Die Rolle der Mikrobiota bei der Entstehung von Adipositas und Typ-2-Diabetes

Zusammenfassung

Typ-2-Diabetes (T2 D) hat sich in den vergangenen Jahrzehnten zu einer Volkskrankheit entwickelt. Nach aktuellen Prognosen wird weltweit die Anzahl von Menschen mit Diabetes weiter ansteigen. Verbesserungen in der Prävention und Behandlung des T2 D als Folge von Übergewicht und Adipositas stellen somit eine enorme Herausforderung für die medizinische Forschung unserer Zeit dar.

Neuere Arbeiten schreiben der Mikrobiota des Darms eine potenzielle Rolle bei diesen Stoffwechselkrankheiten zu. So ist Adipositas mit einer veränderten Zusammensetzung der Mikrobiota des Darms assoziiert, die eine effizientere Energieextraktion aus der Nahrung aufweist. Des Weiteren konnten die Unterschiede in der Darm-Mikrobiota bereits als diagnostischer Marker für die Entwicklung von T2 D bei Patienten mit hohem Risiko identifiziert werden. So konnte bei Patienten mit T2 D eine mikrobielle Dysbiose nachgewiesen werden, die mit einem verminderten Vorkommen von Butyrat produzierenden Bakterien zugunsten von opportunistisch pathogenen Bakterien einherging. Auch führte der Transfer fäkaler Mikrobiota von stoffwechselgesunden Spendern auf Probanden mit metabolischem Syndrom zu einer Erhöhung von Butyrat produzierenden Bakterienstämmen. Diese kurzkettige Fettsäure, Butyrat, kann als ein Fermentationsprodukt der Darmmikroben aus komplexen Kohlenhydraten vorteilhafte metabolische Effekte haben. Dazu gehören die Verhinderung von metabolischer Endotoxinämie sowie die Aktivierung der intestinalen Glukoneogenese durch eine veränderte Genexpression und die direkte Wirkung auf den Glukosestoffwechsel durch Beeinflussung der Sekretion der Inkretine.

Therapeutisch sollte nicht nur dem sog. Fäkaltransfer neue Aufmerksamkeit geschenkt werden. Zukünftige Untersuchungen werden sich sicher auch auf die bakteriellen Stoffwechselprodukte (wie Butyrat) konzentrieren. Von Interesse ist vor allem, ob diese Stoffwechselprodukte die gleichen Wirkungen aufweisen wie die Darmbakterien, die sie produzieren, vor allem im Hinblick auf die Sekretion der Darmhormone (Inkretine). Zum anderen wird eine personalisierte Therapie angestrebt werden, um das Mikrobiom individuell zu modulieren. Dadurch wird letztlich der Weg geebnet für die Entwicklung weiterer Erfolg versprechender Interventionen bei Adipositas und T2 D.

Abstract

The prevalence for type 2 diabetes is increasing worldwide. According to current prognosis, the number of people with diabetes will increase worldwide. Improvements in the prevention and treatment of T2 D, as a result of obesity, are the current challenge of medical research.

Recent studies identified the gut microbiota as an important factor in the development of metabolic diseases. Thus, obesity is associated with an altered composition of the gut microbiota which seems to have a more efficient energy extraction from the diet. Furthermore, the differences in the intestinal microbiota may serve as a diagnostic marker for the development of T2 D in patients at high risk. So, a microbial dysbiosis, which was accompanied by a reduced occurrence of butyrate-producing bacteria in favour of opportunistic pathogens, could be detected in patients with T2 D. Also the transfer of fecal microbiota of metabolism-healthy donors on subjects with metabolic syndrome led to an increase of butyrate-producing bacterial strains. This short-chain fatty acid, butyrate, as fermentation product of intestinal microbes from complex carbohydrates, has beneficial metabolic effects on the host. These include the prevention of metabolic endotoxemia as well as the activation of intestinal gluconeogenesis by altered gene expression and direct effects on the intestinal hormones.

To develop new therapeutic strategies, future investigations will focus not only on the fecal transplantation but also on bacterial metabolic products, such as butyrate. However, in a first approach it will be of interest whether the application of the metabolic products has the same effect on the host as the intestinal bacteria that produce them, especially with regard to the secretion of intestinal hormones (incretins). This new research field may help to find new intervention strategies to prevent and treat obesity and T2 D.

• Literatur

• 1 Danaei G, Finucane MM, Lu Y et al. National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants. Lancet 2011; 378: 31-40
• 2 IDF. International Diabetes Federation (IDF) Diabetes Atlas. 2013 6th ed. Im Internet: http://www.idf.org/sites/default/files/EN_6E_Atlas_Full_0.pdf
• 3 Tilg H, Kaser A. Gut microbiome, obesity, and metabolic dysfunction. J Clin Invest 2011; 121: 2126-2132
• 4 Tilg H, Moschen AR. Inflammatory mechanisms in the regulation of insulin resistance. Mol Med 2008; 14: 222-231
• 5 Palermo A, Maggi D, Maurizi AR et al. Prevention of type 2 diabetes mellitus: is it feasible?. Diabetes Metab Res Rev 2014; 30 (Suppl. 01) 4-12
• 6 Friedman JM. Modern science versus the stigma of obesity. Nat Med 2004; 10: 563-569
• 7 Tremaroli V, Backhed F. Functional interactions between the gut microbiota and host metabolism. Nature 2012; 489: 242-249
• 8 Sommer F, Backhed F. The gut microbiota – masters of host development and physiology. Nat Rev Microbiol 2013; 11: 227-238
• 9 Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 2012; 486: 207-214
• 10 Zhu B, Wang X, Li L. Human gut microbiome: the second genome of human body. Protein Cell 2010; 1: 718-725
• 11 Shanahan F. The gut microbiota – a clinical perspective on lessons learned. Nat Rev Gastroenterol Hepatol 2012; 9: 609-614
• 12 Lepage P, Leclerc MC, Joossens M et al. A metagenomic insight into our gut’s microbiome. Gut 2013; 62: 146-158
• 13 Eckburg PB, Bik EM, Bernstein CN et al. Diversity of the human intestinal microbial flora. Science 2005; 308: 1635-1638
• 14 Costello EK, Lauber CL, Hamady M et al. Bacterial community variation in human body habitats across space and time. Science 2009; 326: 1694-1697
• 15 Qin J, Li R, Raes J et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 2010; 464: 59-65
• 16 Lee YK, Mazmanian SK. Has the microbiota played a critical role in the evolution of the adaptive immune system?. Science 2010; 330: 1768-1773
• 17 Backhed F, Manchester JK, Semenkovich CF et al. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci U S A 2007; 104: 979-984
• 18 Turnbaugh PJ, Ley RE, Mahowald MA et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006; 444: 1027-1031
• 19 Ley RE, Backhed F, Turnbaugh P et al. Obesity alters gut microbial ecology. Proc Natl Acad Sci U S A 2005; 102: 11070-11075
• 20 Ley RE, Turnbaugh PJ, Klein S et al. Microbial ecology: human gut microbes associated with obesity. Nature 2006; 444: 1022-1023
• 21 Backhed 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; 101: 15718-15723
• 22 Vrieze A, Van Nood E, Holleman F et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 2012; 143: 913-916
• 23 Van Nood E, Vrieze A, Nieuwdorp M et al. Duodenal infusion of donor feces for recurrent clostridium difficile. N Engl J Med 2013; 368: 407-415
• 24 Smits LP, Bouter KE, de Vos WM et al. Therapeutic potential of fecal microbiota transplantation. Gastroenterology 2013; 145: 946-953
• 25 Kootte RS, Vrieze A, Holleman F et al. The therapeutic potential of manipulating gut microbiota in obesity and type 2 diabetes mellitus. Diabetes Obes Metab 2012; 14: 112-120
• 26 Karlsson FH, Tremaroli V, Nookaew I et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 2013; 498: 99-103
• 27 Qin J, Li Y, Cai Z et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 2012; 490: 55-60
• 28 Larsen N, Vogensen FK, van den Berg FW et al. Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults. PLoS One 2010; 5: e9085
• 29 Shin NR, Lee JC, Lee HY et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 2014; 63: 727-735
• 30 Olle B. Medicines from microbiota. Nat Biotechnol 2013; 31: 309-315
• 31 de Vos WM, Nieuwdorp M. Genomics: A gut prediction. Nature 2013; 498: 48-49
• 32 Cani PD, Delzenne NM. The gut microbiome as therapeutic target. Pharmacol Ther 2011; 130: 202-212
• 33 Flint HJ, Bayer EA, Rincon MT et al. Polysaccharide utilization by gut bacteria: potential for new insights from genomic analysis. Nat Rev Microbiol 2008; 6: 121-131
• 34 Robertson MD, Bickerton AS, Dennis AL et al. Insulin-sensitizing effects of dietary resistant starch and effects on skeletal muscle and adipose tissue metabolism. Am J Clin Nutr 2005; 82: 559-567
• 35 Robertson MD, Currie JM, Morgan LM et al. Prior short-term consumption of resistant starch enhances postprandial insulin sensitivity in healthy subjects. Diabetologia 2003; 46: 659-665
• 36 Mendeloff AI. Dietary fiber and human health. N Engl J Med 1977; 297: 811-814
• 37 Elamin EE, Masclee AA, Dekker J et al. Short-chain fatty acids activate AMP-activated protein kinase and ameliorate ethanol-induced intestinal barrier dysfunction in Caco-2 cell monolayers. J Nutr 2013; 143: 1872-1881
• 38 Ma X, Fan PX, Li LS et al. Butyrate promotes the recovering of intestinal wound healing through its positive effect on the tight junctions. J Anim Sci 2012; 90 (Suppl. 04) 266-268
• 39 Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest 2005; 115: 1111-1119
• 40 Hotamisligil GS. Inflammatory pathways and insulin action. Int J Obes Relat Metab Disord 2003; 27 (Suppl. 03) S53-S55
• 41 Cani PD, Amar J, Iglesias MA et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 2007; 56: 1761-1772
• 42 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: 1091-1103
• 43 Mithieux G. The new functions of the gut in the control of glucose homeostasis. Curr Opin Clin Nutr Metab Care 2005; 8: 445-449
• 44 Mithieux G, Misery P, Magnan C et al. Portal sensing of intestinal gluconeogenesis is a mechanistic link in the diminution of food intake induced by diet protein. Cell Metab 2005; 2: 321-329
• 45 Delaere F, Duchampt A, Mounien L et al. The role of sodium-coupled glucose co-transporter 3 in the satiety effect of portal glucose sensing. Mol Metab 2012; 2: 47-53
• 46 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
• 47 Brown AJ, Goldsworthy SM, Barnes AA et al. The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem 2003; 278: 11312-11319
• 48 Le Poul E, Loison C, Struyf S et al. Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. J Biol Chem 2003; 278: 25481-25489
• 49 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
• 50 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: 364-371
• 51 Mithieux G, Gautier-Stein A. Intestinal glucose metabolism revisited. Diabetes Res Clin Pract 2014; 105: 295-301
• 52 Tazoe H, Otomo Y, Kaji I et al. Roles of short-chain fatty acids receptors, GPR41 and GPR43 on colonic functions. J Physiol Pharmacol 2008; 59 (Suppl. 02) 251-262
• 53 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 U S A 2008; 105: 16767-16772
• 54 Hirasawa A, Tsumaya K, Awaji T et al. Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat Med 2005; 11: 90-94
• 55 Ichimura A, Hirasawa A, Poulain-Godefroy O et al. Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human. Nature 2012; 483: 350-354
• 56 Gao Z, Yin J, Zhang J et al. Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes 2009; 58: 1509-1517
• 57 Cani PD, Neyrinck AM, 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 2007; 50: 2374-2383
• 58 Cani PD, Osto M, Geurts L et al. Involvement of gut microbiota in the development of low-grade inflammation and type 2 diabetes associated with obesity. Gut Microbes 2012; 3: 279-288
• 59 Cotillard A, Kennedy SP, Kong LC et al. Dietary intervention impact on gut microbial gene richness. Nature 2013; 500: 585-588