Journal of Molecular Medicine

, Volume 95, Issue 1, pp 21–28 | Cite as

Microbiome and chronic inflammatory bowel diseases

Review

Abstract

It is nowadays generally accepted that the microbiome is a central driver of chronic inflammatory bowel diseases based on observations from human patients as well as inflammatory rodent models. Many studies focussed on different aspects of microbiota and some scientists believe that a primary dis-balance results in a direct microbial induced inflammatory situation. It is also clear that the microbiome is influenced by environmental and genetic factors and is also tightly regulated by host defense molecules such as antimicrobial peptides (defensins et al.). Different lines of investigations showed different complex antimicrobial barrier defects in inflammatory bowel diseases which also influence the composition of the microbiome and generally impact on the microbial-mucosal interface. In this review, we aim to discuss the bigger picture of these different aspects and current views and conclude about therapeutic consequences for future concepts beyond anti-inflammatory treatment.

Keywords

Microbiota Antimicrobial peptides Paneth cells Inflammatory bowel diseases LPS Endotoxin 

References

  1. 1.
    Donaldson GP, Lee SM, Mazmanian SK (2016) Gut biogeography of the bacterial microbiota. Nat Rev Microbiol 14:20–32CrossRefPubMedGoogle Scholar
  2. 2.
    Dominguez-Bello MG, Costello EK, Contreras M, Magris M, Hidalgo G, Fierer N, Knight R (2010) Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci U S A 107:11971–11975CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Blekhman R, Goodrich JK, Huang K, Sun Q, Bukowski R, Bell JT, Spector TD, Keinan A, Ley RE, Gevers D et al (2015) Host genetic variation impacts microbiome composition across human body sites. Genome Biol 16:191CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Ubeda C, Pamer EG (2012) Antibiotics, microbiota, and immune defense. Trends Immunol 33:459–466CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Zimmer J, Lange B, Frick JS, Sauer H, Zimmermann K, Schwiertz A, Rusch K, Klosterhalfen S, Enck P (2012) A vegan or vegetarian diet substantially alters the human colonic faecal microbiota. Eur J Clin Nutr 66:53–60CrossRefPubMedGoogle Scholar
  6. 6.
    Jackson MA, Goodrich JK, Maxan ME, Freedberg DE, Abrams JA, Poole AC, Sutter JL, Welter D, Ley RE, Bell JT et al (2016) Proton pump inhibitors alter the composition of the gut microbiota. Gut 65:749–756CrossRefPubMedGoogle Scholar
  7. 7.
    Hollister EB, Riehle K, Luna RA, Weidler EM, Rubio-Gonzales M, Mistretta TA, Raza S, Doddapaneni HV, Metcalf GA, Muzny DM et al (2015) Structure and function of the healthy pre-adolescent pediatric gut microbiome. Microbiome 3:36CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE, Relman DA (2005) Diversity of the human intestinal microbial flora. Science 308:1635–1638CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Sender R, Fuchs S, Milo R (2016) Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. Cell 164:337–340CrossRefPubMedGoogle Scholar
  10. 10.
    Lange A, Beier S, Steimle A, Autenrieth IB, Huson DH, Frick JS (2016) Extensive mobilome-driven genome diversification in mouse gut-associated Bacteroides vulgatus mpk. Genome Biol Evol 8:1197–1207CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Coyne MJ, Zitomersky NL, McGuire AM, Earl AM, Comstock LE (2014) Evidence of extensive DNA transfer between bacteroidales species within the human gut. MBio 5:e01305–e01314CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Arumugam M, Raes J, Pelletier E, Le Paslier D, Yamada T, Mende DR, Fernandes GR, Tap J, Bruls T, Batto JM et al (2011) Enterotypes of the human gut microbiome. Nature 473:174–180CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Martens EC, Koropatkin NM, Smith TJ, Gordon JI (2009) Complex glycan catabolism by the human gut microbiota: the Bacteroidetes Sus-like paradigm. J Biol Chem 284:24673–24677CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Wright DP, Rosendale DI, Robertson AM (2000) Prevotella enzymes involved in mucin oligosaccharide degradation and evidence for a small operon of genes expressed during growth on mucin. FEMS Microbiol Lett 190:73–79CrossRefPubMedGoogle Scholar
  15. 15.
    Derrien M, Vaughan EE, Plugge CM, de Vos WM (2004) Akkermansia muciniphila gen. Nov., sp. nov., a human intestinal mucin-degrading bacterium. Int J Syst Evol Microbiol 54:1469–1476CrossRefPubMedGoogle Scholar
  16. 16.
    Pedersen HK, Gudmundsdottir V, Nielsen HB, Hyotylainen T, Nielsen T, Jensen BA, Forslund K, Hildebrand F, Prifti E, Falony G et al (2016) Human gut microbes impact host serum metabolome and insulin sensitivity. Nature 535:376–381CrossRefPubMedGoogle Scholar
  17. 17.
    Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F, Liang S, Zhang W, Guan Y, Shen D et al (2012) A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490:55–60CrossRefPubMedGoogle Scholar
  18. 18.
    Waidmann M, Bechtold O, Frick JS, Lehr HA, Schubert S, Dobrindt U, Loeffler J, Bohn E, Autenrieth IB (2003) Bacteroides vulgatus protects against Escherichia coli-induced colitis in gnotobiotic interleukin-2-deficient mice. Gastroenterology 125:162–177CrossRefPubMedGoogle Scholar
  19. 19.
    Muller M, Fink K, Geisel J, Kahl F, Jilge B, Reimann J, Mach N, Autenrieth IB, Frick JS (2008) Intestinal colonization of IL-2 deficient mice with non-colitogenic B. vulgatus prevents DC maturation and T-cell polarization. PLoS One 3:e2376CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Morton ER, Lynch J, Froment A, Lafosse S, Heyer E, Przeworski M, Blekhman R, Segurel L (2015) Variation in rural African gut microbiota is strongly correlated with colonization by Entamoeba and subsistence. PLoS Genet 11:e1005658CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Stecher B (2015) The roles of inflammation, nutrient availability and the commensal microbiota in enteric pathogen infection. Microbiol Spectr 3Google Scholar
  22. 22.
    Michail S, Durbin M, Turner D, Griffiths AM, Mack DR, Hyams J, Leleiko N, Kenche H, Stolfi A, Wine E (2012) Alterations in the gut microbiome of children with severe ulcerative colitis. Inflamm Bowel Dis 18:1799–1808CrossRefPubMedGoogle Scholar
  23. 23.
    Morgan XC, Tickle TL, Sokol H, Gevers D, Devaney KL, Ward DV, Reyes JA, Shah SA, LeLeiko N, Snapper SB et al (2012) Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol 13:R79CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, Sogin ML, Jones WJ, Roe BA, Affourtit JP et al (2009) A core gut microbiome in obese and lean twins. Nature 457:480–484CrossRefPubMedGoogle Scholar
  25. 25.
    Sokol H, Pigneur B, Watterlot L, Lakhdari O, Bermudez-Humaran LG, Gratadoux JJ, Blugeon S, Bridonneau C, Furet JP, Corthier G et al (2008) Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A 105:16731–16736CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Sokol H, Seksik P, Furet JP, Firmesse O, Nion-Larmurier I, Beaugerie L, Cosnes J, Corthier G, Marteau P, Dore J (2009) Low counts of Faecalibacterium prausnitzii in colitis microbiota. Inflamm Bowel Dis 15:1183–1189CrossRefPubMedGoogle Scholar
  27. 27.
    Machiels K, Joossens M, Sabino J, De Preter V, Arijs I, Eeckhaut V, Ballet V, Claes K, Van Immerseel F, Verbeke K et al (2013) A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut. doi:10.1136/gutjnl-2013-304833 Google Scholar
  28. 28.
    Matsuoka K, Kanai T (2015) The gut microbiota and inflammatory bowel disease. Semin Immunopathol 37:47–55CrossRefPubMedGoogle Scholar
  29. 29.
    Frank DN, St Amand AL, Feldman RA, Boedeker EC, Harpaz N, Pace NR (2007) Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci U S A 104:13780–13785CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Manichanh C, Rigottier-Gois L, Bonnaud E, Gloux K, Pelletier E, Frangeul L, Nalin R, Jarrin C, Chardon P, Marteau P et al (2006) Reduced diversity of faecal microbiota in Crohn's disease revealed by a metagenomic approach. Gut 55:205–211CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Willing BP, Dicksved J, Halfvarson J, Andersson AF, Lucio M, Zheng Z, Jarnerot G, Tysk C, Jansson JK, Engstrand L (2010) A pyrosequencing study in twins shows that gastrointestinal microbial profiles vary with inflammatory bowel disease phenotypes. Gastroenterology 139:1844–1854CrossRefPubMedGoogle Scholar
  32. 32.
    Tong M, Li X, Wegener Parfrey L, Roth B, Ippoliti A, Wei B, Borneman J, McGovern DP, Frank DN, Li E et al (2013) A modular organization of the human intestinal mucosal microbiota and its association with inflammatory bowel disease. PLoS One 8:e80702CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Gophna U, Sommerfeld K, Gophna S, Doolittle WF, Veldhuyzen van Zanten SJ (2006) Differences between tissue-associated intestinal microfloras of patients with Crohn's disease and ulcerative colitis. J Clin Microbiol 44:4136–4141CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Scanlan PD, Shanahan F, O'Mahony C, Marchesi JR (2006) Culture-independent analyses of temporal variation of the dominant fecal microbiota and targeted bacterial subgroups in Crohn's disease. J Clin Microbiol 44:3980–3988CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Peterson DA, Frank DN, Pace NR, Gordon JI (2008) Metagenomic approaches for defining the pathogenesis of inflammatory bowel diseases. Cell Host Microbe 3:417–427CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Ostaff MJ, Stange EF, Wehkamp J (2013) Antimicrobial peptides and gut microbiota in homeostasis and pathology. EMBO Mol Med 5:1465–1483CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Schroeder BO, Wu Z, Nuding S, Groscurth S, Marcinowski M, Beisner J, Buchner J, Schaller M, Stange EF, Wehkamp J (2011) Reduction of disulphide bonds unmasks potent antimicrobial activity of human beta-defensin 1. Nature 469:419–423CrossRefPubMedGoogle Scholar
  38. 38.
    Bevins CL (2013) Innate immune functions of alpha-defensins in the small intestine. Dig Dis 31:299–304CrossRefPubMedGoogle Scholar
  39. 39.
    Chu H, Pazgier M, Jung G, Nuccio SP, Castillo PA, de Jong MF, Winter MG, Winter SE, Wehkamp J, Shen B et al (2012) Human alpha-defensin 6 promotes mucosal innate immunity through self-assembled peptide nanonets. Science 337:477–481CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Schroeder BO, Ehmann D, Precht JC, Castillo PA, Kuchler R, Berger J, Schaller M, Stange EF, Wehkamp J (2015) Paneth cell alpha-defensin 6 (HD-6) is an antimicrobial peptide. Mucosal Immunol 8:661–671CrossRefPubMedGoogle Scholar
  41. 41.
    Salzmann A, Guipponi M, Lyons PJ, Fricker LD, Sapio M, Lambercy C, Buresi C, Ouled Amar Bencheikh B, Lahjouji F, Ouazzani R et al (2012) Carboxypeptidase A6 gene (CPA6) mutations in a recessive familial form of febrile seizures and temporal lobe epilepsy and in sporadic temporal lobe epilepsy. Hum Mutat 33:124–135CrossRefPubMedGoogle Scholar
  42. 42.
    Clevers HC, Bevins CL (2013) Paneth cells: maestros of the small intestinal crypts. Annu Rev Physiol 75:289–311CrossRefPubMedGoogle Scholar
  43. 43.
    Wehkamp J, Stange EF (2010) Paneth’s disease. J Crohns Colitis 4:523–531CrossRefPubMedGoogle Scholar
  44. 44.
    Wehkamp J, Salzman NH, Porter E, Nuding S, Weichenthal M, Petras RE, Shen B, Schaeffeler E, Schwab M, Linzmeier R et al (2005) Reduced Paneth cell alpha-defensins in ileal Crohn’s disease. Proc Natl Acad Sci U S A 102:18129–18134CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Courth LF, Ostaff MJ, Mailander-Sanchez D, Malek NP, Stange EF, Wehkamp J (2015) Crohn’s disease-derived monocytes fail to induce Paneth cell defensins. Proc Natl Acad Sci U S A 112:14000–14005CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Selsted ME, Ouellette AJ (2005) Mammalian defensins in the antimicrobial immune response. Nat Immunol 6:551–557CrossRefPubMedGoogle Scholar
  47. 47.
    Harder J, Bartels J, Christophers E, Schroder JM (2001) Isolation and characterization of human beta -defensin-3, a novel human inducible peptide antibiotic. J Biol Chem 276:5707–5713CrossRefPubMedGoogle Scholar
  48. 48.
    Wehkamp J, Fellermann K, Herrlinger KR, Baxmann S, Schmidt K, Schwind B, Duchrow M, Wohlschlager C, Feller AC, Stange EF (2002) Human beta-defensin 2 but not beta-defensin 1 is expressed preferentially in colonic mucosa of inflammatory bowel disease. Eur J Gastroenterol Hepatol 14:745–752CrossRefPubMedGoogle Scholar
  49. 49.
    Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL (2005) An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122:107–118CrossRefPubMedGoogle Scholar
  50. 50.
    Mazmanian SK, Round JL, Kasper DL (2008) A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453:620–625CrossRefPubMedGoogle Scholar
  51. 51.
    Haag LM, Siegmund B (2015) Intestinal microbiota and the innate immune system—a crosstalk in Crohn’s disease pathogenesis. Front Immunol 6:489CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Franke A, McGovern DP, Barrett JC, Wang K, Radford-Smith GL, Ahmad T, Lees CW, Balschun T, Lee J, Roberts R et al (2010) Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet 42:1118–1125CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, Almer S, Tysk C, O'Morain CA, Gassull M et al (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411:599–603CrossRefPubMedGoogle Scholar
  54. 54.
    Fava F, Danese S (2011) Intestinal microbiota in inflammatory bowel disease: friend of foe? World journal of gastroenterology: WJG 17:557–566CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Raetz CR, Whitfield C (2002) Lipopolysaccharide endotoxins. Annu Rev Biochem 71:635–700CrossRefPubMedGoogle Scholar
  56. 56.
    Pulendran B, Kumar P, Cutler CW, Mohamadzadeh M, Van Dyke T, Banchereau J (2001) Lipopolysaccharides from distinct pathogens induce different classes of immune responses in vivo. JImmunol 167:5067–5076CrossRefGoogle Scholar
  57. 57.
    Dixon DR, Darveau RP (2005) Lipopolysaccharide heterogeneity: innate host responses to bacterial modification of lipid A structure. J Dent Res 84:584–595CrossRefPubMedGoogle Scholar
  58. 58.
    Schumann RR, Pfeil D, Lamping N, Kirschning C, Scherzinger G, Schlag P, Karawajew L, Herrmann F (1996) Lipopolysaccharide induces the rapid tyrosine phosphorylation of the mitogen-activated protein kinases erk-1 and p38 in cultured human vascular endothelial cells requiring the presence of soluble CD14. Blood 87:2805–2814PubMedGoogle Scholar
  59. 59.
    Sanchez Carballo PM, Rietschel ET, Kosma P, Zahringer U (1999) Elucidation of the structure of an alanine-lacking core tetrasaccharide trisphosphate from the lipopolysaccharide of Pseudomonas aeruginosa mutant H4. Eur J Biochem 261:500–508CrossRefPubMedGoogle Scholar
  60. 60.
    Steimle A, Autenrieth IB, Frick JS (2016) Structure and function: lipid A modifications in commensals and pathogens. Int J Med Microbiol. doi:10.1016/j.ijmm.2016.03.001 PubMedGoogle Scholar
  61. 61.
    Montminy SW, Khan N, McGrath S, Walkowicz MJ, Sharp F, Conlon JE, Fukase K, Kusumoto S, Sweet C, Miyake K et al (2006) Virulence factors of Yersinia pestis are overcome by a strong lipopolysaccharide response. Nat Immunol 7:1066–1073CrossRefPubMedGoogle Scholar
  62. 62.
    Okan NA, Kasper DL (2013) The atypical lipopolysaccharide of Francisella. Carbohydr Res 378:79–83CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Needham BD, Trent MS (2013) Fortifying the barrier: the impact of lipid A remodelling on bacterial pathogenesis. Nat Rev Microbiol 11:467–481CrossRefPubMedGoogle Scholar
  64. 64.
    Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R (2004) Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118:229–241CrossRefPubMedGoogle Scholar
  65. 65.
    Wittmann A, Bron PA, van Swam II, Kleerebezem M, Adam P, Gronbach K, Menz S, Flade I, Bender A, Schafer A et al (2015) TLR signaling-induced CD103-expressing cells protect against intestinal inflammation. Inflamm Bowel Dis 21:507–519CrossRefPubMedGoogle Scholar
  66. 66.
    Gronbach K, Flade I, Holst O, Lindner B, Ruscheweyh HJ, Wittmann A, Menz S, Schwiertz A, Adam P, Stecher B et al (2014) Endotoxicity of lipopolysaccharide as a determinant of T-cell-mediated colitis induction in mice. Gastroenterology 146:765–775CrossRefPubMedGoogle Scholar
  67. 67.
    Hirschfeld M, Weis JJ, Toshchakov V, Salkowski CA, Cody MJ, Ward DC, Qureshi N, Michalek SM, Vogel SN (2001) Signaling by toll-like receptor 2 and 4 agonists results in differential gene expression in murine macrophages. Infect Immun 69:1477–1482CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Bainbridge BW, Coats SR, Pham TT, Reife RA, Darveau RP (2006) Expression of a Porphyromonas gingivalis lipid A palmitylacyltransferase in Escherichia coli yields a chimeric lipid A with altered ability to stimulate interleukin-8 secretion. Cell Microbiol 8:120–129CrossRefPubMedGoogle Scholar
  69. 69.
    Yamamoto M, Akira S (2009) Lipid A receptor TLR4-mediated signaling pathways. Adv Exp Med Biol 667:59–68CrossRefGoogle Scholar
  70. 70.
    Wehkamp J, Harder J, Wehkamp K, Wehkamp-von MB, Schlee M, Enders C, Sonnenborn U, Nuding S, Bengmark S, Fellermann K et al (2004) NF-kappaB- and AP-1-mediated induction of human beta defensin-2 in intestinal epithelial cells by Escherichia coli Nissle 1917: a novel effect of a probiotic bacterium. Infect Immun 72:5750–5758CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Schlee M, Wehkamp J, Altenhoefer A, Oelschlaeger TA, Stange EF, Fellermann K (2007) Induction of human beta-defensin 2 by the probiotic Escherichia coli Nissle 1917 is mediated through flagellin. Infect Immun 75:2399–2407CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, Visser CE, Kuijper EJ, Bartelsman JF, Tijssen JG et al (2013) Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 368:407–415CrossRefPubMedGoogle Scholar
  73. 73.
    De Leon LM, Watson JB, Kelly CR (2013) Transient flare of ulcerative colitis after fecal microbiota transplantation for recurrent Clostridium difficile infection. Clin Gastroenterol Hepatol 11:1036–1038CrossRefPubMedGoogle Scholar
  74. 74.
    Alang N, Kelly CR (2015) Weight gain after fecal microbiota transplantation. Open Forum Infect Dis 2:ofv004CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Geisel J, Kahl F, Muller M, Wagner H, Kirschning CJ, Autenrieth IB, Frick JS (2007) IL-6 and maturation govern TLR2 and TLR4 induced TLR agonist tolerance and cross-tolerance in dendritic cells. J Immunol 179:5811–5818CrossRefPubMedGoogle Scholar
  76. 76.
    Frick JS, Zahir N, Muller M, Kahl F, Bechtold O, Lutz MB, Kirschning CJ, Reimann J, Jilge B, Bohn E et al (2006) Colitogenic and non-colitogenic commensal bacteria differentially trigger DC maturation and Th cell polarization: an important role for IL-6. Eur J Immunol 36:1537–1547CrossRefPubMedGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.Medical Clinic IUniversity Hospital TübingenTübingenGermany
  2. 2.Institute of Medical Microbiology and HygieneUniversity of TübingenTübingenGermany

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