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The Gut Microbiota and IBD

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Pediatric Inflammatory Bowel Disease

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Abstract

The gut microbiota and its mammalian host have co-evolved to live together in a mutualistic relationship where the host provides a unique niche for the growth of bacteria while the gut microbiota provides essential metabolic functions and helps to maintain immune homeostasis in the host. Nevertheless, the gut microbiota plays a critical role in the pathogenesis of several disease processes including inflammatory bowel disease (IBD). In this chapter, we review how advances in deep DNA sequencing technology have provided an improved understanding of factors that regulate the composition of the gut microbiota, their relevance to the pathogenesis of IBD, and how this information provides insights into the development of innovative therapeutic approaches for the treatment of patients with this disease.

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References

  1. Bernstein CN, Shanahan F. Disorders of a modern lifestyle: reconciling the epidemiology of inflammatory bowel diseases. Gut. 2008;57(9):1185–91.

    Article  PubMed  Google Scholar 

  2. Sartor RB. Mechanisms of disease: pathogenesis of Crohn’s disease and ulcerative colitis. Nat Clin Pract Gastroenterol Hepatol. 2006;3(7):390–407.

    Article  PubMed  CAS  Google Scholar 

  3. Rath HC, et al. Normal luminal bacteria, especially Bacteroides species, mediate chronic colitis, gastritis, and arthritis in HLA-B27/human beta2 microglobulin transgenic rats. J Clin Invest. 1996;98(4):945–53.

    Article  PubMed  CAS  Google Scholar 

  4. Sartor RB. Microbial influences in inflammatory bowel diseases. Gastroenterology. 2008;134(2):577–94.

    Article  PubMed  CAS  Google Scholar 

  5. Rutgeerts P, et al. Controlled trial of metronidazole treatment for prevention of Crohn’s recurrence after ileal resection. Gastroenterology. 1995;108(6):1617–21.

    Article  PubMed  CAS  Google Scholar 

  6. Rutgeerts P, et al. Ornidazole for prophylaxis of postoperative Crohn’s disease recurrence: a randomized, double-blind, placebo-controlled trial. Gastroenterology. 2005;128(4):856–61.

    Article  PubMed  CAS  Google Scholar 

  7. Sachar DB. Management of acute, severe ulcerative colitis. J Dig Dis. 2012;13(2):65–8.

    Article  PubMed  CAS  Google Scholar 

  8. Harper PH, et al. Role of the faecal stream in the maintenance of Crohn’s colitis. Gut. 1985;26(3):279–84.

    Article  PubMed  CAS  Google Scholar 

  9. Rutgeerts P, et al. Effect of faecal stream diversion on recurrence of Crohn’s disease in the neoterminal ileum. Lancet. 1991;338(8770):771–4.

    Article  PubMed  CAS  Google Scholar 

  10. Swidsinski A, et al. Comparative study of the intestinal mucus barrier in normal and inflamed colon. Gut. 2007;56(3):343–50.

    Article  PubMed  Google Scholar 

  11. Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature. 2011;474(7351):307–17.

    Article  PubMed  CAS  Google Scholar 

  12. Uhlig HH, Powrie F. Dendritic cells and the intestinal bacterial flora: a role for localized mucosal immune responses. J Clin Invest. 2003;112(5):648–51.

    PubMed  CAS  Google Scholar 

  13. Lozupone CA, Knight R. Species divergence and the measurement of microbial diversity. FEMS Microbiol Rev. 2008;32(4):557–78.

    Article  PubMed  CAS  Google Scholar 

  14. Xu J, Gordon JI. Inaugural article: honor thy symbionts. Proc Natl Acad Sci U S A. 2003;100(18):10452–9.

    Article  PubMed  CAS  Google Scholar 

  15. Kelsen JR, et al. Recurrence rate of clostridium difficile infection in hospitalized pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis. 2011;17(1):50–5.

    Article  PubMed  Google Scholar 

  16. Costello EK, et al. Bacterial community variation in human body habitats across space and time. Science. 2009;326(5960):1694–7.

    Article  PubMed  CAS  Google Scholar 

  17. Reid G, et al. Microbiota restoration: natural and supplemented recovery of human microbial communities. Nat Rev Microbiol. 2011;9(1):27–38.

    Article  PubMed  CAS  Google Scholar 

  18. Marchesi JR. Prokaryotic and eukaryotic diversity of the human gut. Adv Appl Microbiol. 2010;72:43–62.

    Article  PubMed  Google Scholar 

  19. Hamady M, Knight R. Microbial community profiling for human microbiome projects: tools, techniques, and challenges. Genome Res. 2009;19(7):1141–52.

    Article  PubMed  CAS  Google Scholar 

  20. Palmer C, et al. Development of the human infant intestinal microbiota. PLoS Biol. 2007;5(7):e177.

    Article  PubMed  Google Scholar 

  21. Koenig JE, et al. Succession of microbial consortia in the developing infant gut microbiome. Proc Natl Acad Sci U S A. 2011;108 Suppl 1:4578–85.

    Article  PubMed  CAS  Google Scholar 

  22. Spor A, Koren O, Ley R. Unravelling the effects of the environment and host genotype on the gut microbiome. Nat Rev Microbiol. 2011;9(4):279–90.

    Article  PubMed  CAS  Google Scholar 

  23. Diamond J. Evolution, consequences and future of plant and animal domestication. Nature. 2002;418(6898):700–7.

    Article  PubMed  CAS  Google Scholar 

  24. Walter J, Ley R. The human gut microbiome: ecology and recent evolutionary changes. Annu Rev Microbiol. 2011;65:411–29.

    Article  PubMed  CAS  Google Scholar 

  25. Pflughoeft KJ, Versalovic J. Human microbiome in health and disease. Annu Rev Pathol. 2012;7:9–12.

    Article  Google Scholar 

  26. Ley RE, et al. Evolution of mammals and their gut microbes. Science. 2008;320(5883):1647–51.

    Article  PubMed  CAS  Google Scholar 

  27. Muegge BD, et al. Diet drives convergence in gut microbiome functions across mammalian phylogeny and within humans. Science. 2011;332(6032):970–4.

    Article  PubMed  CAS  Google Scholar 

  28. Wu GD, et al. Linking long-term dietary patterns with gut microbial enterotypes. Science. 2011;334(6052):105–8.

    Article  PubMed  CAS  Google Scholar 

  29. Arumugam M, et al. Enterotypes of the human gut microbiome. Nature. 2011;473(7346):174–80.

    Article  PubMed  CAS  Google Scholar 

  30. De Filippo C, 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(33):14691–6.

    Article  PubMed  Google Scholar 

  31. Hooper LV, Gordon JI. Commensal host-bacterial relationships in the gut. Science. 2001;292(5519):1115–8.

    Article  PubMed  CAS  Google Scholar 

  32. Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med. 2009;361(21):2066–78.

    Article  PubMed  CAS  Google Scholar 

  33. Santaolalla R, Abreu MT. Innate immunity in the small intestine. Curr Opin Gastroenterol. 2012;28(2):124–9.

    Article  PubMed  CAS  Google Scholar 

  34. Fukata M, et al. Cox-2 is regulated by Toll-like receptor-4 (TLR4) signaling: role in proliferation and apoptosis in the intestine. Gastroenterology. 2006;131(3):862–77.

    Article  PubMed  CAS  Google Scholar 

  35. Shang L, et al. Toll-like receptor signaling in small intestinal epithelium promotes B-cell recruitment and IgA production in lamina propria. Gastroenterology. 2008;135(2):529–38.

    Article  PubMed  CAS  Google Scholar 

  36. Cario E, Gerken G, Podolsky DK. Toll-like receptor 2 enhances ZO-1-associated intestinal epithelial barrier integrity via protein kinase C. Gastroenterology. 2004;127(1):224–38.

    Article  PubMed  CAS  Google Scholar 

  37. Rehman A, et al. Nod2 is essential for temporal development of intestinal microbial communities. Gut. 2011;60(10):1354–62.

    Article  PubMed  CAS  Google Scholar 

  38. Neish AS. Microbes in gastrointestinal health and disease. Gastroenterology. 2009;136(1):65–80.

    Article  PubMed  Google Scholar 

  39. Peterson DA, et al. IgA response to symbiotic bacteria as a mediator of gut homeostasis. Cell Host Microbe. 2007;2(5):328–39.

    Article  PubMed  CAS  Google Scholar 

  40. Ivanov II, et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell. 2009;139(3):485–98.

    Article  PubMed  CAS  Google Scholar 

  41. Surana NK, Kasper DL. The yin yang of bacterial polysaccharides: lessons learned from B. fragilis PSA. Immunol Rev. 2012;245(1):13–26.

    Article  PubMed  CAS  Google Scholar 

  42. Atarashi K, et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science. 2011;331(6015):337–41.

    Article  PubMed  CAS  Google Scholar 

  43. Garrett WS, Gordon JI, Glimcher LH. Homeostasis and inflammation in the intestine. Cell. 2010;140(6):859–70.

    Article  PubMed  CAS  Google Scholar 

  44. Cadwell K, et al. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature. 2008;456(7219):259–63.

    Article  PubMed  CAS  Google Scholar 

  45. Cadwell K, et al. Virus-plus-susceptibility gene interaction determines Crohn’s disease gene Atg16L1 phenotypes in intestine. Cell. 2010;141(7):1135–45.

    Article  PubMed  CAS  Google Scholar 

  46. Salzman NH, et al. Enteric defensins are essential regulators of intestinal microbial ecology. Nat Immunol. 2010;11(1):76–83.

    Article  PubMed  CAS  Google Scholar 

  47. Molodecky NA, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012;142(1):46–54 e42; quiz e30.

    Google Scholar 

  48. Chapman-Kiddell CA, et al. Role of diet in the development of inflammatory bowel disease. Inflamm Bowel Dis. 2010;16(1):137–51.

    PubMed  Google Scholar 

  49. Shaw SY, Blanchard JF, Bernstein CN. Association between the use of antibiotics and new diagnoses of Crohn’s disease and ulcerative colitis. Am J Gastroenterol. 2011;106(12):2133–42.

    Article  PubMed  Google Scholar 

  50. Molodecky NA, Kaplan GG. Environmental risk factors for inflammatory bowel disease. Gastroenterol Hepatol (N Y). 2010;6(5):339–46.

    Google Scholar 

  51. Flanagan P, Campbell BJ, Rhodes JM. Bacteria in the pathogenesis of inflammatory bowel disease. Biochem Soc Trans. 2011;39(4):1067–72.

    Article  PubMed  CAS  Google Scholar 

  52. Vanderploeg R, et al. Influences of intestinal bacteria in human inflammatory bowel disease. Infect Dis Clin North Am. 2010;24(4):977–93, ix.

    Google Scholar 

  53. Barnich N, et al. CEACAM6 acts as a receptor for adherent-invasive E. coli, supporting ileal mucosa colonization in Crohn disease. J Clin Invest. 2007;117(6):1566–74.

    Article  PubMed  CAS  Google Scholar 

  54. Selby W, et al. Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn’s disease. Gastroenterology. 2007;132(7):2313–9.

    Article  PubMed  CAS  Google Scholar 

  55. Van de Merwe JP, et al. The obligate anaerobic faecal flora of patients with Crohn’s disease and their first-degree relatives. Scand J Gastroenterol. 1988;23(9):1125–31.

    Article  PubMed  Google Scholar 

  56. Walker AW, et al. High-throughput clone library analysis of the mucosa-associated microbiota reveals dysbiosis and differences between inflamed and non-inflamed regions of the intestine in inflammatory bowel disease. BMC Microbiol. 2011;11:7.

    Article  PubMed  Google Scholar 

  57. Manichanh C, et al. Reduced diversity of faecal microbiota in Crohn’s disease revealed by a metagenomic approach. Gut. 2006;55(2):205–11.

    Article  PubMed  CAS  Google Scholar 

  58. Gophna U, et al. Differences between tissue-associated intestinal microfloras of patients with Crohn’s disease and ulcerative colitis. J Clin Microbiol. 2006;44(11):4136–41.

    Article  PubMed  CAS  Google Scholar 

  59. Frank DN, et al. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci U S A. 2007;104(34):13780–5.

    Article  PubMed  CAS  Google Scholar 

  60. Martinez-Medina M, et al. Abnormal microbiota composition in the ileocolonic mucosa of Crohn’s disease patients as revealed by polymerase chain reaction-denaturing gradient gel electrophoresis. Inflamm Bowel Dis. 2006;12(12):1136–45.

    Article  PubMed  Google Scholar 

  61. Prescott NJ, et al. A nonsynonymous SNP in ATG16L1 predisposes to ileal Crohn’s disease and is independent of CARD15 and IBD5. Gastroenterology. 2007;132(5):1665–71.

    Article  PubMed  CAS  Google Scholar 

  62. Swidsinski A, et al. Active Crohn’s disease and ulcerative colitis can be specifically diagnosed and monitored based on the biostructure of the fecal flora. Inflamm Bowel Dis. 2008;14(2):147–61.

    Article  PubMed  Google Scholar 

  63. Sokol H, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A. 2008;105(43):16731–6.

    Article  PubMed  CAS  Google Scholar 

  64. Sartor RB. Therapeutic correction of bacterial dysbiosis discovered by molecular techniques. Proc Natl Acad Sci U S A. 2008;105(43):16413–4.

    Article  PubMed  CAS  Google Scholar 

  65. Mangin I, et al. Molecular inventory of faecal microflora in patients with Crohn’s disease. FEMS Microbiol Ecol. 2004;50(1):25–36.

    Article  PubMed  CAS  Google Scholar 

  66. Seksik P, et al. Alterations of the dominant faecal bacterial groups in patients with Crohn’s disease of the colon. Gut. 2003;52(2):237–42.

    Article  PubMed  CAS  Google Scholar 

  67. Baumgart M, et al. Culture independent analysis of ileal mucosa reveals a selective increase in invasive Escherichia coli of novel phylogeny relative to depletion of Clostridiales in Crohn’s disease involving the ileum. ISME J. 2007;1(5):403–18.

    Article  PubMed  CAS  Google Scholar 

  68. Dicksved J, et al. Molecular analysis of the gut microbiota of identical twins with Crohn’s disease. ISME J. 2008;2(7):716–27.

    Article  PubMed  CAS  Google Scholar 

  69. Sartor RB. Genetics and environmental interactions shape the intestinal microbiome to promote inflammatory bowel disease versus mucosal homeostasis. Gastroenterology. 2010;139(6):1816–9.

    Article  PubMed  Google Scholar 

  70. Willing BP, et al. A pyrosequencing study in twins shows that gastrointestinal microbial profiles vary with inflammatory bowel disease phenotypes. Gastroenterology. 2010;139(6):1844–54 e1.

    Google Scholar 

  71. Tamboli CP, et al. Dysbiosis in inflammatory bowel disease. Gut. 2004;53(1):1–4.

    Article  PubMed  CAS  Google Scholar 

  72. Garrett WS, et al. Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell. 2007;131(1):33–45.

    Article  PubMed  CAS  Google Scholar 

  73. Garrett WS, et al. Enterobacteriaceae act in concert with the gut microbiota to induce spontaneous and maternally transmitted colitis. Cell Host Microbe. 2010;8(3):292–300.

    Article  PubMed  CAS  Google Scholar 

  74. Elinav E, et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell. 2011;145(5):745–57.

    Article  PubMed  CAS  Google Scholar 

  75. Hou JK, Abraham B, El-Serag H. Dietary intake and risk of developing inflammatory bowel disease: a systematic review of the literature. Am J Gastroenterol. 2011;106(4):563–73.

    Article  PubMed  CAS  Google Scholar 

  76. Sandhu BK, et al. Guidelines for the management of inflammatory bowel disease in children in the United Kingdom. J Pediatr Gastroenterol Nutr. 2010.

    Google Scholar 

  77. Caprilli R, et al. European evidence based consensus on the diagnosis and management of Crohn’s disease: special situations. Gut. 2006;55 Suppl 1:i36–58.

    Article  PubMed  Google Scholar 

  78. Leach ST, et al. Sustained modulation of intestinal bacteria by exclusive enteral nutrition used to treat children with Crohn’s disease. Aliment Pharmacol Ther. 2008;28(6):724–33.

    Article  PubMed  CAS  Google Scholar 

  79. Callaway TR, et al. Probiotics, prebiotics and competitive exclusion for prophylaxis against bacterial disease. Anim Health Res Rev. 2008;9(2):217–25.

    Article  PubMed  CAS  Google Scholar 

  80. Haller D, et al. Guidance for substantiating the evidence for beneficial effects of probiotics: probiotics in chronic inflammatory bowel disease and the functional disorder irritable bowel syndrome. J Nutr. 2010;140(3):690S–7.

    Article  PubMed  CAS  Google Scholar 

  81. Bibiloni R, et al. VSL#3 probiotic-mixture induces remission in patients with active ulcerative colitis. Am J Gastroenterol. 2005;100(7):1539–46.

    Article  PubMed  Google Scholar 

  82. Tursi A, et al. Low-dose balsalazide plus a high-potency probiotic preparation is more effective than balsalazide alone or mesalazine in the treatment of acute mild-to-moderate ulcerative colitis. Med Sci Monit. 2004;10(11):PI126–31.

    PubMed  CAS  Google Scholar 

  83. Martin FP, et al. A top-down systems biology view of microbiome-mammalian metabolic interactions in a mouse model. Mol Syst Biol. 2007;3:112.

    Article  PubMed  Google Scholar 

  84. Spurbeck RR, Arvidson CG. Inhibition of Neisseria gonorrhoeae epithelial cell interactions by vaginal Lactobacillus species. Infect Immun. 2008;76(7):3124–30.

    Article  PubMed  CAS  Google Scholar 

  85. Medellin-Pena MJ, et al. Probiotics affect virulence-related gene expression in Escherichia coli O157:H7. Appl Environ Microbiol. 2007;73(13):4259–67.

    Article  PubMed  CAS  Google Scholar 

  86. Sartor RB. Efficacy of probiotics for the management of inflammatory bowel disease. Gastroenterol Hepatol (N Y). 2011;7(9):606–8.

    Google Scholar 

  87. Kolida S, Gibson GR. Synbiotics in health and disease. Annu Rev Food Sci Technol. 2011;2:373–93.

    Article  PubMed  Google Scholar 

  88. Welters CF, et al. Effect of dietary inulin supplementation on inflammation of pouch mucosa in patients with an ileal pouch-anal anastomosis. Dis Colon Rectum. 2002;45(5):621–7.

    Article  PubMed  Google Scholar 

  89. Casellas F, et al. Oral oligofructose-enriched inulin supplementation in acute ulcerative colitis is well tolerated and associated with lowered faecal calprotectin. Aliment Pharmacol Ther. 2007;25(9):1061–7.

    Article  PubMed  CAS  Google Scholar 

  90. Lindsay JO, et al. Clinical, microbiological, and immunological effects of fructo-oligosaccharide in patients with Crohn’s disease. Gut. 2006;55(3):348–55.

    Article  PubMed  CAS  Google Scholar 

  91. Steidler L, et al. Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science. 2000;289(5483):1352–5.

    Article  PubMed  CAS  Google Scholar 

  92. Hamady ZZ, et al. Treatment of colitis with a commensal gut bacterium engineered to secrete human TGF-beta1 under the control of dietary xylan 1. Inflamm Bowel Dis. 2011;17(9):1925–35.

    Article  PubMed  Google Scholar 

  93. Eiseman B, et al. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery. 1958;44(5):854–9.

    PubMed  CAS  Google Scholar 

  94. Garborg K, et al. Results of faecal donor instillation therapy for recurrent Clostridium difficile-associated diarrhoea. Scand J Infect Dis. 2010;42(11–12):857–61.

    Article  PubMed  Google Scholar 

  95. Rohlke F, Surawicz CM, Stollman N. Fecal flora reconstitution for recurrent Clostridium difficile infection: results and methodology. J Clin Gastroenterol. 2010;44(8):567–70.

    Article  PubMed  Google Scholar 

  96. Khoruts A, et al. Changes in the composition of the human fecal microbiome after bacteriotherapy for recurrent Clostridium difficile-associated diarrhea. J Clin Gastroenterol. 2010;44(5):354–60.

    PubMed  Google Scholar 

  97. Landy J, et al. Review article: faecal transplantation therapy for gastrointestinal disease. Aliment Pharmacol Ther. 2011;34(4):409–15.

    Article  PubMed  CAS  Google Scholar 

  98. Bennet JD, Brinkman M. Treatment of ulcerative colitis by implantation of normal colonic flora. Lancet. 1989;1(8630):164.

    Article  PubMed  CAS  Google Scholar 

  99. Borody TJ, et al. Treatment of ulcerative colitis using fecal bacteriotherapy. J Clin Gastroenterol. 2003;37(1):42–7.

    Article  PubMed  Google Scholar 

  100. Kahn SA, Gorawara-Bhat R, Rubin DT. Fecal bacteriotherapy for ulcerative colitis: patients are ready, are we? Inflamm Bowel Dis. 2012;18(4):676–84.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, 34th Street & Civic Center Boulevard, Philadelphia, PA, 19104, USA

    Judith Kelsen MD

  2. Department of Gastroenterology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA

    Gary D. Wu MD, PhD

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  1. Judith Kelsen MD
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  2. Gary D. Wu MD, PhD
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Correspondence to Judith Kelsen MD .

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Editors and Affiliations

  1. Perelman School of Medicine, The Children’s Hospital of Philadelphia, University of Pennsylvania, 34th St. & Civic Ctr. Blvd., Philadelphia, 19104, Pennsylvania, USA

    Petar Mamula

  2. School of Medicine--Greenville, Pediatric Gastroenterology & Nutrition, University of South Carolina, 200 Patewood Drive, Suite A-140, Greenville, 29615, South Carolina, USA

    Jonathan E. Markowitz

  3. Perelman School of Medicine, The Children's Hospital of Philadelphia, University of Pennsylvania, 34th St. & Civic Ctr. Blvd., Philadelphia, 19104, Pennsylvania, USA

    Robert N. Baldassano

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Kelsen, J., Wu, G.D. (2013). The Gut Microbiota and IBD. In: Mamula, P., Markowitz, J., Baldassano, R. (eds) Pediatric Inflammatory Bowel Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5061-0_4

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