CC BY
25
—1 ' ,—1 ® Огляд лператури
b
— /Literature Review/
International Journal of Endocrinology
UDC 613.2:613.25:616.34-008.87 DOI: https://doi.Org/10.22141/2224-0721.16.8.2020.222886
N.M. Kobyliak1 G, Ludovico Abenavoli2 , G.P. Pavlenko3, Yu.I. Komisarenko1 ¡>
1 Bogomolets National Medical University, Kyiv, Ukraine
2 University "Magna Graecia", Germaneto, Italy
3 Kyiv City Clinical Endocrinology Center, Kyiv, Ukraine
Gut microbiota composition changes associated with obesity: new lights from metagenomic analysis
For citation: Miznarodnij endokrinologicnij zurnal. 2020;16(8):654-661. doi: 10.22141/2224-0721.16.8.2020.222886
Abstract. The worldwide prevalence of obesity more than doubled between 1980 and 2014. The most frequent cause, which leads to the obesity development, is an imbalance between energy intake and expenditure. In this complex process, genetic susceptibility, environmental and lifestyle factors are involved. The gut microbiota is a part of a complex network. Numerous studies have shown that the gut microbiota interacts with the host metabolism and plays an important role in various processes. The core gut microbial profile mainly embodies bacteria, belonging to the Gram-positive Firmicutes and the Gram-negative Bacteroidetes. An increase in gut Firmicutes/ Bacteroidetes ratio is detected in obese patients and during high-fat diet consumption in human and animal studies. Strains belonging to the genera Lactobacillus and Bifidobacterium are commonly used as probiotics and are most studied for the treatment and prevention of obesity-associated disorders. Moreover, several potential bacterial candidates, such as Akkermansia muciniphila, Faecalibacterium prausnitzii, Prevotella copri, Roseburia or Ruminococcus, have been identified and novel mechanisms of action intervening their positive effects for obesity have been elucidated. Consequently, the gut microbiota is gaining significant research interest in relation to obesity and associated metabolic disorders in an attempt to better understand the etiology of obesity and potentially new methods of its prevention and treatment. However, traditional culture methods are very limited for identifying microbes. With the application of molecular biologic technologies, especially metagenomic next-generation sequencing, progress has been made in the study of the human intestinal microbiome.
Keywords: Akkermansia muciniphila; Faecalibacterium prausnitzii; gut microbiota; insulin resistance; metage-nomics; obesity; Roseburia; Ruminococcus; Prevotella copri; probiotics; review
Introduction
Overweight and obesity are defined as abnormal or excessive fat accumulation that may impair health. The worldwide prevalence of obesity more than doubled between 1980 and 2014 and for today World Health Organization has declared obesity a global epidemic and took it under control [1, 2]. In 2014, more than 1.9 billion adults older than 18 years (39 %) were overweight. Overall, about 13 % or 600 million of this adult population (11 % of men and 15 % of women) were obese [3]. Overweight and obesity cause a number of diseases, namely, cardio-
vascular diseases [4], type 2 diabetes mellitus (T2DM) [5], dyslipidemia [6], premature death, hepatobiliary disease (non-alcoholic fatty liver disease, gallbladder dys-kinesia, cholelithiasis) [7, 8] and a number of cancers [9, 10]. Diabetes mellitus is a chronic disease that alters the metabolism of carbohydrates, proteins, and fats, which is caused by inability of P-cells to secrete insulin or failure of peripheral cells to respond normally to insulin [11]. In recent decades, the incidence of diabetes mellitus has increased worldwide and according to the International Diabetes Federation, 8.8 % of the world's population
© 2020. The Authors. This is an open access article under the terms of the Creative Commons Attribution 4.0 International License, CC BY, which allows others to freely distribute the published article, with the obligatory reference to the authors of original works and original publication in this journal.
Для кореспонденци: Кобиляк Назарм Миколайович, кандидат медичних наук, доцент кафедри ендокринологи, Нацюнальний медичний ушверситет iMeHi О.О. Богомольця, бульв. Т. Шев-ченка, 13, м. КиТв, 02000, УкраТна; e-mail: [email protected]
For correspondence: Nazarii Kobyliak, PhD, Associate Professor at the Department of Endocrinology, Bogomolets National Medical University, T. Shevchenko boulevard, 13, Kyiv, 02000, Ukraine; e-mail: [email protected]
Full list of author information is available at the end of the article.
(~ 425 million) had this disease in 2017, which is estimated to reach 628.6 million in 2045 [12]. It will have a profound impact on the quality of life, economic costs and demand for health care.
The most frequent cause, which leads to the obesity development, is a imbalance between energy intake and expenditure [13]. Obesity is associated with T2DM and insulin resistance, which is due to the increased secretion of unsaturated fatty acids from adipose tissue [11]. In general, various factors (genetics, lack of physical activity, and obesity) play an important role in the development of T2DM, but the change in gut microbiota is a new and important factor that is associated with increased metabolic disorders, such as obesity and associated diseases [14, 15].
The complex interaction between intestinal micro-biota and the host organism has been investigated for over 100 years. Approval of the germ theory of disease led to an original classification of some human disorders, which are caused by microbes, inclusive of conditions that were ultimately going to be revised as non-infectious [16]. The term "microbiome" was first coined by Lederberg in 2001 and refers to all microbes that have been colonized in humans and their genes [17]. It is estimated that about 100 trillion microbes colonize the body of an adult, they are often present in the gastrointestinal tract, so resistant microorganisms in it are collectively referred to as intestinal microbiota [18]. The composition of microbial populations varies throughout the gastrointestinal tract. In the small intestine, aerobic and facultative anaerobes predominate and rapidly metabolize simple carbohydrates, while bacteria in the ileum can break down complex carbohydrates. The colon contains large amounts of anaerobic bacteria that are involved in the fermentation of indigestible fiber in the diet and the conjugation of bile acids [19]. In general, microbiota of mammals is mainly composed of 4 types of phyla, including Actinobacteria, Firmicutes, Bacteroidetes, and Proteobacteria, which represent the largest population of the microbiota [18]. And it works in harmony with the host body and provides the conditions for the host to perform important actions that it has not been able to perform alone, so they are vital for the host metabolism and regulation of its physiological conditions [20, 21].
Microbiota and host metabolism
The gut microbiota is a part of a complex network. Numerous studies have shown that the gut microbiota interacts with the host metabolism and plays an important role in various functions, including the following: key compound in the immune system, protection against pathogens, regulation of intestinal hormone secretion, regulation of gastrointestinal nerve function, synthesis of vitamins K, B12, folate, production of short-chain fatty acids (SCFAs) through fermentation of indigestible carbohydrates, and breaking down toxins and drugs [22]. Microbiota affects intestinal peristalsis as well as the expression of various host genes involved in the regulation of metabolism, angiogenesis, mucosal barrier function, the development of the enteric nervous system, and the maturation of mucosal immunity [23].
Intestinal bacteria also produce many types of signaling molecules, such as low-molecular weight compounds. These products can turn on and turn off host genes, pathogenic genes, and microbial metabolism [24]. The intestinal microbiota is also involved in the fat deposition, regulates glucose, lipid, and energy homeostasis via activating the FXR and TGR5 nuclear receptors [25].
Gut bacteria digest fibers in complex plant polysaccharides to SCFAs, such as acetate, propionate and butyrate, which vary in ratio from 3 : 1 : 1 to 10 : 2 : 1, that play a role as a source of energy and regulate food and energy intake [26, 27]. Acetate and propionate enter the bloodstream and are removed by the liver and peripheral organs, where they are used as substrates for gluconeogenesis and lipogenesis. Butyrate is used in colonocytes, goblet and mast cells to energize cellular metabolism, regulates apoptosis, cell differentiation, chemical modifications of nuclear proteins, and nucleic acid [28]. In addition, SCFAs can generate a wide range of cellular responses through G protein-coupled receptors — GPR41 and GPR43 [29]. SCFAs bind to these receptors can stimulate the secretion of GLP-1, GLP-2, and Y-peptide [30].
Gut microbiota composition in obesity
Analysis of data from the PubMed database shows that research in the field of gut microbiota has developed rapidly over the past 20 years. The first document on the keywords "gut microbiota and obesity" in the PubMed database was posted in 2004. In that study, scientists showed that conventionalization of adult GF C57BL/6 mice with a normal microbiota harvested from the cecum of conventionally raised animals produced a 60% increase in total body fat content, adipocyte hypertrophy, and insulin resistance within 14 days despite a reduced food intake [31]. And already in 2005, an extensive metagenomic study of the gut was conducted by Eckburg et al. This analysis helped in entire genomic germ profiles formation [32].
Based on molecular phylogeny, the analysis of 16S ribo-somal RNA sequences of all microorganisms detected in the human intestinal tract showed the presence of three main domains — bacteria, eukarya, and archaea. When analyzing the microbiota of fecal bacteria, two main phylogenetic lines were identified: Firmicutes and Bacteroidetes [20, 33]. An increment in the ratio of Firmicutes/Bacteroidetes was confirmed in obese mice compared to those with normal weight [34, 35]. An effect of different types of bacteria on weight loss and other metabolic parameters has been recently analyzed. The significant upshot was revealed for Lactobacillus and/or Bifidobacterium strains [36].
It has been shown that the use of additional bacteria has a positive correlation with glucose and lipid levels and helps reduce body weight and chronic systemic inflammation [37]. According to another research, lyophilized probiotic strains of bacteria showed a promising result. Specifically, decreased visceral fat levels, levels of adiponectin, leptin in adipose tissue, and total lipid metabolism alterations have been shown in obese rats treated with multistrain lyophilized or alive bacteria [38—41].
Some studies have found no correlation between the abundance of major groups of human colonic bacteria,
including Bacteroidetes, and body mass index. But the data obtained suggested a specific effect of several phyla or genera on obesity [42]. Additionally, a notable study was conducted by Kalliomaki et al., where the ratio of gut microbiota in infancy was shown to be a probable prerequisite for overweight. Bifidobacteria amount was shown to be higher in normal-weight children than in obese ones, while reduced levels of S.aureus were observed at normal weight [43].
Novel strains associated with obesity
Akkermansia muciniphila
Akkermansia muciniphila is a species present in fecal specimens of healthy individuals and is one of the dominant bacteria in the gut microbiome closely linked to the progression of obesity [44]. A.muciniphila comprises up to 4 % of fecal microbiota, centrally involved in controlling fat storage and glucose homeostasis, this bacterium stimulates the mucosal-microbial networks and thus creates a complete intestinal barrier and influences the formation of immunity [45]. Besides, A.muciniphila and its metabolite propionate stimulated expression of fasting-induced adipose factor, G protein-coupled receptor 43, histone deacetylases, and peroxisome prolifera-tor-activated receptor gamma, important regulators of transcription factor regulation, cell cycle control, lipoly-sis and satiety [46]. In preclinical and clinical studies, it was confirmed that in the case of obesity and metabolic syndrome, the amount of A.muciniphila was significantly diminished. Therefore, it can be assumed that A.muciniphila may become the next-generation therapeutic agent [47]. Wu et al. showed a positive effect of A.muciniphilasub on body weight, the level of glucose, and the facilitation of the memory decay caused by a high-fat diet (HFD) in mice [48].
Depommier et al. demonstrated that people who were overweight and had T2DM or hypertension had a low abundance of A.muciniphila. The experimental application of A.muciniphila during 3 months in obese individuals was shown to promote increased cell sensitivity to insulin, a reduction of insulinemia, cholesterol level, and inflammatory markers. Interestingly, the use of A.muciniphila did not affect the correlation between the composition of the bacteria of the gut microbiome [49]. Similar results were observed by Kim et al., who studied the impact of intestinal A.muciniphila on non-alcoholic fatty liver disease. They have shown that administration of A.muciniphila decreased serum triglyceride, alanine aminotransferase, and IL-6 levels and normalized the bacterial organization of the gut microbiome in HFD mice [50].
Prevotella copri
The Bacteroidetes phylum is the second most populous in the human gut after Firmicutes (Gram-positive) [51]. Prevotella copri is a succinate-producing bacterium, where succinate plays the role of substrate for intestinal gluco-neogenesis [52]. Intestinal gluconeogenesis indeed is a gut function initiating various metabolic benefits by generating a gut-brain nervous signal that positively interferes in energy homeostasis and glucose control [53].
Hamilton et al. demonstrated that one week after the beginning of the HFD, paracellular permeability was increased, IL-10 expression and Clostridia abundance were decreased. After 6 weeks of HFD, the expression of the pro-inflammatory cytokine IL-10 was ameliorated. In obese rats, the dominant species of intestinal microbiota were Lactococcus and Bacteroides, and in chow-fed rats — the Clostridiaceae and Prevotella [54]. In pediatric patient with non-alcoholic fatty liver disease, a high abundance of Prevotella copri was associated with severe liver fibrosis (F3) [55].
Pean et al. showed how bariatric surgery affected the glucose homeostasis in a model of spontaneously occurring type 2 diabetes in rats (Goto-Kakizaki rats). After bariatric surgery, glucose tolerance and alteration in the gut micro-biome were found to be caused by significant enrichment of caecal Prevotella copri [56].
Recently, 2 very interesting studies, which reported opposite data, were published. De Vadder et al. have shown that fiber-enriched diet is associated with increased succinate synthesis and thereby improve glucose tolerance and insulin sensitivity [52]. Moreover, similar changes in metabolic parameters were observed in HFD mice after colonization with Prevotella copri and disappeared in glucose-6-phosphatase (—/—) knockout; glucose-6-phosphatase is a specific intestinal epithelial rate-limiting enzyme that regulates gluconeogenesis [52]. On the other hand, Pedersen et al. the same year received the opposite results. The researchers found a positive relationship between Prevotella copri and serum metabolo-mics in patients with insulin resistance, which is characterized by elevated levels of branched-chain amino acids. To confirm this association between Prevotella copri and impaired glucose metabolism, probiotic or placebo were administered to HFD animals. Prevotella copri has been shown to increase glucose intolerance, total level of branched-chain amino acids in serum and reduce insulin sensitivity [57].
Christensenella minuta
As it is known, Christensenella minuta is a Gram-negative bacterium, which is associated with the weight loss. To investigate the impact of host genes on the formation of intestinal microbiota, more than 1,000 fecal samples of microbiota obtained from twins were studied. Many microbial taxa have been identified, the number of which was influenced by host genetics, but the most hereditary taxon was the family Christensenellaceae. Furthermore, Chris-tensenellaceae was present in greater numbers in people with a low body mass index. Moreover, the injection of cultured bacteria C.minuta to germ-free mice is associated with a decrease in weight gain [58]. Gut bacteria from fat mice, when transplanted to genetically lean mice, transform the lean phenotype to obesity-associated one [59, 60]. Subsequent studies demonstrated that skinny germfree mice plump up on receiving a fecal transplant from a human donor implying that the bacteria help the recipient digest and metabolize more efficiently [59—61]. But if the fecal transplant of the human donor was supplemented with C.minuta, the recipient mice were thinner indicating anti-obesity effect [62].
Faecalibacterium prausnitzii
Faecalibacterium prausnitzii is a Gram-positive, anaerobic bacterium that is one of the most numerous and important in the human gut microbiota. F.prausnitzii is one of the main butyrate producers in the healthy human gut. Studies have been performed to change the amount of F.prausnitzii in obese individuals. For example, Ba-lamurugan et al. have compared the fecal samples of obese and lean children from south India. They showed that in the case of obesity, there were no significant differences between the two groups in fecal levels of Pre-votella, Bifidobacterium species, L.acidophilus group, or Eubacterium rectale. However, the level of F.prausnitzii was significantly higher in obese children than in non-obese participants [63].
Feng et al. tried to find out whether the number of F.prausnitzii depends on gender and obesity. When comparing fecal samples of the obese group and lean individuals, there were no significant differences in the number of F.prausnitzii. However, gender affected the number of bacteria, with a lower level of fecal F.prausnitzii in men as compared to women. It can be concluded that in future studies of F.prausnitzii, the gender-specific effect must be taken into account [64]. Remely et al. determined how weight loss affects the abundance of F.prausnitzii before, during, and after the HFD. It has been shown that after the diet and weight loss, the number of bacteria, such as Archaea, A.muciniphila, Clostridium and F.prausnitzii, increased significantly [65].
Hippe et al. found that F.prausnitzii was present in different phylotypes in conditions of obesity, T2DM and in normal-weight patients. The lowest content of F.prausnitzii was in a group with T2DM and the highest — in a group with normal weight [66].
To test the hypothesis whether the gut microbiota is related to age and obesity, Del Chierico et al. have studied the microbiota profiles in obese adults and adolescents and compared it with samples obtained from normal-weight individuals. It was determined that the composition of intestinal microbiota is different in obese adolescents and adults: the former had high levels of Actinobacteria, and the latter — high Bacteroidetes amount. A negative correlation was found between the age, body mass index and F.prausnitzii abundance [67].
Ruminococcus
Ruminococcus is a genus of bacteria in the class Clos-tridia. They are anaerobic, Gram-positive gut microbes. Ruminococcus breaks down cellulose (with the formation of methane), accumulates a reserve iodophilic polymer of glucose in the cytoplasm. In 2016, Togo et al. described a new bacterium species, Ruminococcus phoceensis strain AT10 (CSUR = P2086, DSM = 100837), which was isolated from the feces of a 37-year-old woman from Marseille, France, with morbid obesity before bariatric surgery. Bacterial cells were Gram-positive, rod-shaped, and polymorphic, ranging 0.2—0.5 x 1.2—1.5 ^m by electron microscopy. Strain AT10 was catalase-positive and oxidase-negative. Strain AT10 exhibited 98.2 % of 16S rRNA gene sequence similarity with Ruminococcus torques ATCC 27756 [68].
K. Nirmalkar et al. have studied the association between gut microbiota diversity and endothelial dysfunction markers in obese Mexican children and adolescents. Markers of endothelial inflammation (triglycerides, insulin, C-reactive protein, leptin) were increased in children and adolescents with obesity. Moreover, obesity was established to be positively associated with total cholesterol and Ruminococcus [69].
The effect of vitamin D on the gut microbiome in overweight or obese people has been studied by Nader-poor et al. It was found that the use of vitamin D did not affect the microbiome a-diversity. However, there was a significant association between community composition and vitamin D supplementation at the genus level. The vitamin D group had a higher abundance of genus Lach-nospira, Coprococcus and lower abundance of genus Blau-tia, Ruminococcus [70].
Roseburia
Roseburia is a member of the Firmicutes phylum of bu-tyrate-producing, Gram-positive anaerobic bacteria that inhabit the human colon. Usually, an increased abundance of Roseburia is associated with weight loss and reduced glucose intolerance. Under the conditions of a HFD, an increase in the amount of deoxycholic acid and taurodeoxycholic acid in plasma and liver tissues was detected. Also, the number of genera Blautia, Coprococcus, Intestinimonas, Lactococcus, Roseburia and Ruminococcus was increased [68].
In obese groups with metabolic disorders (high uric acid concentration, serum lipids, high blood pressure), an increased amount of Clostridium XIVa, Bacteroides and Rose-buria was observed. Blautia, Romboutsia, Ruminococcus, Clostridium sensu stricto and Dorea had a positive correlation with body mass index and blood lipids. In contrast, Bacte-roides, Roseburia, Butyricicoccus, Alistipes, Parasutterella, Parabacteroides and Clostridium IV had a negative correlation with these parameters. Thus, these types of bacteria can be used as biomarkers of metabolic disorders associated with obesity [71]. Zohreh et al. clarified the role of Roseburia in the metabolism of the host, the impact on obesity, and its role in certain pathologies. It was shown that Roseburia spp. is actively involved in maintaining intestinal immunity, and influences peristalsis and anti-inflammatory properties. In pathologies, such as irritable bowel syndrome, obesity, T2D and allergies, Roseburia spp. could alter various metabolic pathways through butyrate-inhibiting NF-kB activation or influence on T-cell proliferation. Also, Roseburia spp. may be a biomarker of gallstone formation [72].
Future perspectives
Gut microbiota is important for metabolism and a large number of studies have shown that the microbiota changes under obesity. So, the question arises whether certain manipulations of intestinal bacteria can improve the composition of the gut microbiome in obese people in terms of weight loss and metabolism improvement. This may be a potential therapeutic strategy for the treatment of obesity in the future.
Moreover, due to challenges in sampling from the intestine of humans, most studies use stool samples for micro-
biota analysis. However, the stool microbiota profile does not fully reflect the gut microbiome. Furthermore, most studies focused on genomics rarely study the transcriptome, proteome or metabolome. Even at the genomic level, deep shotgun sequencing is expensive, making marker-based amplicon sequencing, such as 16S rRNA gene sequencing, prevail. Further, the existing sequencing and analysis technologies seldom identify microbes at species or strain levels. Considering that the functional capacity varies between strains from the same species, identification of microbes and microbial genes associated with the disease is challenging.
Conflicts of interests. Authors declare the absence of any conflicts of interests and their own financial interest that might be construed to influence the results or interpretation of their manuscript.
References
1. Wang Y, Beydoun MA, Min J, Xue H, Kaminsky LA, Che-skin LJ. Has the prevalence of overweight, obesity and central obesity levelled off in the United States? Trends, patterns, disparities, and future projections for the obesity epidemic. Int J Epidemiol. 2020 Jun 1;49(3):810-823. doi: 10.1093/ije/dyz273.
2. Lim YM, Song S, Song WO. Prevalence and Determinants of Overweight and Obesity in Children and Adolescents from Migrant and Seasonal Farmworker Families in the United States-A Systematic Review and Qualitative Assessment. Nutrients. 2017 Feb 24;9(3):188. doi: 10.3390/nu9030188.
3. WHO. Obesity. Available from: https://www.who.int/top-ics/obesity/en/. Accessed at June 13, 2020.
4. Jiang J, Ahn J, Huang WY, Hayes RB. Association of obesity with cardiovascular disease mortality in the PLCO trial. Prev Med. 2013 Jul;57(1):60-4. doi: 10.1016/j.ypmed.2013.04.014.
5. Phillips CM. Metabolically healthy obesity: definitions, determinants and clinical implications. Rev Endocr Metab Disord. 2013 Sep;14(3):219-27. doi: 10.1007/s11154-013-9252-x.
6. Jung DH, Kim JY, Kim JK, Koh SB, Park JK, Ahn SV Relative contribution of obesity and .serum adiponectin to the development of hypertension. Diabetes Res Clin Pract. 2014 Jan;103(1):51-6. doi: 10.1016/j.diabres.2013.09.018.
7. Aludwan M, Kobyliak N, Abenavoli L, et al. Hepatic steatosis indices as predictors of vitamin D 3 deficiency in patients with NAFLD associated with type 2 diabetes. ClinicalDiabetology. 2020;9(5):313-320. doi: 10.5603/DK.2020.0036.
8. Polyzos SA, Kountouras J, Mantzoros CS. Obesity and nonalcoholic fatty liver disease: From pathophysiology to therapeutics. Metabolism. 2019 Mar;92:82-97. doi: 10.1016/j.metab-ol.2018.11.014.
9. Eslami M, Sadrifar S, Karbalaei M, Keikha M, Kobyliak NM, Yousefi B. Importance of the Microbiota Inhibitory Mechanism on the Warburg Effect in Colorectal Cancer Cells. J Gastro-intest Cancer. 2020 Sep;51(3):738-747. doi: 10.1007/s12029-019-00329-3.
10. Karimi K, Lindgren TH, Koch CA, Brodell RT. Obesity as a risk factor for malignant melanoma and non-melanoma skin cancer. Rev Endocr Metab Disord. 2016 Sep;17(3):389-403. doi: 10.1007/s11154-016-9393-9.
11. Al-Goblan AS, Al-Alfi MA, Khan MZ. Mechanism linking diabetes mellitus and obesity. Diabetes Metab Syndr Obes. 2014
Dec 4;7:587-91. doi: 10.2147/DMSO.S67400.
12. American Diabetes Association. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2020. Diabetes Care. 2020 Jan;43(Suppl 1):S14-S31. doi: 10.2337/dc20-S002.
13. Eslami M, Bahar A, Hemati M, et al. Dietary pattern, colonic microbiota and immunometabolism interaction: new frontiers for diabetes mellitus and related disorders. Diabet Med. 2020 Oct 6:e14415. doi: 10.1111/dme.14415.
14. Divella R, Mazzocca A, Daniele A, Sabba C, Paradiso A. Obesity, Nonalcoholic Fatty Liver Disease and Adipocyto-kines Network in Promotion of Cancer. Int J Biol Sci. 2019 Jan 1;15(3):610-616. doi: 10.7150/ijbs.29599.
15. Kobyliak N, Falalyeyeva T, Tsyryuk O, et al. New insights on strain-specific impacts of probiotics on insulin resistance: evidence from animal study. J Diabetes Metab Disord. 2020 Feb 16;19(1):289-296. doi: 10.1007/s40200-020-00506-3.
16. Abenavoli L, Scarpellini E, Colica C, et al. Gut Micro-biota and Obesity: A Role for Probiotics. Nutrients. 2019 Nov 7;11(11):2690. doi: 10.3390/nu11112690.
17. NIH HMP Working Group, Peterson J, Garges S, Giovanni M, et al. The NIH Human Microbiome Project. Genome Res. 2009Dec;19(12):2317-23. doi: 10.1101/gr.096651.109.
18. Qin J, Li R, Raes J, et al; MetaHIT Consortium, Bork P, Ehrlich SD, Wang J. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010 Mar 4;464(7285):59-65. doi: 10.1038/nature08821.
19. Utzschneider KM, Kratz M, Damman CJ, Hullar M. Mechanisms Linking the Gut Microbiome and Glucose Metabolism. J Clin Endocrinol Metab. 2016 Apr; 101 (4): 1445-54. doi: 10.1210/jc.2015-4251.
20. Sarwar R, Pierce N, Koppe S. Obesity and nonalcoholic fatty liver disease: current perspectives. Diabetes Metab Syndr Obes. 2018Sep 25;11:533-542. doi: 10.2147/DMSO.S146339.
21. PatellR, Dosi R, Joshi H, Sheth S, Shah P, Jasdanwala S. Non-Alcoholic Fatty Liver Disease (NAFLD) in Obesity. J Clin Di-agnRes. 2014Jan;8(1):62-6. doi: 10.7860/JCDR/2014/6691.3953.
22. Eslami M, Bahar A, Keikha M, Karbalaei M, Kobyliak NM, Yousefi B. Probiotics function and modulation of the immune system in allergic diseases. Allergol Immunopathol (MMadr). 2020 Nov-Dec;48(6):771-788. doi: 10.1016/j.aller.2020.04.005.
23. Grigorescu I, Dumitrascu DL. Implication of gut micro-biota in diabetes mellitus and obesity. Acta Endocrinol (Buchar). 2016Apr-Jun;12(2):206-214. doi: 10.4183/aeb.2016.206.
24. Tremaroli V, Bäckhed F. Functional interactions between the gut microbiota and host metabolism. Nature. 2012 Sep 13;489(7415):242-9. doi: 10.1038/nature11552.
25. Watanabe M, Houten SM, Mataki C, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature. 2006 Jan 26;439(7075):484-9. doi: 10.1038/nature04330.
26. Tan J, McKenzie C, Potamitis M, Thorburn AN, Mackay CR, Macia L. The role of short-chain fatty acids in health and disease. Adv Immunol. 2014;121:91-119. doi: 10.1016/B978-0-12-800100-4.00003-9.
27. Belizario JE, Faintuch J, Garay-Malpartida M. Gut Mi-crobiome Dysbiosis and Immunometabolism: New Frontiers for Treatment of Metabolic Diseases. Mediators Inflamm. 2018 Dec 9;2018:2037838. doi: 10.1155/2018/2037838.
28. Meijer K, de Vos P, Priebe MG. Butyrate and other short-
chain fatty acids as modulators of immunity: what relevance for health? Curr Opin Clin NutrMetab Care. 2010Nov;13(6):715-21. doi: 10.1097/MCO. 0b013e32833eebe5.
29. Kim MH, Kang SG, Park JH, Yanagisawa M, Kim CH. Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice. Gastroenterology. 2013 Aug; 145(2):396-406.e 1-10. doi: 10.1053/j. gastro.2013.04.056.
30. Kimura I, Ozawa K, Inoue D, et al. The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat Commun. 2013;4:1829. doi: 10.1038/ncomms2852.
31. Bäckhed F, Ding H, Wang T, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A. 2004 Nov 2; 101 (44): 15718-23. doi: 10.1073/ pnas.0407076101.
32. Eckburg PB, Bik EM, Bernstein CN, et al. Diversity of the human intestinal microbial flora. Science. 2005 Jun 10;308(5728):1635-8. doi: 10.1126/science.1110591.
33. Nash AK, Auchtung TA, Wong MC, et al. The gut myco-biome of the Human Microbiome Project healthy cohort. Microbi-ome. 2017Nov 25;5(1):153. doi: 10.1186/s40168-017-0373-4.
34. Pedersen R, Ingerslev HC, Sturek M, et al. Characterisation of gut microbiota in Ossabaw and Göttingen minipigs as models of obesity and metabolic .syndrome. PLoS One. 2013;8(2):e56612. doi: 10.1371/journal.pone.0056612.
35. Hansen AK, Hansen CH, Krych L, Nielsen DS. Impact of the gut microbiota on rodent models of human disease. World J Gastroenterol. 2014 Dec 21;20(47):17727-36. doi: 10.3748/wjg. v20.i47.17727.
36. Cani PD, de Vos WM. Next-Generation Beneficial Microbes: The Case of Akkermansia muciniphila. Front Microbiol. 2017Sep 22;8:1765. doi: 10.3389/fmicb.2017.01765.
37. Godoy-Matos AF, Silva Júnior WS, Valerio CM. NAFLD as a continuum: from obesity to metabolic syndrome and diabetes. Diabetol Metab Syndr. 2020 Jul 14;12:60. doi: 10.1186/s13098-020-00570-y.
38. Brunner KT, Henneberg CJ, Wilechansky RM, Long MT. Nonalcoholic Fatty Liver Disease and Obesity Treatment. Curr Obes Rep. 2019 Sep;8(3):220-228. doi: 10.1007/s13679-019-00345-1.
39. Cerdó T, García-Santos JA, G Bermúdez M, Campoy C. The Role of Probiotics and Prebiotics in the Prevention and Treatment of Obesity. Nutrients. 2019 Mar 15;11(3):635. doi: 10.3390/ nu11030635.
40. Luoto R, Kalliomäki M, Laitinen K, Isolauri E. The impact of perinatalprobiotic intervention on the development of overweight and obesity: follow-up study from birth to 10 years. Int J Obes (Lond). 2010 Oct;34(10):1531-7. doi: 10.1038/ijo.2010.50.
41. Fabbrini E, Sullivan S, Klein S. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology. 2010 Feb;51(2):679-89. doi: 10.1002/ hep.23280.
42. Duncan SH, Lobley GE, Holtrop G, et al. Human colonic microbiota associated with diet, obesity and weight loss. Int J Obes (Lond). 2008Nov;32(11):1720-4. doi: 10.1038/ijo.2008.155.
43. Kalliomäki M, Collado MC, Salminen S, Isolauri E. Early differences in fecal microbiota composition in children may predict overweight. Am J Clin Nutr. 2008 Mar;87(3):534-8. doi: 10.1093/ajcn/87.3.534.
44. Ottman N, Geerlings SY, Aalvink S, de Vos WM, Belzer C. Action and function of Akkermansia muciniphila in microbiome ecology, health and disease. Best Pract Res Clin Gastroenterol. 2017Dec;31(6):637-642. doi: 10.1016fj.bpg.2017.10.001.
45. Macchione IG, Lopetuso LR Ianiro G, et al. Akkerman-sia muciniphila: key player in metabolic and gastrointestinal disorders. Eur Rev Med Pharmacol Sci. 2019 Sep;23(18):8075-8083. doi: 10.26355/eurrev_201909_19024.
46. Lukovac S, Belzer C, Pellis L, et al. Differential modulation by Akkermansia muciniphila and Faecalibacterium praus-nitzii of host peripheral lipid metabolism and histone acetylation in mouse gut organoids. mBio. 2014 Aug 12;5(4):e01438-14. doi: 10.1128/mBio.01438-14.
47. Xu Y, Wang N, Tan HY, Li S, Zhang C, Feng Y. Function of Akkermansia muciniphila in Obesity: Interactions With Lipid Metabolism, Immune Response and Gut Systems. Front Microbiol. 2020Feb 21;11:219. doi: 10.3389/fmicb.2020.00219.
48. Wu F, Guo X, Zhang M, et al. An Akkermansia muciniphila subtype alleviates high-fat diet-induced metabolic disorders and inhibits the neurodegenerative process in mice. Anaerobe. 2020 Feb;61:102138. doi: 10.1016/j.anaerobe.2019.102138.
49. Depommier C, EverardA, Druart C, et al. Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study. Nat Med. 2019 Jul;25(7):1096-1103. doi: 10.1038/s41591-019-0495-2.
50. Kim S, Lee Y, Kim Y, et al. Akkermansia muciniphila Prevents Fatty Liver Disease, Decreases Serum Triglycerides, and Maintains Gut Homeostasis. Appl Environ Microbiol. 2020 Mar 18;86(7):e03004-19. doi: 10.1128/AEM.03004-19.
51. Wexler HM. Bacteroides: the good, the bad, and the nitty-gritty. Clin Microbiol Rev. 2007 0ct;20(4):593-621. doi: 10.1128/ CMR.00008-07.
52. De Vadder F, Kovatcheva-Datchary P, Zitoun C, Du-champt A, Bäckhed F, Mithieux G. Microbiota-Produced Succinate Improves Glucose Homeostasis via Intestinal Gluconeo-genesis. Cell Metab. 2016 Jul 12;24(1): 151-7. doi: 10.1016/j. cmet.2016.06.013.
53. Mithieux G. Gut Microbiota and Host Metabolism: What Relationship. Neuroendocrinology. 2018; 106(4): 352-356. doi: 10.1159/000484526.
54. Hamilton MK, Boudry G, Lemay DG, Raybould HE. Changes in intestinal barrier function and gut microbiota in high-fat diet-fed rats are dynamic and region dependent. Am J Physiol Gastrointest Liver Physiol. 2015 May 15;308(10):G840-51. doi: 10.1152/ajpgi. 00029.2015.
55. Schwimmer JB, Johnson JS, Angeles JE, et al. Microbi-ome Signatures Associated With Steatohepatitis and Moderate to Severe Fibrosis in Children With Nonalcoholic Fatty Liver Disease. Gastroenterology. 20190ct;157(4):1109-1122. doi: 10.1053/j.gas-tro.2019.06.028.
56. Pean N, Le Lay A, Brial F, et al. Dominant gut Prevotella copri in gastrectomised non-obese diabetic Goto-Kakizaki rats improves glucose homeostasis through enhanced FXR signalling. Diabetologia. 2020 Jun;63(6): 1223-1235. doi: 10.1007/s00125-020-05122-7.
57. Pedersen HK, Gudmundsdottir V, Nielsen HB, et al. Human gut microbes impact host serum metabolome and insulin sensitivity. Nature. 2016 Jul 21;535(7612):376-81. doi: 10.1038/ nature18646.
58. Goodrich JK, Waters JL, Poole AC, et al. Human genet-
ics shape the gut microbiome. Cell. 2014 Nov 6;159(4):789-99. doi: 10.1016/j.cell.2014.09.053.
59. Castaner O, Goday A, Park YM, et al. The Gut Micro-biome Profile in Obesity: A Systematic Review. Int J Endocrinol. 2018Mar 22;2018:4095789. doi: 10.1155/2018/4095789.
60. Braga RM, Dourado MN, Araujo WL. Microbial interactions: ecology in a molecular perspective. Braz J Microbiol. 2016 Dec;47Suppl 1(Suppl 1):86-98. doi: 10.1016/j.bjm.2016.10.005.
61. Wang PX, Deng XR, Zhang CH, Yuan HJ. Gut micro-biota and metabolic syndrome. Chin Med J (Engl). 2020 Apr 5;133(7):808-816. doi: 10.1097/CM9.0000000000000696.
62. Shivaji S. We are not alone: a case for the human micro-biome in extra intestinal diseases. Gut Pathog. 2017 Mar 7;9:13. doi: 10.1186/s13099-017-0163-3.
63. Balamurugan R, George G, Kabeerdoss J, Hepsiba J, Chandragunasekaran AM, Ramakrishna BS. Quantitative differences in intestinal Faecalibacterium prausnitzii in obese Indian children. Br J Nutr. 2010 Feb; 103(3):335-8. doi: 10.1017/ S0007114509992182.
64. Feng J, Tang H, Li M, et al. The abundance of fecal Fae-calibacterium prausnitzii in relation to obesity and gender in Chinese adults. Arch Microbiol. 2014 Jan;196(1):73-7. doi: 10.1007/ s00203-013-0942-2.
65. Remely M, Tesar I, Hippe B, Gnauer S, RustP, Haslberger AG. Gut microbiota composition correlates with changes in body fat content due to weight loss. Benef Microbes. 2015;6(4):431-9. doi: 10.3920/BM2014.0104.
66. Hippe B, Remely M, Aumueller E, Pointner A, Magnet U, Haslberger AG. Faecalibacterium prausnitzii phylotypes in type two diabetic, obese, and lean control subjects. Benef Microbes.
2016Sep;7(4):511-7. doi: 10.3920/BM2015.0075.
67. Del Chierico F, Abbatini F, Russo A, et al. Gut Microbiota Markers in Obese Adolescent and Adult Patients: Age-Dependent Differential Patterns. Front Microbiol. 2018 Jun 5;9:1210. doi: 10.3389/fmicb. 2018.01210.
68. Lin H, An Y, Tang H, Wang Y. Alterations of Bile Acids and Gut Microbiota in Obesity Induced by High Fat Diet in Rat Model. J Agric Food Chem. 2019 Apr 3;67(13):3624-3632. doi: 10.1021/acs.jafc. 9b00249.
69. Nirmalkar K, Murugesan S, Pizano-Zarate ML, et al. Gut Microbiota and Endothelial Dysfunction Markers in Obese Mexican Children and Adolescents. Nutrients. 2018 Dec 19;10(12):2009. doi: 10.3390/nu10122009.
70. Naderpoor N, Mousa A, Fernanda Gomez Arango L, Barrett HL, Dekker Nitert M, de Courten B. Effect of Vitamin D Supplementation on Faecal Microbiota: A Randomised Clinical Trial. Nutrients. 2019 Nov 27;11(12):2888. doi: 10.3390/nu11122888.
71. Naderpoor N, Mousa A, Fernanda Gomez Arango L, Barrett HL, Dekker Nitert M, de Courten B. Effect of Vitamin D Supplementation on Faecal Microbiota: A Randomised Clinical Trial. Nutrients. 2019 Nov 27;11(12):2888. doi: 10.3390/nu11122888.
72. Tamanai-Shacoori Z, Smida I, Bousarghin L, et al. Roseburia spp. : a marker of health? Future Microbiol. 2017 Feb;12:157-170. doi: 10.2217/fmb-2016-0130.
Received 27.10.2020 Revised 25.11.2020 Accepted 02.12.2020 ■
Information about authors
Nazarii Kobyliak, PhD, Associate Professor at the Department of Endocrinology, Bogomolets National Medical University, Kyiv, Ukraine; https://orcid.org/0000-0001-9814-689X Ludovico Abenavoli, MD, PhD, MSc, Associate Professor of Digestive Diseases at the University "Magna Graecia', Germaneto, Italy; https://orcid.org/0000-0002-5922-1524 Ganna Pavlenko, MD, Chief Physician of the Kyiv City Clinical Endocrinology Center, Kyiv, Ukraine
Yulia Komisarenko, MD, PhD, Professor, Head of the Department of Endocrinology, Bogomolets National Medical University, Kyiv, Ukraine; https://orcid.org/0000-0001-9912-4879
Кобиляк Н.М.1, Abenavoli Ludovico2, Павленко Г.П.3, Комсаренко Ю.1.1
1 Нацюнальний медичний у^верситет iM. О.О. Богомольця, м. КИв, Украна
2 University "Magna Graecia", Germaneto, Italy
3 Ки'/вський мський ендокринолопчний центр, м. Ки'/в, Украна
Змши складу мкробюти кишечника, пов'язан з ожиршням: HOBi результати метагеномного aHaAÎ3y
Резюме. Поширенють ожиршня зросла бшьше шж ygpiqi з 1980 по 2014 р. Найчастшою причиною його розвитку е дисбаланс м1ж споживанням та витратами енергй. Цей складний процес обумовлений генетичною схильнютю, факторами навколишнього середовища та способом життя. Мжробюта кишечника е частиною складно! мереж! У численних досль дженнях показано, що мжробюта кишечника впливае на ме-таболiзм органзму i вщграе важливу роль у рiзних процесах в оргашзм! Основу мжробюти кишечника становлять бак-терй, що належать до грампозитивного фшотипу Firmicutes i грамнегативного Bacteroidetes. У досладженнях за участю людей i тварин виявлено збшьшення спшвщношення Firmicutes/ Bacteroidetes у кишечнику пащенйв з ожиршням i при дотри-манш дiети з високим умютом жиру. Штами, що належать до родiв Lactobacillus та Bifidobacterium, зазвичай використовують-ся як пробютики та е найбшьш вивченими для лжування та профшактики ожиршня. Бшьше того, серед бактерш було ви-
явлено декшька потенцшних кандидайв, таких як Akkermansia muciniphila, Faecalibacterium prausnitzii, Prevotella copri, Roseburia та Ruminococcus, i з'ясовано нов1 мехатзми дц, що обумов-люють ix позитивт ефекти при ожиршш. Отже, мжробюта кишечника набувае значного дослщницького штересу щодо ожиршня та пов'язаних i3 ним метабол1чних розлащв, до-зволяе краще зрозумпи етюлогш ожиршня та розробити по-тенцшш нов1 методи його профшактики та лшування. Однак традицшш методи культивування на поживних середовищах дуже обмежеш щодо щентифшаци м1кроб1в. При застосуванш молекулярно-бюлопчних технологи, особливо метагеномного секвенування нового поколшня, було досягнуто значного прогресу у вивченш мжробюму кишечника людини. K™40Bi слова: Akkermansia muciniphila; Faecalibacterium prausnitzii; мжробюта кишечника; шсулшорезистентшсть; метагеномжа; ожиршня; Roseburia; Ruminococcus; Prevotella copri; пробютики; огляд
КобилякН.Н.1, AbenavoliLudovico2, Павленко А.П.3, Комиссаренко Ю.И.1
1 Национальный медицинский университет им. А.А. Богомольца, г. Киев, Украина
2 University "Magna Graecia", Germaneto, Italy
3 Киевский городской эндокринологический центр, г. Киев, Украина
Изменения состава микробиоты кишечника, связанные с ожирением: новые результаты метагеномного анализа
Резюме. Распространенность ожирения возросла более чем вдвое с 1980 по 2014 г. Наиболее частой причиной его развития является дисбаланс между потреблением и расходом энергии. Этот сложный процесс обусловлен генетической предрасположенностью, факторами окружающей среды и образом жизни. Микробиота кишечника является частью сложной сети. В многочисленных исследованиях было показано, что микробиота кишечника влияет на метаболизм и играет важную роль в различных процессах в организме. Основу микробиоты кишечника составляют бактерии, относящиеся к грамположительному филотипу Firmicutes и грамотрицательному Bacteroidetes. В исследованиях с участием людей и животных обнаружено увеличение соотношения Firmicutes/Bacteroidetes в кишечнике пациентов с ожирением и при соблюдении диеты с высоким содержанием жира. Штаммы, принадлежащие к родам Lactobacillus и Bifidobacterium, обычно используются как пробиотики и являются наиболее изученными для лечения и профилактики ожирения. Более того, среди бактерий было обна-
ружено несколько потенциальных кандидатов, таких как Akkermansia muciniphila, Faecalibacterium prausnitzii, Prevotella copri, Roseburia и Ruminococcus, и выяснены новые механизмы действия, обусловливающие их положительные эффекты при ожирении. Итак, микробиота кишечника представляет весомый исследовательский интерес в отношении ожирения и связанных с ним метаболических расстройств, позволяет лучше понять этиологию ожирения и разработать потенциальные новые методы его профилактики и лечения. Однако традиционные методы культивирования на питательных средах очень ограничены в отношении идентификации микробов. При использовании молекулярно-биологических технологий, особенно метагеномного секвенирования нового поколения, был достигнут значительный прогресс в изучении кишечного микробиома человека. Ключевые слова: Akkermansia muciniphila; Faecalibacterium prausnitzii; микробиота кишечника; инсулинорезистентность; метагеномика; ожирение; Roseburia; Ruminococcus; Prevotella copri; пробиотики; обзор
