The perspectives of the means of metabolic syndrome correction in Xinjiang-Uyghur region of China

Alexander Suvorov, Tatiana Gupalova, Halmurat Upur, Denis Dubrovin,

(1Pavlov′s Institute of Experimental Medicine, Russian Academy of Science,Saint-Petersburg 197000, Russia; 2Xinjiang Medical University, Urumqi 830011, China)



·Silk Road Medicine Research·

The perspectives of the means of metabolic syndrome correction in Xinjiang-Uyghur region of China

Alexander Suvorov1, Tatiana Gupalova1, Halmurat Upur2, Denis Dubrovin1,2

(1Pavlov′sInstituteofExperimentalMedicine,RussianAcademyofScience,Saint-Petersburg197000,Russia;2XinjiangMedicalUniversity,Urumqi830011,China)

Absract:There has been proved the link between the intestinal microbiota composition characteristics and the development of diseases, in particular colorectal cancer, kidney failure, irritable bowel syndrome, intestinal infections, obesity, type I diabetes and metabolic syndrome (MS). Metagenomic studies demonstrated the presence of significant differences in the structure of the intestinal microbiota in populations of Europeans and Asians. In this aspect, the Xinjiang Uygur Autonomous region of China is the most affected district, where substantially the indigenous Uighur, Kazakh and also Han populations is affected. There is an objective need to ascertain the microecological and metabolic status of persons of the indigenous population in Western China, which are in the risk zone. The test for microalbuminuria is reliable method of kidney failure primary stages diagnosis, reflecting the initial stages of vessel pathology and the development of MS. It invariably correlates with an increase of cardiovascular morbidity and mortality. We introduce this screening test for early detection of predisposition to the development of the MS in the example of Xinjiang population for use also in other regions of China. There is a need to carry out the search, selection and analysis of the new strains of probiotics in the Xinjiang from national milk products with lactic acid or other fermented products with the purpose of studying their clinical characteristics. This will have an impact on increasing life expectancy and improving the quality of life of the population of Xinjiang.

microbiota; probiotics; metabolic syndrome correction; microalbuminuria test; Xinjiang-Uyghur region

The microbiota is currently considered as the organ responsible for maintaining homeostasis of the internal environment of the human body. Numerous studies have demonstrated the digestive and immunostimulating functions realization by symbiotic microorganisms included in the composition of the microbiota. The role of the resident microbiota as a factor of nonspecific protection against pathogens (the phenomenon of "colonization resistance") is well described. Despite the fact that the microbial community of symbionts of the human colon can be attributed to three major types, depending on the prevalence Bacteriodete ssp. (Enterotype 1), Prevotella (Enterotype 2) or Ruminococcus (Enterotype 3)[1], their biological and genetic diversity is very high and is determined by a variety of geographic, ethnic, and age characteristics of human populations, and dietary preferences[2].

Metagenomic studies demonstrated the presence of significant differences in the structure of the intestinal microbiota in populations of Europeans, Africans, American Indians and the white population of North America[3-4], associated mainly with diet. At the same time, a number of studies have noted the link between the characteristics of the composition of the intestinal microbiota and the development of diseases, in particular colorectal cancer[5], irritable bowel syndrome[6], intestinal infections[7], obesity[8]and type I diabetes[9].

Studies that reveal the mechanisms of participation of representatives of the intestinal microbiota in the development of these diseases, have, as a rule, the nature of experimental or observational. In different regions of the world, there are significant differences in the composition of the intestinal microbiota, due to the differences in the diet of the population in specific regions. Thus, microbiocenosis of Europeans who eat large amounts of animal protein and refined foods, is fundamentally different from the microbiocenosis of Africans, whose diet is dominated by plant fibers able to ferment cellulose. On this basis, for each specific region the comparative studies of the microbiota of healthy populations of different ages of patients with different diseases should be done to identify the most typical for this region composition of the normal microflora and to determine the diagnostic features of disturbed microbial balance. However, practically there are no large-scale prospective epidemiological studies, which would evaluate the significance of microbial communities and of individual genotypes of symbiotic microorganisms in the development of various diseases and pathological conditions. However, verification of the significance of microbial factor in metabolic diseases, which can be carried out in population-based epidemiological studies, is crucial to identify the priority areas of prevention of these diseases and to develop therapies, including correction of the composition of the microbiota and the elimination of microorganisms - the etiological factors of disease development. The study of biodiversity of microbial communities in different ethnic and geographical groups will allow identifying region-specific features of the microbiota and create a scientific basis for personalized therapy of diseases with regional specificity.

In accordance with the forecast of scientific and technological development of the Russian Federation for the period till 2030[10]the main focus will be addressed to the studies which could control the anthropogenic effects of intensive economic development of society, leading to the growth of human diseases associated with disorders of human metabolism, accompanied by a sharp increase in cardio-vascular pathologies. Another important direction is the strengthening of diagnosis and preventive treatment of diseases involving genomic and post-genomic technologies. In this regard, the search for new strains of probiotics that are intended for the correction of metabolic disorders in metabolic syndrome (MS), and the use of molecular diagnostic approaches for early diagnosis of metabolic disorders is extremely important.

MS, characterized by obesity, increased blood pressure and development of type II diabetes refers to the most common symptom-complexes of the modern world, affecting up to 30% of people in developed countries, including the United States and Western Europe. For the treatment of MS the following approaches are currently used: Approach 1: Assign of low-calorie (especially low carbohydrate) diet and increase physical activity. This approach is justified and necessary. However, only strong-willed efforts, with which it is possible to achieve weight reduction, will usually lead to stress and end with the reverse effect of weight gain larger than the original. Approach 2: The administration of drugs that increase tissue sensitivity to insulin, the prescription of statins to reduce the levels of total cholesterol and LDL (in case of violation of lipid exchange), the appointment of antihypertensive drugs (AD). If Metformin (Ciofora, Glucophage tablets), increasing the sensitivity of cells to insulin, at least has no side effects, the statins have serious side effects (encephalocele and hepatotoxic), due to their mechanism of action-blockade of cholesterol synthesis. This mechanism, unfortunately, leads to lower levels of total cholesterol, and LDL and HDL, i.e., atherogenic index, if it increases, does not change when taking statins. The intake of hypotensive drugs is also not devoid of side effects and requires constant monitoring and adjustment of therapy because of the effect of "habituation".

Our approach is to use the probiotics for the correction of MS. This does not exclude a partial use of the first approach, i.e. restrict carbohydrate component of the diet and total amount of food (obesity). However, with the use of probiotics we could see the decrease of stress reactions, mood enhancement, increased mental and physical activity. Therefore, the restriction in the diet requires not so much willpower, as in the case of non-use of probiotics. Moreover, it is much easier to start doing physical activities and sports, it also requires less emotional cost, physical exercise is much better tolerated, and the result will be better. Compared with the second approach, probiotics can normalize the level of total cholesterol, reduce LDL cholesterol and, unlike statins, increase HDL levels, i.e., reduce the atherogenic index. Moreover, because they does not block the synthesis of cholesterol, in normal levels of lipoproteins, the levels aren't changing. Therefore, the use of probiotics does not reduce, and normalizes the levels of LP. And so they are not just deprived of side effects of statins, but rather improve the functional performance of the liver and the function of the cerebral cortex. Thus, the proposed approach, including existing approaches, considerably reduces the side reactions and seems more practical and leading the favorable prognosis. The novelty of the proposed solution lies in the fact that for the first time in reliably selected and randomised groups of individuals with precursors to the development of metabolic disorders (obesity, dyslipidemia, microalbuminuria) will be characterized microbiocenosis of the intestine with the use of genomic and post-genomic technologies. These is based on the results of metagenomic analysis. Using of Pro - and Prebiotic preparations is carried out for correction of disturbed microbiocenosis or dysbiosis. Thus, the reference group initially is characterized by using of biochemical and molecular genetic analysis, and then the use of probiotics performs the correction of microbiocenosis. Evaluation of biochemical changes is carried out by classical biochemical blood tests, and in addition - we will make a test of the potential presence of microalbuminuria with the use of unique recombinant diagnostic system made for the detection of traces of albumin. There is a need to carry out the search, selection and analysis of the new strains of probiotics in the Xinjiang Uygur Autonomous region of China from national milk products with lactic acid or other fermented products with the purpose of studying their clinical characteristics.

An integrated approach to the study of the microbiocenosis and correction of dysbiotic disorders has distinct characteristics, suggesting the possibility of patent protection as the approach, and identified in the study of probiotic strains.

If the 20th century in many respects can be regarded as the age of antibiotics, modern medicine "pays" for the excessive enthusiasm that arose after the beginning of the wide use of antimicrobial agents. Currently the medicine has changed enormously in the spectrum of morbidity in general (the forefront of cardiovascular diseases, oncological pathologies, diseases of metabolism), and in the spectrum of infectious pathologies, largely caused by pathogens previously associated as low pathogen (Enterococci, E. coli Staphylococcus epidermidis, Group B Streptococcus, Helicobacter pylori) and possessing multiple resistance to most antimicrobial drugs. An inadequate antibiotic therapy is often accompanied by serious dysbiotic conditions, caused by disruption of the microbiota. Thus, the serious complications, leading to frequent deaths is pseudomembranous colitis caused by Clostridium difficile[11].

The emergence and dominance of infectious processes caused by pathogenic Streptococci, Staphylococci, Enterococci has led to search of approaches for the elimination of not the species or genera of pathogens per se, but certain genetic lines (strains) of pathogens with potential pathogenicity. The advent of metagenomic technologies and new methodological possibilities of molecular immunology and spectrometry allowed reassessing ideas about the microbiota and its implications in the functioning of organs and systems. If earlier, the microbiota or the so-called opportunistic bacteria was considered by the researchers only as potential pathogens, in recent years, the view on the microorganisms was dramatically changed. It turned out that microbiota not merely interacts with potential pathogens, providing barrier function of the body, but also affects the functioning of the immune system[12], on metabolism[13-14], endocrine system[15-16]on the functioning of the cardiovascular system[17]and even on the development and functioning of the сentral nervous system[18]. The resulting understanding of the global and previously undervalued role of microbiota for the formation of health and prevention of various human diseases have revived the scientific interest of researchers to use tools of correction of the microbiota, the living microorganisms (probiotics) or substances that are beneficial to the restoration of the microbiota (prebiotics)[19]. In parallel to microbial therapy it is started to develop the microbial or "fecal" transplantation, when the microorganisms are transplanted to the patient from a healthy donor[20-21]. Given the fact that the above data were obtained in the very recent past, and an array of knowledge is in the accumulation phase, it is natural that gaps that require a full scientific understanding of far more than factual knowledge. Therefore, the development of the proposed research area will allow to significantly replenishing the necessary baggage of fundamental knowledge and will allow generating a number of new approaches for the treatment and prevention of human diseases of non-infectious and infectious nature. Major world researches in this direction are implemented in several government projects and private research projects, such as the "human Microbiome" of the National centre of Health, USA http://commonfund.nih.gov/hmp/index, MetaHIT funded by the European Union and "American gut"[22]also, in scientific and private projects, such as the "Microbiome of the earth"[23].

Basic research on this field of fundamental character have concentrated in the University centers in the USA and Europe (Switzerland, Germany, Sweden, Denmark). The resolution of these tasks will be performed by the features of metagenomic studies using sequencing of microbiota sample of an indigenous group in the Xinjiang Uygur Autonomous region with the use of new generation sequencing and bioinformatics approaches. In the study of the microbial composition in persons with certain conditions, it is possible to link these diseases with manifestations and the extent of microbial imbalance. The use of well-studied probiotics to correct microbial imbalances will develop the most effective scheme for efficient complex treatment of diseases. The prebiotic components inclusions to traditional recipes, typical for this region, will create the most effective treatment-and-prophylactic products or dietary supplements or pharmaceutical preparations for correction of dysbiotic disorders and related diseases.

MS, characterized by obesity, increased blood pressure and development of type II diabetes refers to the most common symptom-complexes of the modern world, affecting up to 30% of people in developed countries, including the United States and Western Europe[24-26]. In this case, MS develops in different degree in different categories of the world's population. This is due to peculiarities of heredity and is characteristic of certain peoples’ customs, living conditions and nutrition. In this aspect, the Xinjiang Uygur Autonomous region of China is the most affected district, where substantially the indigenous Uighur and Kazakh populations is affected[27-29]. In turn, MS is manifested in a complex of severe somatic pathology, leading to a long period of disability significant socio-economic losses. The development of diabetes, severe cardiovascular disorders begins gradually and on the early stages appear by insignificant obesity, dyslipidemia and microalbuminuria. Microalbuminuria is one of the earliest signs of kidney damage in patients with diabetes mellitus. Therefore, an early and reliable method of diagnosis of primary stages of kidney failure is the test for microalbuminuria. Since this stage is only reversible in timely by prescription of MS pathogenetic therapy, its identification is a prerequisite for successful fight with diabetic nephropathy and chronic renal failure in diabetes of both types. In addition, microalbuminuria is an important early sign of kidney damage, reflecting the initial stages of vessel pathology and invariably correlates with an increase in cardiovascular morbidity and mortality. As shown by clinical studies, already the small increase of excretion of albumin with urine clearly associated with a significant increased risk of cardiovascular events, including fatal and progressive over time, the increase in the level of microalbuminuria clearly shows the deterioration of blood vessels and, consequently, leads to an additional increased risk. In this regard, microalbuminuria is recognized as an independent cardiovascular risk factor and most of the early (preclinical) sign of defeat of vulnerable target organ, as the kidneys. It is therefore imperative to timely diagnose the presence microalbuminuria to start preventive and therapeutic measures. Most recently as a significant factor determining the development of MS, discusses the state of intestinal microbiota and, in particular, the development of intestinal dysbiosis as a trigger factor of MS[30-31]. It is now clear that a significant number of functional disorders and diseases are happening due to the imbalance in the system "human-indigenous microbiota". In the personal human indigenous microbiota of the intestine consists of more than 800 species of microorganisms, the total weight in an adult is 2-3 kg, and the total genome is 12 times more of the human genome. Laboratory results indicate that in the natural habitat, there is no any single biochemical process, any function of the human body, which could be exercised without direct or indirect participation of indigenous microorganisms. The Impact of antimicrobial factors, pharmaceuticals, technology, food additives, pesticides, radiation, stress agents of any nature, as changes of way of life, including food, is accompanied by a noticeable violation of the composition of the indigenous microbiota - microecological imbalance. The distribution frequency of microecological imbalance in different world's populations depending on regions ranges from 60 to 90% and tends to constant increase. Immunological imbalance is directly connected with the manifestations of microecological imbalance, because intestinal microflora changes its association with the surface of M-cells of Peyer plaques and, as a consequence, the suppression of stimulation of lymphoid tissues, innate immune responses, cellular and humoral immune response and activation of cytokine production. Microecological and immune imbalances are clinically manifested as intestinal dysbiosis - a violation of the quantitative and qualitative composition of microbiota. The most significant etiological factors of dysbiosis are medical factors such as antibiotic, antitumor agents. Other causes of dysbiosis are radiation exposure, stress, stay in extreme conditions, acute and chronic intoxication, including poor quality of water and food products containing toxic impurities, even in small quantities.

Microecological and immune imbalances lead not only to MS but also to diseases of the digestive system: chronic gastritis and peptic ulcer disease associated with Helicobacter pylori; exposure to acute intestinal infections-dysentery, salmonellosis, staphylococcal enterocolitis, rotavirus infections; diarrhea; colitis; diseases of the genitourinary system (pelvic inflammatory disease, vaginosis, vaginitis, colpitis, endocervitis of different etiology); diseases of the cardiovascular system (atherosclerosis and its complications), respiratory allergies (asthma) and skin (atopic dermatitis, diathesis, etc.); diseases associated with metabolic disorders (MS, obesity, diabetes mellitus, osteoporosis, etc.).

The most common technique for the correction of microecological imbalance is the use of specially selected probiotic microorganisms (probiotics are live microorganisms that benefit the host organism). It is shown that probiotics can be very effective in normalize of dysbiotic condition in various diseases including MS[32-33]. An important contributory factor for the normal formation of microbiocenosis, is the use of probiotic products obtained in the neighborhoods of the local population. The factor of "food attachments" to the special kind of probiotics is extremely important. Prebiotics, substances of vegetable origin, containing food fiber (including mucopolysaccharides), trace elements and vitamins, which provide the substrate support of probiotics, and also have the specified influence on macroorganism. If prebiotics could be used in formulations of traditional Chinese medicine it will provided additional therapeutic and prophylactic effect.

Thus, we face now the perspective to develop innovative approaches for early diagnosis and prevention of pathologies related to MS (hypertension, obesity, type II diabetes). For this purpose there is important to examine the state of microbiocenosis of the population in the Xinjiang Uighur Autonomous region of China, constituting the well-known risk of developing MS. Then, to identify the most common types of dysbiotic states and composition of the intestinal microbiota, metabolic and immune disorders in patients of MS risk group. This would help to develop medical technology for the correction, immunological, nutritional status and microbial associations using the studied probiotic bacterial strains and prebiotic complexes used in Chinese folk medicine. Also, it is necessary to allocate from the national food of individuals living in Western China and to study in detail the strains of bacteria, promising as new probiotic preparations.

The maintenance of the measures of prevention and treatment of most common complex diseases of people in the modern society is MS - introduction of the screening test population in a certain region for early detection of predisposition to the development of the MS on their own unique method of determining the microalbuminuria in the example of Xinjiang with the subsequent patenting of the method, widespread use in other regions of China development of methodology for isolation and study of strains of bacteria from national products as promising new probiotic drugs for the dissemination of the results work in other countries. Also, there is an objective need to ascertain the microecological and metabolic status of persons of the indigenous population in Western China, which are in the risk zone. The widespread introduction of developed probiotics (health care products or dietary supplements or pharmaceutical products) will significantly improve the public health, would prevent the spread of MS and other metabolic disorders, support the immune system and fight effectively against infectious diseases. This will have an impact on increasing life expectancy and improving the quality of life of the population of the Xinjiang Uyghur Autonomous region of China.

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(Edited by: YANG Chenchen)

R29

A

1009-5551(2016)10-1338-07

10.3969/j.issn.1009-5551.2016.10.031

2016-09-01]

s: International Cooperation Project of China,France and Russia (87EZA0313397)

s: Denis Dubrovin (1960-), male, prof., MD. Research field: integrated Chinese medicine, Uyghur medicine and Modern medicine development in complex diseases and syndromes. E-mail: silospradotm@mail.ru.

Biography: Alexander Suvorov (1956-), male, prof., PhD, MD. Head of the Deapartment of Molecular Microbiology. Research field: molecular microbiology, streptocci, gut microbiota, probiotics, enterococci. E-mail: alexander_suvorov1@hotmail.com.