Патофизиологические взаимосвязи метаболического синдрома и микробиоты кишечника

В условиях современного мира все глобальнее становится проблема ожирения и метаболического синдрома. Социальные и экологические факторы, играющие роль в развитии этих состояний, еще не до конца изучены, однако уже сейчас накапливаются данные, свидетельствующие о том, что развитию ожирения и метаболического синдрома способствуют неблагоприятные условия раннего периода жизни, например, заболевания матери в периоды беременности и лактации, использование различных химических и лекарственных агентов, низкая масса плода при рождении, неблагоприятные режим и качество питания. Все эти факторы оказывают воздействие на состояние желудочно-кишечного тракта, в частности приводят к дисбалансу кишечной микрофлоры. Накапливаются данные о том, что микробиом кишечника людей с ожирением структурно и функционально отличен от микрофлоры кишечника здорового человека. Выявление прочной корреляционной связи между этими параметрами может открыть перспективы для профилактики метаболического синдрома и всех ассоциированных с ним состояний путем поддержания здоровья кишечной микрофлоры. Целью данной статьи является освещение данных исследований, проводимых на животных и людях, которые подтверждают наличие патофизиологических механизмов влияния кишечной микрофлоры на развитие ожирения и сопутствующего метаболического синдрома, а также поиск возможностей профилактики данных состояний посредством добавления пре- и пробиотиков к пище.

1. Dinan TG, Cryan JF. Brain–gut–microbiota axis—Mood, metabolism and behaviour. Nat. Rev. Gastroenterol. Hepatol. 2017;14:69–70. doi: https://doi.org/10.1111/spc3.12309

2. Bäckhed F, Ley RE, Sonnenburg JL, et al. Host-Bacterial Mutualism in the Human Intestine. Science. 2005;307:1915. doi: https://doi.org/10.1126/science.1104816

3. Bäckhed F, Ding H, Wang T, et al. The gutmicrobiota as an environmental factor that regulates fat storage. Proc. Natl. Acad. Sci. USA. 2004;101:15718. doi: https://doi.org/10.1073/pnas.0407076101

4. Белоглазов В.А., Яцков И.А., Кумельский Е.Д., Половинкина В.В. Метаболическая эндотоксинемия: возможные причины и последствия // Ожирение и метаболизм. — 2021. — Т.18. — №3 — С.320-326. doi: https://doi.org/10.14341/omet12750

5. Thaiss CA, Itav S, Rothschild D, et al. Persistent microbiome alterations modulate the rate of post-dieting weight regain. Nature. 2016;540:544–551. doi: https://doi.org/10.1038/nature20796

6. Sonnenburg ED, Smits SA, Tikhonov M, et al. Diet-induced extinctions in the gut microbiota compound over generations. Nature. 2016;529:212–215. doi: https://doi.org/10.1038/nature16504

7. Lecerf J-M, Dépeint F, Clerc E, et al. Xylo-oligosaccharide (XOS) in combination with inulin modulates both the intestinal environment and immune status in healthy subjects, while XOS alone only shows prebiotic properties. Br. J. Nutr. 2012;108:1847–1858. doi: https://doi.org/10.1017/S0007114511007252

8. Turnbaugh PJ, Ley RE, Mahowald MA, et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444:1027–1031. doi: https://doi.org/10.1038/nature05414

9. Ridaura VK, Faith JJ, Rey FE, et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science (80- ). 2013. doi: https://doi.org/10.1126/science.1241214

10. Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Human gut microbes associated with obesity. Nature. 2006;444:1022–1023. doi: https://doi.org/10.1038/4441022a

11. Ley RE, Bäckhed F, Turnbaugh P, et al. Obesity alters gut microbialecology. Proc. Natl. Acad. Sci. USA. 2005;102:11070. doi: https://doi.org/10.1073/pnas.0504978102

12. Nadal I, Santacruz A, Marcos A, et al. Shifts in clostridia, bacteroides and immunoglobulin-coating fecalbacteria associated with weight loss in obese adolescents. Int. J. Obes. 2009;33:758–767. doi: https://doi.org/10.1038/ijo.2008.260

13. Remely M, Tesar I, Hippe B, et al. Gut microbiota composition correlateswith changes in body fat content due to weight loss. Benef. Microbes. 2015;6:431–439. doi: https://doi.org/10.3920/BM2014.0104

14. Sze MA, Schloss PD. Looking for a Signal in the Noise: Revisiting Obesity and the Microbiome. MBio. 2016;7:e01018-16. doi: https://doi.org/10.1128/mbio.01018-16

15. Le Chatelier E, Nielsen T, Qin J, et al. Richness of human gut microbiome correlates with metabolic markers. Nature. 2013;500:541–546. doi: https://doi.org/10.1038/nature12506

16. Turnbaugh PJ, Hamady M, Yatsunenko T, et al. A core gut microbiome in obese and lean twins. Nature. 2009;457:480–484. doi: https://doi.org/10.1038/nature07540

17. Canfora EE, Meex RCR, Venema K, Blaak EE. Gut microbial metabolites in obesity, NAFLD and T2DM. Nat. Rev. Endocrinol. 2019;15:261–273. doi: https://doi.org/10.1038/s41574-019-0156-z

18. Nehra V, Allen JM, Mailing LJ, et al. Gut Microbiota: Modulation of Host Physiology in Obesity. Physiology. 2016.31:327–335. doi: https://doi.org/10.1152/physiol.00005.2016

19. Roediger WEW. Utilization of Nutrients by Isolated Epithelial Cells of the Rat Colon. Gastroenterology. 1982;83:424–429

20. Bergman EN. Energy contributions of volatile fatty acids from the gastrointestinal tract in various species. Physiol. Rev. 1990;70:567–590. doi: https://doi.org/10.1152/physrev.1990.70.2.567

21. Den Besten G, Lange K, Havinga R, et al. Gut-derived short-chain fatty acids are vividly assimilated into hostcarbohydrates and lipids. Am. J. Physiol. Gastrointest. Liver Physiol. 2013; 305:G900–G910. doi: https://doi.org/10.1152/ajpgi.00265.2013

22. Høverstad T, Midtvedt T. Short-Chain Fatty Acids in Germfree Mice and Rats. J. Nutr. 1986;116:1772–1776. doi: https://doi.org/10.1093/jn/116.9.1772

23. Agustí A, García-Pardo MP, López-Almela I, et al. Interplay Between the Gut-Brain Axis, Obesity and Cognitive Function. Front. Neurosci. 2018;12:155. doi: https://doi.org/10.3389/fnins.2018.00155

24. Fernandes J, Su W, Rahat-Rozenbloom S, et al. Adiposity, gut microbiota andfaecal short chain fatty acids are linked in adult humans. Nutr. Diabetes. 2014;4:e121. doi: https://doi.org/10.1038/nutd.2014.23

25. Schwiertz A, Taras D, Schäfer K, et al. Microbiota and SCFA in Lean and Overweight Healthy Subjects. Obesity. 2010;18:190–195. doi: https://doi.org/10.1038/oby.2009.167

26. Gogineni V, Morrow L, Malesker M, Gregory P. Probiotics: History and Evolution. J. Anc. Dis. Prev. Remedies. 2013;1:1–7. doi: https://doi.org/10.3920/BM2014.0103

27. Belobrajdi DP, King RA, Christophersen CT, Bird AR. Dietary resistant starch dose-dependently reduces adiposity in obesityprone and obesity-resistant male rats. Nutr. Metab. 2012;9:93. doi: https://doi.org/10.1186/1743-7075-9-93

28. Samuel BS, Shaito A, Motoike T, et al. Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proc. Natl. Acad. Sci. USA. 2008;105:16767. doi: https://doi.org/10.1073/pnas.0808567105

29. De Vadder F, Kovatcheva-Datchary P, Goncalves D, et al. Microbiota-Generated Metabolites Promote Metabolic Benefits via Gut-Brain Neural Circuits. Cell. 2014;156:84–96. doi: https://doi.org/10.1016/j.cell.2013.12.016

30. Tolhurst G, Heffron H, Lam YS, et al. Short-Chain Fatty Acids Stimulate Glucagon-Like Peptide-1 Secretion via the G-Protein–Coupled Receptor FFAR2. Diabetes. 2012;61:364. doi: https://doi.org/10.2337/db11-1019

31. Zaibi MS, Stocker CJ, O’Dowd J, et al. Roles of GPR41 and GPR43 in leptin secretory responses of murine adipocytes to short chainfatty acids. FEBS Lett. 2010;584:2381–2386. doi: https://doi.org/10.1016/j.febslet.2010.04.027

32. Forbes S, Stafford S, Coope G, et al. Selective FFA2 Agonism Appears to Act via Intestinal PYY to Reduce Transit and Food Intake but Does Not Improve Glucose Tolerance in Mouse Models. Diabetes. 2015;64:3763. doi: https://doi.org/10.2337/db15-0481

33. Zhou J, Martin RJ, Tulley RT, et al. Dietary resistant starch upregulates total GLP-1 and PYY in a sustained daylongmanner through fermentation in rodents. Am. J. Physiol. Endocrinol. Metab. 2008;295:E1160–E1166. doi: https://doi.org/10.1152/ajpendo.90637.2008

34. Chambers ES, Viardot A, Psichas A, et al. Effects of targeted delivery of propionate to the human colonon appetite regulation, body weight maintenance and adiposity in overweight adults. Gut. 2015;64:1744. doi: https://doi.org/10.1136/gutjnl-2014-307913

35. Frost G, Sleeth ML, Sahuri-Arisoylu M, et al. The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nat. Commun. 2014;5:3611. doi: https://doi.org/10.1038/ncomms4611

36. Li Z, Yi C-X, Katiraei S, et al. Butyrate reduces appetite and activates brown adipose tissue via the gut-brain neural circuit. Gut. 2018;67:1269. doi: https://doi.org/10.1136/gutjnl-2017-314050

37. Goswami C, Iwasaki Y, Yada T. Short-chain fatty acids suppress food intake by activating vagal afferent neurons. J. Nutr. Biochem. 2018;57:130–135. doi: https://doi.org/10.1016/j.jnutbio.2018.03.009

38. Gao Z, Yin J, Zhang J, et al. Butyrate Improves Insulin Sensitivity and Increases Energy Expenditure in Mice. Diabetes. 2009;58:1509. doi: https://doi.org/10.2337/db08-1637

39. Sahuri-Arisoylu M, Brody LP, Parkinson JR, et al. Reprogramming of hepatic fat accumulation and ‘browning’ of adipose tissue by theshort-chain fatty acid acetate. Int. J. Obes. 2016;40:955–963. doi: https://doi.org/10.1038/ijo.2016.23

40. Kondo T, Kishi M, Fushimi T, Kaga T. Acetic Acid Upregulates the Expression of Genes for Fatty Acid Oxidation Enzymes in Liver To Suppress Body Fat Accumulation. J. Agric. Food Chem. 2009;57:5982–5986. doi: https://doi.org/10.1021/jf900470c

41. Den Besten G, Bleeker A, Gerding A, et al. Short-Chain Fatty Acids Protect Against High-Fat Diet–Induced Obesity via a PPARγ-Dependent Switch From Lipogenesis to Fat Oxidation. Diabetes.2015;64:2398. doi: https://doi.org/10.1194/jlr.R036012

42. Canfora EE, van der Beek CM, Jocken JWE, et al. Colonic infusions of short-chain fatty acid mixtures promote energymetabolism in overweight/obese men: A randomized crossover trial. Sci. Rep. 2017;7:2360. doi: https://doi.org/10.1038/s41598-017-02546-x

43. Chambers ES, Byrne CS, Aspey K, et al. Acute oral sodium propionate supplementation raises resting energy expenditure and lipid oxidation in fasted humans. Diabetes Obes. Metab. 2018;20:1034–1039. doi: https://doi.org/10.1111/dom.13159

44. Choi J, Joseph L, Pilote L. Obesity and C-reactive protein in various populations: A systematic review and meta-analysis. Obes. Rev. 2013;14:232–244. doi: https://doi.org/10.1111/obr.12003

45. Bahceci M, Gokalp D, Bahceci S, et al. The correlation between adiposity and adiponectin, tumor necrosis factor α, interleukin-6 and high sensitivity C-reactive protein levels. Is adipocyte size associated with inflammation in adults? J. Endocrinol. Investig. 2007;30:210–214. doi: https://doi.org/10.1007/BF03347427

46. Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444:860–867. doi: https://doi.org/10.1038/nature05485

47. Yuan M, Konstantopoulos N, Lee J, et al. Reversal of Obesity and Diet-Induced Insulin Resistance with Salicylates or Targeted Disruption of Ikkβ. Science. 2001;293:1673. doi: https://doi.org/10.1126/science.1061620

48. Osborn O, Olefsky JM. The cellular and signaling networks linking the immune system and metabolism in disease. Nat. Med. 2012;18:363–374. doi: https://doi.org/10.1038/nm.2627

49. Ukena SN, Singh A, Dringenberg U, et al. Probiotic Escherichia coli Nissle 1917 inhibits leaky gut by enhancing mucosal integrity. PLoS ONE. 2007;2:e1308. doi: https://doi.org/10.1371/journal.pone.0001308

50. Cani PD, Amar J, Iglesias MA, et al. Metabolic Endotoxemia Initiates Obesity and Insulin Resistance. Diabetes. 2007;56:1761. doi: https://doi.org/10.2337/db06-1491

51. Guarner F, Malagelada J-R. Gut flora in health and disease. Lancet. 2003;361:512–519. doi: https://doi.org/10.1016/S0140-6736(03)12489-0

52. Everard A, Belzer C, Geurts L, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls dietinduced obesity. Proc. Natl. Acad. Sci. USA. 2013;110:9066–9071. doi: https://doi.org/10.1073/pnas.1219451110

53. Ewaschuk JB, Diaz H, Meddings L, et al. Secreted bioactive factors from Bifidobacterium infantis enhance epithelial cell barrier function. Am. J. Physiol. Gastrointest. Liver Physiol. 2008;295:G1025–G1034. doi: https://doi.org/10.1152/ajpgi.90227.2008

54. Shen TY, Qin HL, Gao ZG, et al. Influences of enteral nutrition combined with probiotics on gut microflora and barrier function of rats with abdominal infection. World J. Gastroenterol. 2006;12:4352. doi: https://doi.org/10.3748/wjg.v12.i27.4352

55. Hamer HM, Jonkers D, Venema K, et al. Review article: The role of butyrate on colonic function. Aliment. Pharmacol. Ther. 2008;27:104–119. doi: https://doi.org/10.1111/j.1365-2036.2007.03562.x

56. Topping DL, Clifton PM. Short-Chain Fatty Acids and Human Colonic Function: Roles of Resistant Starch and Nonstarch Polysaccharides. Physiol. Rev. 2001;81:1031–1064. doi: https://doi.org/10.1152/physrev.2001.81.3.1031

57. Vinolo MA, Rodrigues HG, Nachbar RT, Curi R. Regulation of inflammation by short chain fatty acids. Nutrients. 2011;3:858–876. doi: https://doi.org/10.3390/nu3100858

58. Khan MJ, Gerasimidis K, Edwards CA, Shaikh MG. Role of Gut Microbiota in the Aetiology of Obesity:Proposed Mechanisms and Review of the Literature. J. Obes. 2016; 2016:7353642. doi: https://doi.org/10.1155/2016/7353642

59. Cani PD, 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;57:1470. doi: https://doi.org/10.2337/db07-1403

60. Creely SJ, McTernan PG, Kusminski CM, et al. Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 2007;292:E740–E747. doi: https://doi.org/10.1152/ajpendo.00302.2006

61. Pearson J, Brownlee I. The Interaction of Large Bowel Microflora with the Colonic Mucus Barrier. Int. J.Inflamm. 2010;2010:321426. doi: https://doi.org/10.4061/2010/321426

62. Clemente-Postigo M, Oliva-Olivera W, Coin-Aragüez L, et al. Metabolic endotoxemia promotes adipose dysfunction and inflammation in human obesity. Am. J. Physiol. Endocrinol. Metab. 2018;316:E319–E332. doi: https://doi.org/10.1152/ajpendo.00277.2018

63. Harte AL, Varma MC, Tripathi G, et al. High fat intake leads to acute postprandial exposure to circulating endotoxin in type 2 diabetic subjects. Diabetes Care. 2012;35:375–382. doi: https://doi.org/10.2337/dc11-1593

64. Botao W, Qingmin K, Xiu L, et al. A High-Fat Diet Increases Gut Microbiota Biodiversity and Energy Expenditure Due to Nutrient Difference. Nutrients. 2020;20:12. doi: https://doi.org/10.3390/nu12103197

65. Гапонов А.М., Волкова Н.И., Ганенко Л.А., и др. Особенности микробиома толстой кишки у пациентов с ожирением при его различных фенотипах. // Журнал микробиологии, эпидемиологии и иммунобиологии. — 2021. — Т.98. — №2 — С.144-155. doi: https://doi.org/10.36233/0372-9311-66

66. Dewulf EM, Cani PD, Claus SP, et al. Insight into the prebiotic concept: Lessons from an exploratory, double blind intervention study with inulin-type fructans in obese women. Gut. 2013;62:1112. doi: https://doi.org/10.1136/gutjnl-2012-303304

67. Peterson CT, Sharma V, Elmén L, Peterson SN. Immune homeostasis, dysbiosis and the rapeutic modulation of the gut microbiota. Clin. Exp. Immunol. 2015;179:363–377. doi: https://doi.org/10.1111/cei.12474

68. Cani PD, Possemiers S, Van de Wiele T, et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2- driven improvement of gut permeability. Gut. 2009;58:1091. doi: https://doi.org/10.1136/gut.2008.165886

69. Posovszky C, Wabitsch M. Regulation of Appetite, Satiation, and Body Weight by Enteroendocrine Cells. Part 2: Therapeutic Potential of Enteroendocrine Cells in the Treatment of Obesity. Horm. Res. Paediatr. 2015;83:11–18. doi: https://doi.org/10.1159/000369555

70. Cani PD, Hoste S, Guiot Y, Delzenne NM. Dietary nondigestible carbohydrates promote L-cell differentiation in the proximal colon of rats. Br. J. Nutr. 2007;98:32–37. doi: https://doi.org/10.1017/S0007114507691648

71. Cani PD, Lecourt E, Dewulf EM, et al. Gut microbiota fermentation of prebiotics increases satietogenic and incretin gut peptide production with consequences for appetite sensation and glucose response after a meal. Am. J. Clin. Nutr. 2009;90:1236–1243. doi: https://doi.org/10.3945/ajcn.2009.28095

72. Parnell JA, Reimer RA. Weight loss during oligofructose supplementation is associated with decreased ghrelin and increased peptide YY in overweight and obese adults. Am. J. Clin. Nutr. 2009;89:1751–1759. doi: https://doi.org/10.3945/ajcn.2009.27465

73. Chambers ES, Byrne CS, Morrison DJ, et al. Dietary supplementation with inulin-propionate ester or inulin improves insulin sensitivity in adults with overweight and obesity with distinct effects on the gut microbiota, plasma metabolome and systemic inflammatory responses: A randomised cross-over trial. Gut. 2019;68:1430. doi: https://doi.org/10.1136/gutjnl-2019-318424

74. Tschritter O, Fritsche A, Thamer C, et al. Plasma Adiponectin Concentrations Predict Insulin Sensitivity of Both Glucose and Lipid Metabolism. Diabetes. 2003;52:239. doi: https://doi.org/10.2337/diabetes.52.2.239

75. Alligier M, Dewulf EM, Salazar N, et al. Positive interaction between prebiotics and thiazolidinedione treatment on adiposity in diet-induced obese mice. Obesity. 2014;22:1653–1661. doi: https://doi.org/10.1002/oby.20733

76. Thorburn A, Muir J, Proietto J. Carbohydrate fermentation decreases hepatic glucose output in healthy subjects. Metabolism. 1993;42:780–785. doi: https://doi.org/10.1016/0026-0495(93)90249-N

77. Berggren AM, Nyman EMGL, Lundquist I, Björck IME. Influence of orally and rectally administered propionate on cholesterol and glucose metabolism in obese rats. Br. J. Nutr. 1996;76: 287–294. doi: https://doi.org/10.1079/BJN19960032