Journal of microbiology, epidemiology and immunobiologyJournal of microbiology, epidemiology and immunobiologyЖурнал микробиологии, эпидемиологии и иммунобиологии0372-93112686-7613Central Research Institute for Epidemiology13951ArticlesСтатьиReview ArticleINTESTINAL MICROFLORA, OBESITY AND TYPE 2 DIABETESКИШЕЧНАЯ МИКРОФЛОРА, ОЖИРЕНИЕ И ДИАБЕТ 2 ТИПАBondarenkoV. MБондаренкоВ. МMaleevV. VМалеевВ. ВLikhodedV. GЛиходедВ. ГMoscow, RussiaНИИ эпидемиологии и микробиологии им. Н.Ф.Гамалеи, Центральный НИИ эпидемиологии15062014913NO3 (2014)№3 (2014)424909062023Copyright ©; 2014, Bondarenko V.M., Maleev V.V., Likhoded V.G.Copyright ©; 2014, Бондаренко В.М., Малеев В.В., Лиходед В.Г.2014Bondarenko V.M., Maleev V.V., Likhoded V.G.Бондаренко В.М., Малеев В.В., Лиходед В.Г.https://creativecommons.org/licenses/by/4.0https://microbiol.crie.ru/jour/article/view/13951

The review of data of the literature on a role of intestinal microflora, genetic features of a macroorganism, exogenic factors and character of a food is presented at obesity and a type 2 diabetes. Researches establish, that development in experimental animals of the induced obesity and the type 2 diabetes, depends on a diet and presence of intestinal microflora. The factors increasing permeability mucous intestines, promote a translocation of intestinal automicroflora and its toxins into macroorganism and a system blood-circulation. Long introduction LPS (endotoxin) ofgram-negative bacteria to the special laboratory animals led to development of inflammatory reaction, adiposity and resistance to insulin. The specified phenomena did not develop at LPS introduction to the animals, who have lost receptor CD14 which is necessary for linkage and endotoxin action. Data about change of intestinal microflora and a role of immune infringements are discussed at obesity and the type 2 diabetes occurring into background of low-grade chronic inflammation and metabolic disorders.

Представлен обзор данных литературы о роли микрофлоры кишечника, генетических особенностей макроорганизма, экзогенных факторов и характера питания при ожирении и диабете 2 типа. Исследованиями установлено, что развитие у экспериментальных животных индуцированного ожирения и диабета 2 типа зависит от диеты и присутствия кишечной микрофлоры. Факторы, увеличивающие проницаемость слизистой кишечника, способствуют транслокации кишечной аутомикрофлоры и ее токсинов во внутреннюю среду макроорганизма и системный кровоток. Длительное введение животным ЛПС (эндотоксина) грамотрицательных бактерий приводило к развитию воспалительной реакции, ожирению и резистентности к инсулину. Указанные явления не развивались при введении ЛПС животным, утратившим рецептор CD14, который необходим для связывания и действия эндотоксина. Обсуждены данные об изменении кишечной микрофлоры и роли иммунных нарушений при ожирении и диабете 2 типа, происходящих на фоне хронического более или менее выраженного воспаления и метаболических расстройств.

intestinal microfloraobesitytype 2 diabetesмикробиота кишечникаожирениедиабет 2 типаБондаренко В.М., Гинцбург А.Л., Лиходед В.Г. Микробный фактор и врожденный иммунитет в патогенезе атеросклероза. Тверь, Триада, 2013.Рыбальченко О.В., Бондаренко В.М. Образование биопленок симбионтными представителями микробиоты кишечника как форма существования бактерий. Вестник СПбГУ, 2013, 11 (1): 179-186.Рябиченко Е.В., Веткова Л.Г., Бондаренко В.М. Молекулярные аспекты повреждающего действия бактериальных липополисахаридов. Журн. микробиол. 2004, 3: 98-105.Савельев В.С., Петухов В.А. Липидный дистресс-синдром. Руководство для врачей. М., МАКС Пресс. 2010.Чернин В.В., Парфенов А.И., Бондаренко В.М., Рыбальченко О.В. Червинец В.М. Симбионтное пищеварение человека. Физиология, клиника, диагностика и лечение его нарушений. Тверь, Триада, 2013.Шендеров Б.А. «Омик-технологии» и их значение в современной профилактической и восстановительной медицине. Вестник восстановительной медицины.2012, 3 (49): 70-78.Яковлев М.Ю. «Эндотоксиновая агрессия» как предболезнь или универсальный фактор патогенеза заболеваний человека и животных. Успехи современной биологии. 2003, 123 (1): 31-40.Amar J., Chabo C., Waget A. et al. Intestinal mucosal adherence and translocation of commensal bacteria at the early onset of type 2 diabetes: molecular mechanisms and probiotic treatment. EMBO Mol. Med. 2011, 3 (9): 559-572.Backhed F., Ding H., Wang T. et al. The gut microbiota as an environmental factor that regulates fat storage. Proc.Nat.Acad. Sci. USA.2004, 101 (44): 15718-15723.Backhed F., Manchester J.K., Semenkovich C.F., Gordon.J.I. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc.Nat. Acad. Sci. USA. 2007, 104 (3): 979984.Barton G.M., Kagan J.C. A cell biological view of toll-like receptor function: regulation through compartmentalization. Natur. Rev. Immunol. 2009, 9 (8): 535-541.Bjursell M., Admyre T., Goransson M. et al. Improved glucose control and reduced body fat mass in free fatty acid receptor 2-deficient mice fed a high-fat diet. Am. J. Physiol. 2011, 300 (1): E211-E220.Burcelin R., Crivelli V, Dacosta A. et al. Heterogeneous metabolic adaptation of C57BL/6J mice to high-fat diet. Am. J. Physiol. 2002, 282: E834-E842.Cani P.D., Amar J., Iglesias M.A. et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes.2007, 56 (7): 1761-1772.Cani P.D., Bibiloni R., Knauf C. et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes.2008, 57 (6): 1470-1481.Cani P.D., Knauf C., Iglesias M.A. et al. Improvement of glucose tolerance and hepatic insulin sensitivity by oligofructose requires a functional glucagon-like peptide 1 receptor. Diabetes. 2006, 55 (5): 1484-1490.Cani P.D., Neyrinck A.M., Fava F et al. Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia. Diabetologia. 2006, 50 (11): 2374-2383.Carvalho B.M., Saad M.J.A. Influence of gut microbiota on subclinical inflammation and insulin resistance. Mediators of Inflammation. 2013, Article ID 986734.Collins C.D., Purohit S., Podolsky R.H., Zhao H.S., Schatz D. et al. The application of genomic and proteomic technologies in predictive, preventive and personalized medicine. Vascul. Pharmacol. 2006, 45 (5): 258-267.Clarke T.B.,Weiser J.N. Intracellular sensors of extracellular bacteria. Immunol. Rev.2011, 243 (1): 9-25.Cook S., Hugli O., Egli M. et al. Partial gene deletion of endothelial nitric oxide synthase predisposes to exaggerated high-fat diet-induced insulin resistance and arterial hypertension. Diabetes. 2003, 53: 2067-2072.Creely S.J., McTernan G., Kusminski C.M. et al. Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. Am. J. Physiol. 2007, 292 (3): E740-E747.Davis J.E., Gabler N.K., Walker-Daniels J., Spurlock M.E. Tlr-4 deficiency selectively protects against obesity induced by diets high insaturated fat. Obesity. 2008, 16 (6): 1248-1255, 2008.Feingold K.R., Staprans I., Memon R.A. et al. Endotoxin rapidly induces changes in lipid metabolism that produce hypertriglyceridemia: low doses stimulate hepatic triglyceride production while high doses inhibit clearance. J. Lipid Res.1992, 33 (12): 1765-1776.Finucane M.M., Stevens G.A., Cowan M.J. et al. National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9T million participants. Lancet. 2011, 377 (9765): 557-567.De Gonzalez A.B., Hartge P., Cerhan J.R. et al. Body-mass index and mortality among 1.46 million white adults. New Engl. J. Med. 2010, 363 (23): 2211-2219.Ghoshal S., Witta J., Zhong J. et al. Chylomicrons promote intestinal absorption of lipopolysac-charides. J. Lipid Res. 2009, 50: 90-97.Goodacre R. Metabolomics of a superorganism. J. Nutr. 2007, 137 (1): 259S-266S.Gordon J.I., Klaenhammer T.R. A rendezvous with our microbes. Proc. Natl. Acad. Sci. USA. 2011, 108 (1): 4513-4515.Hamann L., Alexander C., Stamme C., Zahringer U.,Schumann R.R. Acute-phase concentrations of lipopolysaccharide (LPS)-binding protein inhibit innate immune cell activation by different LPS chemotypes via different mechanisms. Infect. Immun. 2005, 73 (1): 193-200.Hildebrandt M.A., Hoffmann C., Sherrill-Mix S.A. et al. High-fat diet determines the composition of the murine gut microbiome independently of obesity. Gastroenterology. 2009, 137 (5): 17161716.Himes R.W , Smith C.W Tlr2 is critical for diet-induced metabolic syndrome in a murine model. FASEB J. 2010, 24 (3): 731-739.Hotamisligil G.S. Inflammation and metabolic disorders. Nature. 2006, 444 (7121): 860-867.Kuo L.H., Tsai P.J., Jiang M.J.et al. Toll-like receptor 2 deficiency improves insulin sensitivity and hepatic insulin signalling in the mouse. Diabetologia. 2010, 54 (1): 168-179.Lassenius K.H., Pietilainen K. et al. Bacterial endotoxin activity in human serum is associated with dyslipidemia, insulin resistance, obesity, and chronic inflammation. Diabetes Care. 2011, 34 (8): 1809-1815.Lederberg J. Infectious history. Science. 2000, 444: 287-293.Lee J.Y, Zhao L., Youn H.S. et al. Saturated fatty acid activates but polyunsaturated fatty acid inhibits Toll-like receptor 2 dimerized with Toll-like receptor 6 or 1. J. Biol. Chem. 2004, 279: 1697116979.Lee J.Y, Hwang D.H. The modulation ofinflammatory gene expression by lipids: mediation through toll-like receptors. Molecules and Cells. 2006, 21 (2): 174-185.Ley R.E., Backhed F., Turnbaugh P. et al. Obesity alters gut microbial ecology. Proc. Nat.Acad. Sci. USA. 2005, 102 (31): 11070-11075.Maitra U., Gan L., Chang S., Li L. Low-dose endotoxin induces inflammation by selectively removing nuclear receptors and activating caat/enhancer-binding protein 8. J. Immunol. 2011, 186 (7): 4467-4473.Manco M., Putignani L., Bottazzo G.F. et al. Gut microbiome, obesity, and metabolic dysfunction. J. Clin. Invest. 2011, 121 (6): 2126-2132.Membrez M., Blancher F., Jaquet M. et al. Gut microbiota modulation with norfloxacin and ampicillin enhances glucose tolerance in mice. FASEB J. 2008, 22 (7): 2416-2426.Mujico J.R., Baccan G.C., Gheorghe A. et al. Changes in gut microbiota due to supplemented fatty acids in diet-induced obese mice. Brit. J. Nutr. 2013, 110 (4): 711-720.Murphy E.F., Cotter P.D., Healy S. et al. Composition and energy harvesting capacity of the gut microbiota: relationship to diet, obesity and time in mouse models. Gut. 2010, 59 (12): 16351642.O’Hara A.M., Shanahan F. The gut flora as a forgotten organ. EMBO. 2006, 7 (7): 688-693.Poggi M., Bastelica D., Gual P. et al. C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet. Diabetologia. 2007, 50 (6): 1267-1276.Pussinen P. J., Havulinna A.S., Lehto M. Endotoxemia is associated with an increased risk of incident diabetes. Diabetes Care. 2011, 34 ( 2): 392-397.Rabot S., Membrez M., Bruneau A. et al. Germ-free C57BL/6J mice are resistant to high-fat-diet-induced insulin resistance and have altered cholesterol metabolism. FASEB J. 2010, 24 (12): 49484959.Rachmilevitz D., Katakura K., Karmeli F. et al. Toll-like receptor 9 signaling mediates the antiinflammatory effect of probiotics murine experimental colitis. Gastroenterol. 2004, 126 (2): 520528.Rakoff-Wahoum S., Paglino J., Esmali YF. et al. Recognition of commensal microflora by toll-like receptors is recquired for intestinal homeostasis. Cell. 2004, 118 (2): 229-241.Schertzer J.D., Tamrakar A.K., Magalhaes J.G. et al. NOD1 activators link innate immunity to insulin resistance. Diabetes. 2011, 60 (9): 2206-2215.Shi H., Kokoeva M.V., Inouye K. et al. TLR4 links innate immunity and fatty acid-induced insulin resistance. J.Clin. Investigat. 2006, 116 (11): 3015-3025.Spirig R., Tsui J., Shaw S. The emerging role of TLR and innate immunity in cardiovascular disease. Cardiol. Res. Practice. 2012, Article ID 181394.Tamrakar A.K., Schertzer J.D., Chiu T.T. et al. NOD2 activation induces muscle cell-autonomous innate immune responses and insulin resistance. Endocrinology. 2010, 151 (12): 5624-5637.Turnbaugh PJ.,Ley R.E., Mahowald M.A. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006, 444 (7122): 1027-1031.Venkatesh M.V., Hollis J.H., Gabler N.K. Dietary oil composition differentially modulates intestinal endotoxin transport and postprandial endotoxemia. Nutrit. Metabolism. 2013, 10:6 doi:10.1186/1743-7075-10-16.Vijay-Kumar M., Aitken J.D. , Carvalho F.A. et al. Metabolic syndrome and altered gut microbiota in mice lacking toll-like receptor 5. Science. 2010, 328 (5975): 228-231.Wellen K.E. , Hotamisligil G.S. Inflammation, stress, and diabetes. J. Clin. Invest. 2005, 115 (5): 1111-1119.WHO. Obesity and Overweight. Geneve, 2013.Wu X., Ma C., Han L. et al. Molecular characterization of the faecal microbiota in patients with type II diabetes. Curr. Microbiol. 2010, 61 (1): 69-78.Xiong Y., Miyamoto N., Shibata K. et al. Short-chain fatty acids stimulate leptin production in adipocytes through the G protein-coupled receptor GPR41. Proc. Nat. Acad. Sci. USA. 2004, 101 (4): 1045-1050.Zhang A., Zhang M., Wang S. et al. Interactions between gut microbiota, host genetics and diet relevant to development of metabolic syndromes in mice. ISME J. 2010, 4 (2): 232-241.Zhao L. The gut microbiota and obesity: from correlation to causality. Nature Rev. Microbiol. 2013, 11(9): 639-647.