and obese people showed that fasting 2-3 days per week led to weight loss and reduced body fat, compared with constant calorie restriction.
  • A clinical study in obese people showed that fasting 16 hours daily and three full meals a day moderately reduced participants’ weight.

Intermittent fasting stimulates the formation of beige adipocytes, fat cells that can burn calories to generate heat, and this effect depends on the intestinal microbiota. In a mouse study, alternate-day fasting promoted the accumulation of beige adipocytes in white fat, accompanied by weight loss and altered microbiota composition. Antibiotics reversed the beneficial effects of fasting, but microbiota transplantation improved metabolic health.

Gut microbiota affects energy metabolism:

  • regulates genes that control the absorption of lipids and nutrients;
  • produces substances that promote the formation of beige adipocytes in adipose tissue.

Glycemic control

Intermittent fasting may lower blood glucose levels and improve glycemic control in patients with type 2 diabetes. Calorie restriction has a similar effect.

The composition of the gut microbiota depends on blood glucose levels and adapts to regular fasting and eating periods, circadian rhythms, and intermittent fasting:

At the same time, the high abundance of Akkermansia muciniphila helps to reduce blood glucose levels and improve insulin sensitivity.

A fasting-mimicking diet improves insulin sensitivity and β-cell function, restores gut microbiota, and prevents the progression of diabetes.

Hypertension

Persistent high blood pressure can lead to heart failure and vascular problems. Research confirms the healing effects of fasting in hypertension and its association with the gut microbiota:

  • A five-day fast followed by a low-sodium diet reduced systolic blood pressure in patients with hypertension and metabolic syndrome. This fasting regime also changed the gut microbiota by stimulating the production of short-chain fatty acids.
  • In hypertensive stroke-prone rats, fasting every other day for five weeks significantly reduced blood pressure. Fasting altered the gut microbiota by increasing the abundance of Bacteroides uniformis, Lactobacillus reuteri, and Lactobacillus johnsonii. For microbiota-free rats, microbiota transplantation from fasted rats prevented increased blood pressure.

Intermittent Fasting in Long-term Cardiometabolic Complications

Expected consequences of diabetes are cardiovascular disease and microvascular complications, which include retinopathy (retinal vascular disease) and nephropathy (kidney disease).

Diabetic Retinopathy

Retinopathy can lead to blindness. Nevertheless, the risk of vision loss can be reduced with early detection and timely treatment to control glucose and blood pressure.

The gut microbiota of patients with diabetic retinopathy is significantly different from the microbiota of healthy individuals and the microbiota of patients with type 2 diabetes without retinopathy. Patients with diabetic retinopathy have reduced Bifidobacterium and Turicibacter and increased Akkermansia. Biomarkers for diabetic retinopathy are the bacterial families Pasteurellaceae, Oxalobacteraceae, and Gallionellaceae. The level of Pasteurellaceae in patients with diabetic retinopathy is reduced, and the absence of Pasteurellaceae may mean a poor prognosis.

Studies show that intermittent fasting improves the prognosis of diabetic retinopathy:

Cognitive impairment

T2DM can cause central nervous system complications, including structural changes or atrophy of the brain, damage to brain microvessels, neuroinflammation, and changes in the electrophysiological properties of the brain. These changes ultimately lead to cognitive decline and increase the risk of Alzheimer’s disease.

Intermittent fasting counters the development of neurodegenerative diseases by improving the microbiota. So, in mice with diabetes, a decrease in cognitive functions was observed. Fasting every other day for 28 days reduced anxiety behavior, improved locomotor activity and synaptic structure, maintained insulin sensitivity, increased mitochondrial numbers, and improved energy metabolism in the hippocampus. Improvement in brain function was accompanied by an increase in Lactobacillus and Odoribacter and a decrease in Enterococcus, Streptococcus, and Enterococcaceae. Antibiotics partially reversed the protective effect of intermittent fasting on cognition.

Heart failure

Research confirms the benefits of intermittent fasting for heart and vascular health:

In patients with heart failure, intestinal microbiota balance is disturbed. Intermittent fasting restores the balance of the intestinal microbiota, improving cardiac function:

  • In a study of mice prone to hypertension and heart failure, supplementation with the probiotic bacteria Lactobacillus plantarum 299v reduced the risk of heart failure and resulted in better recovery from myocardial infarction.
  • Intermittent fasting increases the abundance of Bacteroides, which are responsible for producing short-chain fatty acids which provide energy to the heart.
  • Mice fed only while awake before myocardial infarction had better cardiac function than mice fed only when mice would usually sleep.

Nephropathy

Diabetes can lead to the development of end-stage renal disease. In patients with diabetic nephropathy, the gut microbiota is less diverse than in healthy individuals. Several studies have examined the effect of Ramadan fasting on the severity of diabetic nephropathy. Intermittent fasting did not affect renal function.

Conclusion

Intermittent fasting may improve outcomes of cardiometabolic disorders by altering the composition of the gut microbiota. Intermittent fasting promotes the production of short-chain fatty acids, which influence the physiology and course of disease.

Introducing intermittent fasting into clinical practice is complicated because human studies have shown conflicting results on the effect of intermittent fasting on metabolism due to the individual’s response to fasting. Therefore, postbiotic therapy can be used as a therapeutic intervention – applying bioactive molecules that affect metabolism produced by the intestinal microbiota. An example of such molecules is short-chain fatty acids, which contribute to the accumulation of beige adipocytes in white fat, weight loss, improved glycemic control, and cardiac function. However, postbiotic therapy also deserves further study.

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Reference

Time-limited diets and the gut microbiota in cardiometabolic disease

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