細胞生理生化2018;48:1901-1914
Mechanisms of Action of Kefir in Chronic Cardiovascular and Metabolic Diseases
Fabio S Pimentaa
Maria Luaces-Regueirab Alyne MM Tona
Bianca P Campagnaroa
Manuel Campos-Toimilb Thiago MC Pereiraa,c
Elisardo C Vasqueza
Maria Luaces-Regueirab Alyne MM Tona
Bianca P Campagnaroa
Manuel Campos-Toimilb Thiago MC Pereiraa,c
Elisardo C Vasqueza
aLaboratory of Translational Physiology and Pharmacology, Pharmaceutical Sciences Graduate Program, Vila Velha University (UVV), Vila Velha, Brazil, bPharmacology of Chronic Diseases (CDPHARMA), Molecular Medicine and Chronic Diseases Research Centre (CIMUS), University of Santiago de Compostela, Santiago de Compostela, Spain, cFederal Institute of Education, Science and Technology (IFES), Vila Velha, Brazil
Key WordsMicrobiota • Endothelial dysfunction • Baroreflex • Insulin resistance • Hypertension • Dyslipidemia • Atherosclerosis
Abstract
The gut microbiota maintains a complex mutual interaction with different organs of the host. Whereas in normal conditions this natural community of trillions of microorganisms greatly contributes to the human health, gut dysbiosis is related with onset or worsening of diverse chronic systemic diseases. Thus, the reestablishment of gut microbiota homeostasis with consumption of prebiotics and probiotics may be a relevant strategy to prevent or attenuate several cardiovascular and metabolic complications. Among these functional foods, the synbiotic kefir, which is a fermented milk composed of a mixture of bacteria and yeasts, is currently the most used and has attracted the attention of health care professionals. The present review is focused on reports describing the feasibility of kefir consumption to provide benefits in cardiometabolic diseases, including hypertension, vascular endothelial dysfunction, dyslipidemia and insulin resistance. Interestingly, recent studies show that mechanisms of actions of kefir in cardiometabolic diseases include recruitment of endothelial progenitor cells, improvement of the balance vagal/sympathetic nervous system, diminutionof excessive generation of reactive oxygen species, angiotensin converting enzyme inhibition, anti-inflammatory cytokines profile and alteration of the intestinal microbiota. These findings provide a better understanding about the mechanisms of the beneficial actions of kefir and motivate further investigations to determine whether the use of this synbiotic could also be translated into clinical improvements in cardiometabolic diseases.
Background
In recent years, the incidence of cardiovascular and metabolic diseases in developed and developing countries has been increasing year by year, and the damage to global human health and quality of life is increasing. If the existing treatment methods cannot be effectively improved or better health care options can not be provided, the impact of such diseases on the global population will be increasingly serious. In recent years, scientists have found that intestinal flora can interact with human body, and the great changes of intestinal flora may further cause systemic diseases, such as cardiovascular and metabolic diseases. In the health management of these patients, the use of probiotics or their metabolites to improve the intestinal flora and further regulate metabolic diseases has begun to attract the attention of scientists and industry.
Intestinal flora generally refers to non pathogenic microorganisms in the intestinal tract, which can form symbiotic bacteria with intestinal cells. These probiotics and intestinal cells can jointly form a barrier to foreign pathogens, to avoid pathogen infection and kill these bacteria. At the same time, some nutrients of human body also come from the metabolites of intestinal flora. In addition, these intestinal flora can further affect the distal organs of the body. For example, the flora bacteria regulate the brain and autonomic nervous system through the influence of endocrine and circulatory system. Figure 1 shows that the factors that destroy the intestinal flora are quite complex, including acute and chronic intestinal infections, antibiotic use, systemic diseases, aging, diet, living habits, etc. Therefore, this paper reviews the scientific and clinical experiments to further explore the effects of this functional food on cardiovascular system, endothelial cell function, arterial hypertension and hyperlipidemia, insulin antagonistic effect and other cardiovascular diseases.
2、 Kefir fermented milk and functional food
The definition of functional food is that through long-term consumption of the product, in addition to the basic nutrients, it can bring health promotion effect to human body through the active ingredients, which is the lack of general food. With the world's urgent demand for functional food, more and more scientists and companies have invested in the research and development of products or materials, and many functional food have come out, so we are also curious about which functional food can change or improve intestinal flora, and further affect human health. The earliest human cognition of bacteria is a kind of microorganism that can cause disease. But with the progress of science and technology, we gradually understand that there are many kinds of bacteria, better or worse. At the beginning of last century, Dr. Elie Metchnikoff, the Nobel Prize winner of physiology from the Soviet Union, first proposed the theory that eating lactobacillus can bring benefits to human health! Over 100 years ago, kefir fermented milk has not been submerged by the historical trend, but also become one of the super foods. Many studies have pointed out that kefir fermented milk can improve intestinal flora, immune system and body organ function.
Probiotics and synbiotics (mixture of probiotics and probiotics) have been used as dietary supplements to improve the balance of intestinal bacteria for many years. More and more researches have explored how probiotics can improve human health in the intestinal tract, such as producing bacteriostatic substances, occupying the surface of intestinal epithelial cells, making pathogens unable to attach, producing nutrients, immunomodulating, inhibiting pathogens producing toxins, etc. At the same time of using probiotic products, probiotics (such as indigestible oligosaccharides) will be added as probiotic food to promote probiotic colonization in the intestinal tract. Therefore, functional products are mostly composed of probiotics and probiotics at the same time, which can achieve the maximum benefit.
Compared with probiotic products, fermented milk, a health promoting drink, has existed in human society for hundreds or even thousands of years. Hundreds of years ago, kefir fermented milk first appeared in the mountains of the north Caucasus, and it has been passed down from generation to generation and even spread all over the world. With the spread of kefir granule, a fermenting bacterium, more and more people in the world will make fermented milk with kefir granule at home. Kefir granules are symbiotic microfacies composed of a variety of lactic acid bacteria, yeast and acetic acid bacteria. Kefir granules circulated in different places may have differences in microfacies composition and fermented milk function. The lactic acid bacteria and yeast identified by kefir granules used by our team are known to have the effect of avoiding intestinal inflammation.
3、 New concept of kefir fermented milk in cardiovascular health care
Because of the spread and application of kefir fermented milk in the past hundreds of years and the scientific research in the past hundred years, its health promotion function has been accepted by the public in succession, and it has been listed as one of the super foods for health promotion in European and American countries. Scientific teams in various countries have also focused on various studies of kefir fermented milk, hoping to reveal its biological activities through scientific methods, hoping to apply the fermented milk to more health functions such as cardiovascular health care.
3.1 effect of kefir fermented milk on blood pressure regulation
The antihypertensive activity of kefir fermented milk was verified by using spontaneous hypertensive rat model. The antihypertensive activity mainly came from lactic acid bacteria or metabolites in fermented milk. Our team also showed that long-term consumption of kefir fermented milk can not only reduce the high blood pressure of spontaneous hypertensive rat (SHR), but also improve the problems of tachycardia and left ventricular hypertrophy. On the one hand, feeding kefir fermented milk can reduce the reactive oxygen species (ROS) in serum, reduce the oxidative pressure in blood vessels to avoid cardiovascular system abnormalities, such as: inflammation of blood vessels, blood pressure rise, endothelial cell damage, arterial smooth muscle fibrosis, etc. On the other hand, the metabolites in kefir fermented milk can regulate blood pressure by promoting vagal sensitivity and inhibiting vasoconstrictor converting enzyme activity. In addition, other teams also found that different lactic acid bacteria and their metabolites in kefir fermented milk also had the activity of lowering blood pressure.
3.2 kefir fermented milk improves cardiovascular function through autonomic nerve regulation
There are many causes of hypertension in SHR rats, including autonomic nervous disorders. First of all, the activation of sympathetic nerve and the deactivation of parasympathetic nerve (vagus nerve) will lead to the rise of blood pressure. After 60 days of feeding kefir fermented milk, autonomic nerve rebalancing can be achieved, and then the high blood pressure can be reduced.
In addition, cardiovascular diseases and metabolic diseases in SHR rats can also cause abnormal baroreflex. However, if kefir fermented milk is fed for 60 days, the abnormality of improving baroreflex can be detected by observing arterial blood pressure and heartbeat, mainly by adjusting the activity of sympathetic and parasympathetic nerves. However, further analysis is still needed to understand the role of living bacteria and metabolites in improving autonomic disorders and hypertension. Some evidences show that the above functions may be achieved by improving the secretion of GABA, serotonin or catecholamine in the body, but more experiments are needed to prove the above. Therefore, we conclude that the restoration of vagus function and the regulation of blood pressure may be through kefir fermented milk to improve the intestinal flora ecology of SHR rats, and then change the endocrine and brain gut axis.
3.3 kefir fermented milk improves endothelial cell damage
Healthy endothelial cells in blood vessels are important factors to determine the balance of vasoconstriction and relaxation. In patients with cardiovascular and metabolic diseases, abnormal endothelial cell renewal will cause imbalance of vasoconstriction and relaxation regulation, and then induce arteriosclerosis and hypertension. In human body, oxidative pressure is a common factor that damages endothelial cells, because oxidative pressure can destroy the utilization of nitric oxide by endothelial cells, and then affect their functions. We hope that through the use of drugs or functional food to reduce the oxidative pressure in the blood, so as to maintain the status and function of endothelial cells. Physiologically, we can judge whether the vascular endothelium is damaged by analyzing the response of individuals to nitric oxide related mechanisms: we mainly observe whether the vascular vasodilator acetylcholine induced relaxation response is damaged, or the response to α - 1 vasoconstrictor is intensified.
In SHR rats, long-term consumption of kefir fermented milk can improve the injury of vascular endothelial cells, and improve the relaxation response of aortic sinuses induced by acetylcholine. In addition, kefir fermented milk can reduce the production of free radicals such as · O2 - and onoo-h2o2 in blood, increase the utilization of no in vascular endothelial cells, and improve the damage and function of vascular endothelial cells. Because kefir fermented milk can increase the utilization rate of endothelial cells to nitric oxide and reduce the production of free radicals, it is quite suitable to be used as an antioxidant nutrition and health care supplement. It was further found in the literature that kefir fermented milk could further enhance the antioxidant activity of kefir fermented milk by inhibiting the free radicals and NADPH induced by TLR-4 (Toll like receptor-4), reducing the body's oxidative pressure.
In addition to oxidative stress, our team confirmed the relationship between vascular endothelial cell damage and the generation of vascular physiological defects. It was found by SEM that kefir fermented milk could repair the vascular endothelial damage of SHR. The results showed that kefir fermented milk not only had antioxidant activity, but also had the function of attracting endothelial cells to repair endothelial cells, which contributed to its cardiovascular health care.
Although the effects of oxidative stress on endothelial cell injury have been reported, the molecular mechanism of oxidative stress is still unclear. In addition to the influence of probiotics and human body, kefir fermented milk may also increase the synthesis of antioxidant enzymes or other components that can eliminate free radicals, or inhibit the production of vasoconstrictor converting enzymes through ace to avoid the promotion of oxidative pressure. The results show that kefir fermented milk can maintain or improve the function of endothelial cells through multi-faceted and multi mechanism.
3.4 anti inflammation and anti atherosclerotic function of kefir fermented milk
The serious complications of atherosclerotic disease, such as stroke and myocardial infarction, are the main causes of death of patients with cardiovascular disease in the world. Therefore, the development of drugs or functional foods that can be used to prevent or improve atherosclerotic disease is an important topic in the field of cardiovascular medicine and health care. It was pointed out in the literature that the living bacteria and metabolites in kefir fermented milk have the biological activities of reducing blood cholesterol and immune regulation, so as to avoid the occurrence and deterioration of atherosclerotic sclerosis. At present, there are two possible mechanisms of action: 1. Inhibition of mhg-coa reductase activity to inhibit cholesterol synthesis; 2. Promotion of cholangiolysis enzyme activity and elimination of cholic acid to reduce cholesterol production, but more evidence is needed to confirm this statement. In addition, in the model of high cholesterol mice, it was found that the metabolites in kefir fermented milk could promote the increase of high density lipoprotein (HDL), decrease of low density lipoprotein (LDL), inhibit inflammation and immune regulation.
In the anti-inflammatory and immunomodulatory part, both cell test and animal in vivo test showed that kefir fermented milk could significantly reduce the expression of proinflammatory factors such as TNF - α and inf - γ in serum. In addition, some studies show that kefir fermented milk can activate Th2 cells to inhibit Th1 cells, and finally achieve the effect of inhibiting inflammatory response. In recent years, it has been found that the components of non living bacteria in kefir fermented milk can inhibit the deposition of lipid in vascular endothelium and arteriosclerosis without changing blood cholesterol. In conclusion, kefir fermented milk can regulate the synthesis of cholesterol in serum and inhibit the occurrence of inflammatory reaction in blood vessels, and then inhibit the occurrence and deterioration of atherosclerotic arteriosclerosis. Our team's research shows that after long-term treatment with the components of non living bacteria in kefir fermented milk, it can regulate the performance of inflammatory and anti-inflammatory cell hormones, and avoid lipid accumulation of vascular endothelium under the condition of high cholesterol. It shows that kefir fermented milk not only has the effect of anti cholesterol, but also can regulate and inhibit the inflammatory reaction through the immune system, so as to avoid atherosclerosis.
3.5 kefir fermented milk in the regulation of metabolic syndrome function insulin resistance
The prevalence rate of metabolic syndrome population in the world has a considerable gap, about 10% ~ 84%, due to genetic, regional, dietary habits and other factors. Metabolic syndrome is caused by a series of physiological and biochemical disorders, including insulin resistance, hyperlipidemia, hypertension, obesity, liver fibrosis, endothelial cell dysfunction, chronic inflammation, etc. Metabolic syndrome can increase the risk of cardiovascular disease by 2 times, type 2 diabetes by 5 times and death by 1.5 times. Among them, obesity and insulin resistance are the main risk factors for type 2 diabetes and cardiovascular disease.
By changing the current diet habits and medical control, we have achieved little in control and improvement, which shows that we still need more effective methods and products. In the past decade, scientists have found that healthy gut flora can help control obesity and insulin resistance. For example, transplanting gut flora collected from healthy subjects into the gut of insulin resistant patients can effectively improve their metabolism, showing that the adjustment of gut flora can improve the symptoms of metabolic syndrome. The physiological explanation of the above situation is mainly due to the fact that intestinal flora can regulate the metabolism of carbohydrate and lipid, the metabolism of glycogen and the storage of fat in human intestine, so as to improve the function of obesity. For example, using fatty liver animal model analysis, some scientists have confirmed that kefir fermented milk can reduce lipid synthesis and increase fatty acid oxidation, thus improving common liver fatty lesions in metabolic syndrome patients. Therefore, kefir is a kind of fermented milk which can significantly improve the symptoms of metabolic syndrome.
In addition, kefir fermented milk may activate PI 3-kinase and downstream insulin signaling pathway through its metabolites to increase the utilization of glucose by muscle cells. At present, different teams have verified the application of kefir fermented milk to reduce the blood glucose of type I diabetes and type II diabetes animal models by animal experiments, and also found that kefir fermented milk can improve the balance of pro-inflammatory / anti-inflammatory factors, showing the application potential of kefir fermented milk in improving the symptoms of metabolic syndrome.
4、 Conclusion:
At present, studies have shown that there is a very close relationship between intestinal flora and cardiovascular disease. Probiotics in kefir fermented milk and other metabolic derivatives (such as peptides, organic acids, polysaccharides, etc.) can regulate body functions such as central nervous system, immune system, metabolic pathway, and circulatory system, so as to avoid atherosclerotic sclerosis and cardiovascular disease. In this review, we analyzed how kefir fermented milk can affect cardiovascular and metabolic diseases through intestinal flora or metabolites regulation, including autonomic nervous system regulation, cardiovascular function improvement, blood lipid reduction, insulin resistance improvement, and found out the possible mechanism. Kefir fermented milk has a long history of eating, and more and more scientific literature has revealed its activity of prevention of atherosclerotic sclerosis and improvement of metabolic syndrome, which is quite suitable for wide application. In the future, we still need more research to reveal the potential of application hidden in kefir fermented milk, in order to provide the best health promoting products for Chinese people.
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