Intestinales Mikrobiom

Zusammenfassung

Die Zusammensetzung und Funktionalität der intestinalen Mikrobiota steht derzeit im Zentrum des biomedizinischen Interesses. Durch die Entwicklung innovativer molekularer Hochdurchsatzanalysemethoden sowie der bioinformatischen „Big-Data“-Analyse ist es seit ca. 1 Jahrzehnt möglich, das intestinale Ökosystem eines Individuums zu beschreiben. Vergleichende Analysen zeigten in der Folge, dass eine überraschend hohe Anzahl unterschiedlichster Pathologien, von Reizdarm und chronisch entzündlichen Darmerkrankungen (CED) über Multiple Sklerose bis hin zu Adipositas, Diabetes und Atherosklerose mit Veränderungen der intestinalen Mikrobiota assoziiert sind. Die Ursachen und Folgen der beobachteten Veränderungen des intestinalen Ökosystems im Zusammenhang mit der jeweiligen Erkrankung sind weitgehend unbekannt und aktuell Gegenstand intensiver experimenteller sowie klinischer Forschung. Unterschiedliche Faktoren aus Umwelt und Wirt beeinflussen die Zusammensetzung und Funktion des mikrobiellen Ökosystems im Darm, wobei Nahrungsfaktoren einen wesentlichen Beitrag leisten. Basierend auf der Erkenntnis, dass intestinale Mikroorganismen den Stoffwechsel, die Darmbarriere und das Immunsystem des Wirts entscheidend beeinflussen können, ist die gezielte Modulation des mikrobiellen Ökosystems ein vielversprechender Ansatzpunkt in der Prävention und Therapie zahlreicher Erkrankungen.

Abstract

The composition and functionality of the intestinal microbiota is currently in the focus of basic and applied biomedical sciences. The development of innovative deep sequencing methods and bioinformatic big data analyses enabled the description of individual intestinal ecosystems since about one decade ago. Comparative analyses subsequently showed that a surprisingly high number of pathologies, ranging from irritable bowel syndrome (IBS) and inflammatory bowel diseases (IBD) to multiple sclerosis, adiposity, diabetes and atherosclerosis, are associated with alterations in the intestinal microbiota. The causes and consequences of the respective alterations are largely unknown and currently intensively investigated in experimental and clinical studies. Various environmental and host factors modulate the composition and function of the intestinal microbiota. Of all these modulators, diet emerged as one key effector of the intestinal microbiota. Based on the fact, that specific intestinal microorganisms are able to impact on the metabolism, the intestinal barrier and the immune system of the host, the targeted modulation of the microbial ecosystem is a promising starting point in the prevention and therapy of many diseases.

Schlüsselwörter

intestinales Mikrobiom - intestinale Mikrobiota - Darmbakterien - Mikroben-Wirts-Interaktion - Einflussfaktor Ernährung - mikrobielle Therapien

Keywords

intestinal microbiome - intestinal microbiota - gut bacteria - microbe-host interaction - dietary impact - microbial therapies

• Literatur

• 1 Marchesi JR, Ravel J. The vocabulary of microbiome research: a proposal. Microbiome 2015; 3: 31
• 2 Qin J, Li R, Raes J et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 2010; 464: 59-65
• 3 Nielsen HB, Almeida M, Juncker AS et al. Identification and assembly of genomes and genetic elements in complex metagenomic samples without using reference genomes. Nat Biotechnol 2014; 32: 822-828
• 4 Kernbauer E, Ding Y, Cadwell K. An enteric virus can replace the beneficial function of commensal bacteria. Nature 2014; 516: 94-98
• 5 Chehoud C, Albenberg LG, Judge C et al. Fungal Signature in the Gut Microbiota of Pediatric Patients With Inflammatory Bowel Disease. Inflamm Bowel Dis 2015; 21: 1948-1956
• 6 Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 2012; 486: 207-214
• 7 Faith JJ, Guruge JL, Charbonneau M et al. The long-term stability of the human gut microbiota. Science 2013; 341: 1237439
• 8 Gevers D, Kugathasan S, Denson LA et al. The treatment-naive microbiome in new-onset Crohn's disease. Cell Host Microbe 2014; 15: 382-392
• 9 Jost L. Entropy and diversity. Oikos 2006; 113: 363-375
• 10 Ulven T. Short-chain free fatty acid receptors FFA2/GPR43 and FFA3/GPR41 as new potential therapeutic targets. Front Endocrinol (Lausanne) 2012; 3: 111
• 11 Ramakrishna BS. Role of the gut microbiota in human nutrition and metabolism. J Gastroenterol Hepatol 2013; 28 (Suppl. 04) 9-17
• 12 Haller D, Russo MP, Sartor RB et al. IKK beta and phosphatidylinositol 3-kinase/Akt participate in non-pathogenic Gram-negative enteric bacteria-induced RelA phosphorylation and NF-kappa B activation in both primary and intestinal epithelial cell lines. J Biol Chem 2002; 277: 38168-38178
• 13 Smith K, McCoy KD, Macpherson AJ. Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. Seminars in Immunology 2007; 19: 59-69
• 14 Lozupone CA, Stombaugh JI, Gordon JI et al. Diversity, stability and resilience of the human gut microbiota. Nature 2012; 489: 220-230
• 15 Arumugam M, Raes J, Pelletier E et al. Enterotypes of the human gut microbiome. Nature 2011; 473: 174-180
• 16 Rossen NG, Fuentes S, Boonstra K et al. The mucosa-associated microbiota of PSC patients is characterized by low diversity and low abundance of uncultured Clostridiales II. J Crohns Colitis 2015; 9: 342-348
• 17 Kostic AD, Gevers D, Siljander H et al. The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes. Cell Host Microbe 2015; 17: 260-273
• 18 Turnbaugh PJ, Hamady M, Yatsunenko T et al. A core gut microbiome in obese and lean twins. Nature 2009; 457: 480-484
• 19 Nylund L, Nermes M, Isolauri E et al. Severity of atopic disease inversely correlates with intestinal microbiota diversity and butyrate-producing bacteria. Allergy 2015; 70: 241-244
• 20 Cotillard A, Kennedy SP, Kong LC et al. Dietary intervention impact on gut microbial gene richness. Nature 2013; 500: 585-588
• 21 Zhang X, Xang D, Jia H et al. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat Med 2015; 21: 895-905
• 22 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
• 23 Morgan XC, Tickle T, Sokol H et al. Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol 2012; 13: R79
• 24 Turnbaugh PJ, Ridaura VK, Faith JJ et al. The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci Transl Med 2009; 1: 6ra14
• 25 Ridaura VK, Faith JJ, Rey FE et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 2013; 341: 1241214
• 26 Crouzet L, Gaultier E, DelʼHomme C et al. The hypersensitivity to colonic distension of IBS patients can be transferred to rats through their fecal microbiota. Neurogastroenterol Motil 2013; 25: e272-282
• 27 Baxter NT, Zackular JP, Chen GY et al. Structure of the gut microbiome following colonization with human feces determines colonic tumor burden. Microbiome 2014; 2: 20
• 28 Schaubeck M, Clavel T, Calasan J et al. Dysbiotic gut microbiota causes transmissible Crohn's disease-like ileitis independent of failure in antimicrobial defence. Gut 2015; 65: 225-237
• 29 Dominguez-Bello MG, Costelle EK, Contreras M et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci U S A 2010; 107: 11971-11975
• 30 Backhed F, Roswall J, Peng Y et al. Dynamics and Stabilization of the Human Gut Microbiome during the First Year of Life. Cell Host Microbe 2015; 17: 852
• 31 Ma J, Prince AL, Bader D et al. High-fat maternal diet during pregnancy persistently alters the offspring microbiome in a primate model. Nat Commun 2014; 5: 3889
• 32 Golubeva AV, Crampton S, Desbonnet L et al. Prenatal stress-induced alterations in major physiological systems correlate with gut microbiota composition in adulthood. Psychoneuroendocrinology 2015; 60: 58-74
• 33 Musilova S, Rada V, Vlkova E et al. Beneficial effects of human milk oligosaccharides on gut microbiota. Benef Microbes 2014; 5: 273-283
• 34 Liu B, Newburg DS. Human milk glycoproteins protect infants against human pathogens. Breastfeed Med 2013; 8: 354-362
• 35 Koenig JE, Spor A, Scalfone N et al. Succession of microbial consortia in the developing infant gut microbiome. Proc Natl Acad Sci U S A 2011; 108 (Suppl. 01) 4578-4585
• 36 Stewart JA, Chadwick VS, Murray A. Investigations into the influence of host genetics on the predominant eubacteria in the faecal microflora of children. J Med Microbiol 2005; 54: 1239-1242
• 37 Lepage P, Häsler R, Spehlmann ME et al. Twin study indicates loss of interaction between microbiota and mucosa of patients with ulcerative colitis. Gastroenterology 2011; 141: 227-236
• 38 Liu JZ, van Sommeren S, Huang H et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet 2015; 47: 979-986
• 39 Knights D, Silverberg MS, Weersma RK et al. Complex host genetics influence the microbiome in inflammatory bowel disease. Genome Med 2014; 6: 107
• 40 Thaiss CA, Zeevi D, Levy M et al. Transkingdom control of microbiota diurnal oscillations promotes metabolic homeostasis. Cell 2014; 159: 514-529
• 41 Dethlefsen L, Relman DA. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc Natl Acad Sci U S A 2011; 108 (Suppl. 01) 4554-4561
• 42 Ungaro R, Bernstein CN, Gearry R et al. Antibiotics Associated With Increased Risk of New-Onset Crohn's Disease But Not Ulcerative Colitis: A Meta-Analysis. Am J Gastroenterol 2014; 109: 1728-1738
• 43 Wu GD, Chen J, Hoffmann C et al. Linking long-term dietary patterns with gut microbial enterotypes. Science 2011; 334: 105-108
• 44 Salonen A, Lahti L, Salojärvi J et al. Impact of diet and individual variation on intestinal microbiota composition and fermentation products in obese men. ISME J 2014; 8: 2218-2230
• 45 David LA, Maurice CF, Carmody RN et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 2014; 505: 559-563
• 46 O’Keefe SJ, Li JV, Lahti L et al. Fat, fibre and cancer risk in African Americans and rural Africans. Nat Commun 2015; 6: 6342
• 47 Claesson MJ, Jeffery IB, Conde S et al. Gut microbiota composition correlates with diet and health in the elderly. Nature 2012; 488: 178-184
• 48 De Filippo C, Cavalieri D, Di Paola M et al. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci U S A 2010; 107: 14691-14696
• 49 Zimmer J, Lange B, Frick JS et al. A vegan or vegetarian diet substantially alters the human colonic faecal microbiota. Eur J Clin Nutr 2012; 66: 53-60
• 50 Koeth RA, Wang T, Levison BS et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 2013; 19: 576-585
• 51 De Filippis F, Pellegrini N, Vannini L et al. High-level adherence to a Mediterranean diet beneficially impacts the gut microbiota and associated metabolome. Gut 2015; pii: gutjnl-2015-309957 DOI: 10.1136/gutjnl-2015-309957. [Epub ahead of print]
• 52 Suez J, Korem T, Zeevi D et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature 2014; 514: 181-186
• 53 Jaeggi T, Kortman GA, Morett D et al. Iron fortification adversely affects the gut microbiome, increases pathogen abundance and induces intestinal inflammation in Kenyan infants. Gut 2015; 64: 731-742
• 54 Lee T, Clavel T, Smirnov K et al. Oral versus intravenous iron replacement therapy distinctly alters the gut microbiota and metabolome in patients with IBD. GUT 2015; DOI: 10.1136/gutjnl-2015-309940.
• 55 Lagkouvardos I, Kläring K, Heinzmann SS et al. Gut metabolites and bacterial community networks during a pilot intervention study with flaxseeds in healthy adult men. Mol Nutr Food Res 2015; 59: 1614-1628
• 56 Brahe LK, Le Chatelier E, Prifti E et al. Dietary modulation of the gut microbiota – a randomised controlled trial in obese postmenopausal women. Br J Nutr 2015; 114: 406-417
• 57 Yang J, Summanen PH, Henning SM et al. Xylooligosaccharide supplementation alters gut bacteria in both healthy and prediabetic adults: a pilot study. Front Physiol 2015; 6: 216
• 58 Holscher HD, Bauer LL, Gourineni V et al. Agave Inulin Supplementation Affects the Fecal Microbiota of Healthy Adults Participating in a Randomized, Double-Blind, Placebo-Controlled, Crossover Trial. J Nutr 2015; 145: 2025-2032
• 59 Holscher HD, Caporaso JG, Hooda S et al. Fiber supplementation influences phylogenetic structure and functional capacity of the human intestinal microbiome: follow-up of a randomized controlled trial. Am J Clin Nutr 2015; 101: 55-64
• 60 Aroniadis OC, Brandt LJ, Greenberg A et al. Long-term Follow-up Study of Fecal Microbiota Transplantation for Severe and/or Complicated Clostridium difficile Infection: A Multicenter Experience. J Clin Gastroenterol 2015; [Epub ahead of print]
• 61 Agrawal M, Aroniadis OC, Brandt LJ et al. The Long-term Efficacy and Safety of Fecal Microbiota Transplant for Recurrent, Severe, and Complicated Clostridium difficile Infection in 146 Elderly Individuals. J Clin Gastroenterol 2015; [Epub ahead of print]
• 62 Song Y, Garg S, Girotra M et al. Microbiota dynamics in patients treated with fecal microbiota transplantation for recurrent Clostridium difficile infection. PLoS One 2013; 8: e81330
• 63 Vrieze A, Van Nood E, Hollemann F et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 2012; 143: 913-916 e7
• 64 Colman RJ, Rubin DT. Fecal microbiota transplantation as therapy for inflammatory bowel disease: a systematic review and meta-analysis. J Crohns Colitis 2014; 8: 1569-1581
• 65 Rossen NG, Fuentes S, van der Spek MJ et al. Findings From a Randomized Controlled Trial of Fecal Transplantation for Patients With Ulcerative Colitis. Gastroenterology 2015; 149: 110-118 e4
• 66 Moayyedi P, Surette MG, Kim PT et al. Fecal Microbiota Transplantation Induces Remission in Patients With Active Ulcerative Colitis in a Randomized Controlled Trial. Gastroenterology 2015; 149: 102-109 e6
• 67 Jorup-Rönström C, Håkanson A, Sandell S et al. Fecal transplant against relapsing Clostridium difficile-associated diarrhea in 32 patients. Scand J Gastroenterol 2012; 47: 548-552
• 68 Youngster I, Rusell GH, Pindar C et al. Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection. JAMA 2014; 312: 1772-1778
• 69 Petrof EO, Khoruts A. From stool transplants to next-generation microbiota therapeutics. Gastroenterology 2014; 146: 1573-1582
• 70 Ritchie ML, Romanuk TN. A meta-analysis of probiotic efficacy for gastrointestinal diseases. PLoS One 2012; 7: e34938
• 71 Tursi A, Brandimarte G, Papa A et al. Treatment of relapsing mild-to-moderate ulcerative colitis with the probiotic VSL#3 as adjunctive to a standard pharmaceutical treatment: a double-blind, randomized, placebo-controlled study. Am J Gastroenterol 2010; 105: 2218-2227
• 72 Kruis W, Fric P, Pokrotnieks J et al. Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine. Gut 2004; 53: 1617-1623
• 73 Hoveyda N, Heneghan C, Mahtani KR et al. A systematic review and meta-analysis: probiotics in the treatment of irritable bowel syndrome. BMC Gastroenterol 2009; 9: 15
• 74 Pelucchi C, Chatenoud L, Turati F et al. Probiotics supplementation during pregnancy or infancy for the prevention of atopic dermatitis: a meta-analysis. Epidemiology 2012; 23: 402-414
• 75 Ma YY, Li L, Yu CH et al. Effects of probiotics on nonalcoholic fatty liver disease: a meta-analysis. World J Gastroenterol 2013; 19: 6911-6918
• 76 Sanders ME, Akkermans LM, Haller D et al. Safety assessment of probiotics for human use. Gut Microbes 2010; 1: 164-185
• 77 von Schillde MA, Hörmannsperger G, Weiher M et al. Lactocepin secreted by Lactobacillus exerts anti-inflammatory effects by selectively degrading proinflammatory chemokines. Cell Host Microbe 2012; 11: 387-396
• 78 Shen Y, Giardino Torchia ML, Lawson GW et al. Outer membrane vesicles of a human commensal mediate immune regulation and disease protection. Cell Host Microbe 2012; 12: 509-520
• 79 Yan F, Polk DB. Characterization of a probiotic-derived soluble protein which reveals a mechanism of preventive and treatment effects of probiotics on intestinal inflammatory diseases. Gut Microbes 2012; 3: 25-28