Table of Contents Author Guidelines Submit a Manuscript
BioMed Research International
Volume 2017, Article ID 8201672, 17 pages
https://doi.org/10.1155/2017/8201672
Review Article

New Frontiers in Genetics, Gut Microbiota, and Immunity: A Rosetta Stone for the Pathogenesis of Inflammatory Bowel Disease

1Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
2Department of General Surgery, Huashan Hospital of Fudan University, Shanghai 200040, China
3Shanghai Institute for Pediatric Research, Shanghai 200092, China
4Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China

Correspondence should be addressed to Yingwei Chen; nc.moc.demauhnix@iewgniynehc

Received 5 April 2017; Revised 3 June 2017; Accepted 3 July 2017; Published 2 August 2017

Academic Editor: David Bernardo

Copyright © 2017 Mingxia Zhou et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. S. C. Ng, W. Tang, J. Y. Ching et al., “Incidence and phenotype of inflammatory bowel disease based on results from the Asia-Pacific Crohn's and colitis epidemiology study,” Gastroenterology, vol. 145, no. 1, pp. 158–165.e2, 2013. View at Publisher · View at Google Scholar · View at Scopus
  2. S. J. Park, W. H. Kim, and J. H. Cheon, “Clinical characteristics and treatment of inflammatory bowel disease: a comparison of Eastern and Western perspectives,” World Journal of Gastroenterology, vol. 20, no. 33, pp. 11525–11537, 2014. View at Publisher · View at Google Scholar · View at Scopus
  3. G. G. Kaplan, “The global burden of IBD: from 2015 to 2025,” Nature Reviews Gastroenterology & Hepatology, vol. 12, no. 12, pp. 720–727, 2015. View at Publisher · View at Google Scholar · View at Scopus
  4. P. J. Basso, M. T. Fonseca, G. Bonfá et al., “Association among genetic predisposition, gut microbiota, and host immune response in the etiopathogenesis of inflammatory bowel disease,” Brazilian Journal of Medical and Biological Research, vol. 47, no. 9, pp. 727–737, 2014. View at Publisher · View at Google Scholar
  5. L. J. Dixon, A. Kabi, K. P. Nickerson, and C. McDonald, “Combinatorial effects of diet and genetics on inflammatory bowel disease pathogenesis,” Inflammatory Bowel Diseases, vol. 21, no. 4, pp. 912–922, 2015. View at Publisher · View at Google Scholar · View at Scopus
  6. B. Stecher, “The roles of inflammation, nutrient availability and the commensal microbiota in enteric pathogen infection,” Microbiology Spectrum, vol. 3, no. 3, 2015. View at Publisher · View at Google Scholar · View at Scopus
  7. J. R. Marchesi, D. H. Adams, F. Fava et al., “The gut microbiota and host health: a new clinical frontier,” Gut, vol. 65, no. 2, pp. 330–339, 2016. View at Publisher · View at Google Scholar · View at Scopus
  8. G. G. Kaplan and T. Jess, “The changing landscape of inflammatory bowel disease: east meets west,” Gastroenterology, vol. 150, no. 1, pp. 24–26, 2016. View at Publisher · View at Google Scholar · View at Scopus
  9. J. Z. Liu, S. van Sommeren, H. Huang et al., “Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations,” Nat Genet, vol. 47, no. 9, pp. 979–986, 2015. View at Google Scholar
  10. S. N. Hong, C. Park, S. J. Park et al., “Deep resequencing of 131 Crohn's disease associated genes in pooled DNA confirmed three reported variants and identified eight novel variants,” Gut, vol. 65, no. 5, pp. 788–796, 2016. View at Publisher · View at Google Scholar · View at Scopus
  11. J. D. Doecke, L. A. Simms, Z. Z. Zhao et al., “Genetic susceptibility in IBD: overlap between ulcerative Colitis and Crohn's disease,” Inflammatory Bowel Diseases, vol. 19, no. 2, pp. 240–245, 2013. View at Publisher · View at Google Scholar · View at Scopus
  12. T.-C. Liu and T. S. Stappenbeck, “Genetics and pathogenesis of inflammatory bowel disease,” Annual Review of Pathology: Mechanisms of Disease, vol. 11, pp. 127–148, 2016. View at Publisher · View at Google Scholar · View at Scopus
  13. J. R. Kelsen, N. Dawany, A. Martinez et al., “Erratum to: a de novo whole gene deletion of XIAP detected by exome sequencing analysis in very early onset inflammatory bowel disease: a case report,” BMC Gastroenterology, vol. 15, no. 160, 2015. View at Publisher · View at Google Scholar · View at Scopus
  14. S. Zeissig, B. Petersen, M. Tomczak et al., “Early-onset Crohn’s disease and autoimmunity associated with a variant in CTLA-4,” Gut, vol. 64, no. 12, pp. 1889–1897, 2015. View at Publisher · View at Google Scholar
  15. J. R. Kelsen, N. Dawany, C. J. Moran et al., “Exome sequencing analysis reveals variants in primary Immunodeficiency genes in patients with very early onset inflammatory bowel disease,” Gastroenterology, vol. 149, no. 6, pp. 1415–1424, 2015. View at Publisher · View at Google Scholar · View at Scopus
  16. A. M. Muise, W. Xu, C.-H. Guo et al., “NADPH oxidase complex and IBD candidate gene studies: Identification of a rare variant in NCF2 that results in reduced binding to RAC2,” Gut, vol. 61, no. 7, pp. 1028–1035, 2012. View at Publisher · View at Google Scholar · View at Scopus
  17. H. H. Uhlig, T. Schwerd, S. Koletzko et al., “The diagnostic approach to monogenic very early onset inflammatory bowel disease,” Gastroenterology, vol. 147, no. 5, pp. 990–1007, 2014. View at Publisher · View at Google Scholar · View at Scopus
  18. A. P. Hutchins, D. Diez, and D. Miranda-Saavedra, “The IL-10/STAT3-mediated anti-inflammatory response: recent developments and future challenges,” Briefings in Functional Genomics, vol. 12, no. 6, Article ID elt028, pp. 489–498, 2013. View at Publisher · View at Google Scholar · View at Scopus
  19. O. F. Beser, C. D. Conde, N. K. Serwas et al., “Clinical features of interleukin 10 receptor gene mutations in children with very early-onset inflammatory bowel disease,” Journal of Pediatric Gastroenterology and Nutrition, vol. 60, no. 3, pp. 332–338, 2015. View at Publisher · View at Google Scholar · View at Scopus
  20. I. Cleynen, G. Boucher, L. Jostins et al., “Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study,” The Lancet, vol. 387, no. 10014, pp. 156–167, 2016. View at Publisher · View at Google Scholar · View at Scopus
  21. S. K. Yang, M. Hong, W. Zhao et al., “Genome-wide association study of Crohn's disease in Koreans revealed three new susceptibility loci and common attributes of genetic susceptibility across ethnic populations,” Gut, vol. 63, no. 1, pp. 80–87, 2014. View at Publisher · View at Google Scholar · View at Scopus
  22. K. Yamazaki, J. Umeno, A. Takahashi et al., “A genome-wide association study identifies 2 susceptibility loci for Crohn's disease in a Japanese population,” Gastroenterology, vol. 144, no. 4, pp. 781–788, 2013. View at Publisher · View at Google Scholar · View at Scopus
  23. S. C. Ng, K. K. F. Tsoi, M. A. Kamm et al., “Genetics of inflammatory bowel disease in Asia: systematic review and meta‐analysis,” Inflammatory Bowel Diseases, vol. 18, no. 6, pp. 1164–1176, 2012. View at Publisher · View at Google Scholar · View at Scopus
  24. D. P. B. McGovern, S. Kugathasan, and J. H. Cho, “Genetics of inflammatory bowel diseases,” Gastroenterology, vol. 149, no. 5, pp. 1163–1176, 2015. View at Publisher · View at Google Scholar · View at Scopus
  25. I. Loddo and C. Romano, “Inflammatory bowel disease: genetics, epigenetics, and pathogenesis,” Frontiers in Immunology, vol. 6, article 551, 2015. View at Publisher · View at Google Scholar · View at Scopus
  26. E. R. Nimmo, J. G. Prendergast, M. C. Aldhous et al., “Genome-wide methylation profiling in Crohn's disease identifies altered epigenetic regulation of key host defense mechanisms including the Th17 pathway,” Inflammatory Bowel Diseases, vol. 18, no. 5, pp. 889–899, 2012. View at Publisher · View at Google Scholar · View at Scopus
  27. L. G. Tsaprouni, K. Ito, J. J. Powell, I. M. Adcock, and N. Punchard, “Differential patterns of histone acetylation in inflammatory bowel diseases,” Journal of Inflammation, vol. 8, article no. 1, 2011. View at Publisher · View at Google Scholar · View at Scopus
  28. C.-H. Leung, W. Lam, D.-L. Ma, E. A. Gullen, and Y.-C. Cheng, “Butyrate mediates nucleotide-binding and oligomerisation domain (NOD) 2-dependent mucosal immune responses against peptidoglycan,” European Journal of Immunology, vol. 39, no. 12, pp. 3529–3537, 2009. View at Publisher · View at Google Scholar · View at Scopus
  29. J. Z. Liu and C. A. Anderson, “Genetic studies of Crohn's disease: past, present and future,” Best Practice & Research Clinical Gastroenterology, vol. 28, no. 3, pp. 373–386, 2014. View at Publisher · View at Google Scholar · View at Scopus
  30. A. N. Ananthakrishnan, “Epidemiology and risk factors for IBD,” Nature Reviews Gastroenterology & Hepatology, vol. 12, no. 4, pp. 205–217, 2015. View at Publisher · View at Google Scholar
  31. A. Rönnblom, T. Holmström, U. Karlbom, H. Tanghöj, M. Thörn, and D. Sjöberg, “Clinical course of Crohn’s disease during the first 5 years. results from a population-based cohort in Sweden (ICURE) diagnosed 2005–2009,” Scandinavian Journal of Gastroenterology, vol. 52, no. 1, pp. 81–86, 2016. View at Publisher · View at Google Scholar
  32. E. Legaki and M. Gazouli, “Influence of environmental factors in the development of inflammatory bowel diseases,” World Journal of Gastrointestinal Pharmacology and Therapeutics, vol. 7, no. 1, pp. 112–125, 2016. View at Publisher · View at Google Scholar
  33. K. T. Dolan and E. B. Chang, “Diet, gut microbes, and the pathogenesis of inflammatory bowel diseases,” Molecular Nutrition & Food Research, vol. 61, no. 1, 2017. View at Google Scholar
  34. S. C. Ng, R. W. Leong, Y. Ko et al., “Environmental risk factors in inflammatory bowel disease in asia-pacific: a population-based case-control study in Asia-Pacific,” Gut, vol. 64, no. 7, pp. 1063–1071, 2014. View at Publisher · View at Google Scholar
  35. J. L. Opstelten, J. Plassais, S. W. C. Van Mil et al., “Gut microbial diversity is reduced in smokers with Crohn's disease,” Inflammatory Bowel Diseases, vol. 22, no. 9, pp. 2070–2077, 2016. View at Publisher · View at Google Scholar · View at Scopus
  36. A. W. Walker, J. D. Sanderson, C. Churcher 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 Microbiology, vol. 11, no. 7, 2011. View at Publisher · View at Google Scholar · View at Scopus
  37. A. T. Abegunde, B. H. Muhammad, O. Bhatti, and T. Ali, “Environmental risk factors for inflammatory bowel diseases: evidence based literature review,” World Journal of Gastroenterology, vol. 22, no. 27, pp. 6296–6317, 2016. View at Publisher · View at Google Scholar · View at Scopus
  38. H. B. Kim, M. Kim, Y. S. Park, I. Park et al., “Prostaglandin E2 activates YAP and a positive-signaling loop to promote colon regeneration after colitis but also carcinogenesis in mice,” Gastroenterology, vol. 152, no. 3, pp. 616–630, 2017. View at Publisher · View at Google Scholar
  39. Y. Cao, R. Nishihara, Z. R. Qian et al., “Regular aspirin use associates with lower risk of colorectal cancers with low numbers of tumor-infiltrating lymphocytes,” Gastroenterology, vol. 151, no. 5, pp. 879–892.e4, 2016. View at Publisher · View at Google Scholar · View at Scopus
  40. D. Chen, J. Zhao, H. Wang et al., “Oxytocin evokes a pulsatile PGE2 release from ileum mucosa and is required for repair of intestinal epithelium after injury,” Scientific Reports, vol. 5, Article ID 11731, 2015. View at Publisher · View at Google Scholar · View at Scopus
  41. A. Alonso, E. Domènech, A. Julià et al., “Identification of risk loci for crohn's disease phenotypes using a genome-wide association study,” Gastroenterology, vol. 148, no. 4, pp. 794–805, 2015. View at Publisher · View at Google Scholar
  42. A. Hirayama, S. Joshita, K. Kitahara et al., “Lymphocyte antigen 75 polymorphisms are associated with disease susceptibility and phenotype in japanese patients with inflammatory bowel disease,” Disease Markers, vol. 2016, Article ID 6485343, 7 pages, 2016. View at Publisher · View at Google Scholar · View at Scopus
  43. P. N. Kelly, “CD28 is a critical target for PD-1 blockade,” Science, vol. 355, no. 6332, p. 1386, 2017. View at Publisher · View at Google Scholar
  44. H. Fujii, S. Shinzaki, H. Iijima et al., “Core fucosylation on T cells, required for activation of T-cell receptor signaling and induction of colitis in mice, is increased in patients with inflammatory bowel disease,” Gastroenterology, vol. 150, no. 7, pp. 1620–1632, 2016. View at Publisher · View at Google Scholar · View at Scopus
  45. E. Calderón-Gómez, H. Bassolas-Molina, R. Mora-Buch et al., “Commensal-specific CD4+ cells from patients with crohn’s disease have a T-helper 17 inflammatory profile,” Gastroenterology, vol. 151, no. 3, pp. 489.e3–500.e3, 2016. View at Publisher · View at Google Scholar
  46. I. Marafini, I. Monteleone, V. Dinallo et al., “CCL20 is negatively regulated by TGF-beta1 in intestinal epithelial cells and reduced in Crohn's disease patients with a successful response to mongersen, a Smad7 antisense oligonucleotide,” Journal of Crohns & Colitis, vol. 11, no. 5, pp. 603–609, 2017. View at Google Scholar
  47. C. H. Bang-Berthelsen, T. L. Holm, C. Pyke et al., “GLP-1 induces barrier protective expression in brunner's glands and regulates colonic inflammation,” Inflammatory Bowel Diseases, vol. 22, no. 9, pp. 2078–2097, 2016. View at Publisher · View at Google Scholar · View at Scopus
  48. J. Stallhofer, M. Friedrich, A. Konrad-Zerna et al., “Lipocalin-2 is a disease activity marker in inflammatory bowel disease regulated by IL-17A, IL-22, and TNF-α and modulated by IL23R genotype status,” Inflammatory Bowel Diseases, vol. 21, no. 10, pp. 2327–2340, 2015. View at Publisher · View at Google Scholar · View at Scopus
  49. G. Pedersen, “Development, validation and implementation of an in vitro model for the study of metabolic and immune function in normal and inflamed human colonic epithelium,” Danish medical journal, vol. 62, no. 1, p. B4973, 2015. View at Google Scholar · View at Scopus
  50. N. R. West, A. N. Hegazy, B. M. Owens et al., “Erratum: oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor–neutralizing therapy in patients with inflammatory bowel disease,” Nature Medicine, vol. 23, no. 6, p. 788, 2017. View at Publisher · View at Google Scholar
  51. B. Lamas, M. L. Richard, V. Leducq et al., “CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands,” Nature Medicine, vol. 22, no. 6, pp. 598–605, 2016. View at Publisher · View at Google Scholar · View at Scopus
  52. C. K. Porter, M. Welsh, M. S. Riddle, C. Nieh, E. J. Boyko, and G. Gackstetter, “Hooper TI: epidemiology of inflammatory bowel disease among participants of the millennium cohort: incidence, deployment-related risk factors, and antecedent episodes of infectious gastroenteritis,” Alimentary pharmacology & therapeutics, vol. 45, no. 8, pp. 1115–1127, 2017. View at Google Scholar
  53. S. Thiemann, J. H. Man, M. H. Chang, B. Lee, and L. G. Baum, “Galectin-1 regulates tissue exit of specific dendritic cell populations,” The Journal of Biological Chemistry, vol. 290, no. 37, pp. 22662–22667, 2015. View at Publisher · View at Google Scholar · View at Scopus
  54. J. Gomez-Rodriguez, F. Meylan, R. Handon et al., “Itk is required for Th9 differentiation via TCR-mediated induction of IL-2 and IRF4,” Nature Communications, vol. 7, Article ID 10857, 2016. View at Publisher · View at Google Scholar · View at Scopus
  55. C. H. Gabriel, F. Gross, M. Karl et al., “Identification of novel nuclear factor of activated T cell (NFAT)-associated proteins in T cells,” Journal of Biological Chemistry, vol. 291, no. 46, pp. 24172–24187, 2016. View at Publisher · View at Google Scholar · View at Scopus
  56. A. Kaser, S. Zeissig, and R. S. Blumberg, “Inflammatory bowel disease,” Annual Review of Immunology, vol. 28, pp. 573–621, 2010. View at Publisher · View at Google Scholar · View at Scopus
  57. A. Darfeuille-Michaud, J. Boudeau, P. Bulois et al., “High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn's disease,” Gastroenterology, vol. 127, no. 2, pp. 412–421, 2004. View at Publisher · View at Google Scholar · View at Scopus
  58. C. Manichanh, N. Borruel, F. Casellas, and F. Guarner, “The gut microbiota in IBD,” Nature Reviews Gastroenterology and Hepatology, vol. 9, no. 10, pp. 599–608, 2012. View at Publisher · View at Google Scholar · View at Scopus
  59. C. R. Hedin, N. E. McCarthy, P. Louis et al., “Altered intestinal microbiota and blood T cell phenotype are shared by patients with Crohn's disease and their unaffected siblings,” Gut, vol. 63, no. 10, pp. 1578–1586, 2014. View at Publisher · View at Google Scholar · View at Scopus
  60. C. Moran, D. Sheehan, and F. Shanahan, “The small bowel microbiota,” Current Opinion in Gastroenterology, vol. 31, no. 2, pp. 130–136, 2015. View at Publisher · View at Google Scholar · View at Scopus
  61. C. Manichanh, L. Rigottier-Gois, E. Bonnaud et al., “Reduced diversity of faecal microbiota in Crohn's disease revealed by a metagenomic approach,” Gut, vol. 55, no. 2, pp. 205–211, 2006. View at Publisher · View at Google Scholar · View at Scopus
  62. X. C. Morgan, T. L. Tickle, H. Sokol et al., “Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment,” Genome Biology, vol. 13, no. 9, article R79, 2012. View at Publisher · View at Google Scholar · View at Scopus
  63. O. Paliy, H. Kenche, F. Abernathy, and S. Michail, “High-throughput quantitative analysis of the human intestinal microbiota with a phylogenetic microarray,” Applied and Environmental Microbiology, vol. 75, no. 11, pp. 3572–3579, 2009. View at Publisher · View at Google Scholar · View at Scopus
  64. S. Kang, S. E. Denman, M. Morrison et al., “Dysbiosis of fecal microbiota in Crohn's disease patients as revealed by a custom phylogenetic microarray,” Inflammatory Bowel Diseases, vol. 16, no. 12, pp. 2034–2042, 2010. View at Publisher · View at Google Scholar · View at Scopus
  65. A. D. Kostic, R. J. Xavier, and D. Gevers, “The microbiome in inflammatory bowel disease: current status and the future ahead,” Gastroenterology, vol. 146, no. 6, pp. 1489–1499, 2014. View at Publisher · View at Google Scholar · View at Scopus
  66. M. Lopez-Siles, M. Martinez-Medina, D. Busquets et al., “Mucosa-associated faecalibacterium prausnitzii and escherichia coli co-abundance can distinguish irritable bowel syndrome and inflammatory bowel disease phenotypes,” International Journal of Medical Microbiology, vol. 304, no. 3-4, pp. 464–475, 2014. View at Publisher · View at Google Scholar · View at Scopus
  67. R. Hansen, R. K. Russell, C. Reiff et al., “Microbiota of de-novo pediatric IBD: increased faecalibacterium prausnitzii and reduced bacterial diversity in Crohn's but not in ulcerative colitis,” American Journal of Gastroenterology, vol. 107, no. 12, pp. 1913–1922, 2012. View at Publisher · View at Google Scholar · View at Scopus
  68. J. K. Nicholson, E. Holmes, J. Kinross et al., “Host-gut microbiota metabolic interactions,” Science, vol. 336, no. 6086, pp. 1262–1267, 2012. View at Publisher · View at Google Scholar · View at Scopus
  69. A. M. McGuire, K. Cochrane, A. D. Griggs et al., “Evolution of invasion in a diverse set of fusobacterium species,” mBio, vol. 5, no. 6, Article ID e01864-14, 2014. View at Publisher · View at Google Scholar · View at Scopus
  70. The Human Microbiome Project Consortium, “Structure, function and diversity of the healthy human microbiome,” Nature, vol. 486, no. 7402, pp. 207–214, 2012. View at Publisher · View at Google Scholar
  71. A. R. Erickson, B. L. Cantarel, R. Lamendella et al., “Integrated metagenomics/metaproteomics reveals human host-microbiota signatures of Crohn's disease,” PLoS ONE, vol. 7, no. 11, Article ID e49138, 2012. View at Publisher · View at Google Scholar · View at Scopus
  72. M. Davenport, J. Poles, J. M. Leung et al., “Metabolic alterations to the mucosal microbiota in inflammatory bowel disease,” Inflammatory Bowel Diseases, vol. 20, no. 4, pp. 723–731, 2014. View at Publisher · View at Google Scholar · View at Scopus
  73. C. Pereira, D. Grácio, J. P. Teixeira, and F. Magro, “Oxidative stress and DNA damage: implications in inflammatory bowel disease,” Inflammatory Bowel Diseases, vol. 21, no. 10, pp. 2403–2417, 2015. View at Publisher · View at Google Scholar · View at Scopus
  74. B. Cui, P. Li, L. Xu et al., “Step-up fecal microbiota transplantation strategy: a pilot study for steroid-dependent ulcerative colitis,” Journal of Translational Medicine, vol. 13, no. 298, 2015. View at Publisher · View at Google Scholar · View at Scopus
  75. P. Moayyedi, M. G. Surette, P. T. Kim et al., “Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial,” Gastroenterology, vol. 149, no. 1, Article ID 59708, pp. 102–109, 2015. View at Publisher · View at Google Scholar · View at Scopus
  76. N. A. Cohen and N. Maharshak, “Novel indications for fecal microbial transplantation: update and review of the literature,” Digestive Diseases and Sciences, vol. 62, no. 5, pp. 1131–1145, 2017. View at Publisher · View at Google Scholar
  77. S. Paramsothy, A. J. Walsh, T. Borody et al., “Gastroenterologist perceptions of faecal microbiota transplantation,” World Journal of Gastroenterology, vol. 21, no. 38, pp. 10907–10914, 2015. View at Publisher · View at Google Scholar · View at Scopus
  78. R. R. Ren, G. Sun, Y. S. Yang et al., “Chinese physicians' perceptions of fecal microbiota transplantation,” World Journal of Gastroenterology, vol. 22, no. 19, pp. 4757–4765, 2016. View at Publisher · View at Google Scholar · View at Scopus
  79. A. Aratari, G. Cammarota, and C. Papi, “Fecal microbiota transplantation for recurrent C. difficile infection in a patient with chronic refractory ulcerative colitis,” Journal of Crohn's & colitis, vol. 9, no. 4, p. 367, 2015. View at Publisher · View at Google Scholar · View at Scopus
  80. K. Garber, “Drugging the gut microbiome,” Nature Biotechnology, vol. 33, no. 3, pp. 228–231, 2016. View at Publisher · View at Google Scholar · View at Scopus
  81. L. Steidler, W. Hans, L. Schotte et al., “Treatment of murine colitis by Lactococcus lactis secreting interleukin-10,” Science, vol. 289, no. 5483, pp. 1352–1355, 2000. View at Publisher · View at Google Scholar · View at Scopus
  82. H. Sokol, V. Leducq, H. Aschard et al., “Fungal microbiota dysbiosis in IBD,” Gut, pp. 1039–1048, 2016. View at Publisher · View at Google Scholar · View at Scopus
  83. G. Liguori, B. Lamas, M. L. Richard et al., “Fungal dysbiosis in mucosa-associated microbiota of Crohn's disease patients,” Journal of Crohn's and Colitis, vol. 10, no. 3, pp. 296–305, 2016. View at Publisher · View at Google Scholar · View at Scopus
  84. C. Chehoud, L. G. Albenberg, C. Judge et al., “Fungal signature in the gut microbiota of pediatric patients with inflammatory bowel disease,” Inflammatory Bowel Diseases, vol. 21, no. 8, pp. 1948–1956, 2015. View at Publisher · View at Google Scholar · View at Scopus
  85. K. R. Engelhardt and B. Grimbacher, “Mendelian traits causing susceptibility to mucocutaneous fungal infections in human subjects,” Journal of Allergy and Clinical Immunology, vol. 129, no. 2, pp. 294–305, 2012. View at Publisher · View at Google Scholar · View at Scopus
  86. K. Ray, “Gut microbiota: dysbiosis in fungal microbiota in IBD,” Nature Reviews Gastroenterology and Hepatology, vol. 13, no. 4, p. 188, 2016. View at Publisher · View at Google Scholar · View at Scopus
  87. S. J. Ott, T. Kühbacher, M. Musfeldt et al., “Fungi and inflammatory bowel diseases: alterations of composition and diversity,” Scandinavian Journal of Gastroenterology, vol. 43, no. 7, pp. 831–841, 2008. View at Publisher · View at Google Scholar · View at Scopus
  88. C. Casén, H. C. Vebo, M. Sekelja et al., “Deviations in human gut microbiota: a novel diagnostic test for determining dysbiosis in patients with IBS or IBD,” Alimentary Pharmacology and Therapeutics, vol. 42, no. 1, pp. 71–83, 2015. View at Publisher · View at Google Scholar · View at Scopus
  89. H. Duboc, S. Rajca, D. Rainteau et al., “Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bowel diseases,” Gut, vol. 62, no. 4, pp. 531–539, 2013. View at Publisher · View at Google Scholar · View at Scopus
  90. J. Brooks and A. J. M. Watson, “The enteric virome in inflammatory bowel disease,” Gastroenterology, vol. 149, no. 4, pp. 1120-1121, 2015. View at Publisher · View at Google Scholar · View at Scopus
  91. J. M. Norman, S. A. Handley, M. T. Baldridge et al., “Disease-specific alterations in the enteric virome in inflammatory bowel disease,” Cell, vol. 160, no. 3, pp. 447–460, 2015. View at Publisher · View at Google Scholar · View at Scopus
  92. S. M. Karst, “Viral safeguard: the enteric virome protects against gut inflammation,” Immunity, vol. 44, no. 4, pp. 715–718, 2016. View at Publisher · View at Google Scholar · View at Scopus
  93. J. K. Pfeiffer and H. W. Virgin, “Viral immunity: transkingdom control of viral infection and immunity in the mammalian intestine,” Science, vol. 351, no. 6270, Article ID aad5872, 2016. View at Publisher · View at Google Scholar · View at Scopus
  94. V. Pérez-Brocal, R. García-López, P. Nos, B. Beltrán, I. Moret, and A. Moya, “Metagenomic analysis of Crohn's disease patients identifies changes in the virome and microbiome related to disease status and therapy, and detects potential interactions and biomarkers,” Inflammatory Bowel Diseases, vol. 21, no. 11, pp. 2515–2532, 2015. View at Publisher · View at Google Scholar · View at Scopus
  95. M. de Paepe, M. Leclerc, C. R. Tinsley, and M.-A. Petit, “Bacteriophages: an underestimated role in human and animal health?” Frontiers in Cellular and Infection Microbiology, vol. 4, no. 39, 2014. View at Publisher · View at Google Scholar · View at Scopus
  96. A. Stern, E. Mick, I. Tirosh, O. Sagy, and R. Sorek, “CRISPR targeting reveals a reservoir of common phages associated with the human gut microbiome,” Genome Research, vol. 22, no. 10, pp. 1985–1994, 2012. View at Publisher · View at Google Scholar · View at Scopus
  97. J. J. Barr, R. Auro, M. Furlan et al., “Bacteriophage adhering to mucus provide a non-host-derived immunity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 26, pp. 10771–10776, 2013. View at Publisher · View at Google Scholar · View at Scopus
  98. P. Lepage, J. Colombet, P. Marteau, T. Sime-Ngando, J. Doré, and M. Leclerc, “Dysbiosis in inflammatory bowel disease: a role for bacteriophages?” Gut, vol. 57, no. 3, pp. 424-425, 2008. View at Publisher · View at Google Scholar · View at Scopus
  99. S. L. La Rosa, L.-G. Snipen, B. E. Murray et al., “A genomic virulence reference map of Enterococcus faecalis reveals an important contribution of phage03-like elements in nosocomial genetic lineages to pathogenicity in a caenorhabditis elegans infection model,” Infection and Immunity, vol. 83, no. 5, pp. 2156–2167, 2015. View at Publisher · View at Google Scholar · View at Scopus
  100. N. L. Harris, “Intimate gut interactions: helminths and the microbiota,” Cell Research, vol. 26, no. 8, pp. 861-862, 2016. View at Publisher · View at Google Scholar · View at Scopus
  101. D. Ramanan, M. S. Tang, R. Bowcutt, P. Loke, and K. Cadwell, “Bacterial sensor Nod2 prevents inflammation of the small intestine by restricting the expansion of the commensal bacteroides vulgatus,” Immunity, vol. 41, no. 2, pp. 311–324, 2014. View at Publisher · View at Google Scholar · View at Scopus
  102. M. M. Zaiss, A. Rapin, L. Lebon et al., “The intestinal microbiota contributes to the ability of helminths to modulate allergic inflammation,” Immunity, vol. 43, no. 5, pp. 998–1010, 2015. View at Publisher · View at Google Scholar · View at Scopus
  103. P. Giacomin, Z. Agha, and A. Loukas, “Helminths and intestinal flora team up to improve gut health,” Trends in Parasitology, vol. 32, no. 9, pp. 664–666, 2016. View at Publisher · View at Google Scholar · View at Scopus
  104. S. K. Garg, A. M. Croft, and P. Bager, “Helminth therapy (worms) for induction of remission in inflammatory bowel disease,” The Cochrane Database of Systematic Reviews, no. 1, p. D9400, 2014. View at Google Scholar · View at Scopus
  105. J. O. Fleming, A. Isaak, J. E. Lee et al., “Probiotic helminth administration in relapsing-remitting multiple sclerosis: a phase 1 study,” Multiple Sclerosis Journal, vol. 17, no. 6, pp. 743–754, 2011. View at Publisher · View at Google Scholar · View at Scopus
  106. P. Bager, J. Arnved, S. Ronborg et al., “Trichuris suis ova therapy for allergic rhinitis: a randomized, double-blind, placebo-controlled clinical trial,” Journal of Allergy and Clinical Immunology, vol. 125, no. 1-3, pp. 123–130, 2010. View at Publisher · View at Google Scholar · View at Scopus
  107. A. A. Da'dara and D. A. Harn, “Elimination of helminth infection restores HIV-1C vaccine-specific T cell responses independent of helminth-induced IL-10,” Vaccine, vol. 28, no. 5, pp. 1310–1317, 2010. View at Publisher · View at Google Scholar · View at Scopus
  108. B. Damania and D. P. Dittmer, “What lies within: coinfections and immunity,” Cell Host and Microbe, vol. 16, no. 2, pp. 145–147, 2014. View at Publisher · View at Google Scholar · View at Scopus
  109. M. G. De Agüero, S. C. Ganal-Vonarburg, T. Fuhrer et al., “The maternal microbiota drives early postnatal innate immune development,” Science, vol. 351, no. 6279, pp. 1296–1302, 2016. View at Publisher · View at Google Scholar · View at Scopus
  110. M. R. Hepworth, L. A. Monticelli, T. C. Fung et al., “Innate lymphoid cells regulate CD4+ T-cell responses to intestinal commensal bacteria,” Nature, vol. 498, no. 7452, pp. 113–117, 2013. View at Publisher · View at Google Scholar · View at Scopus
  111. H. S. P. de Souza and C. Fiocchi, “Immunopathogenesis of IBD: current state of the art,” Nature Reviews Gastroenterology and Hepatology, vol. 13, no. 1, pp. 13–27, 2016. View at Publisher · View at Google Scholar · View at Scopus
  112. E. Elinav, T. Strowig, A. L. Kau et al., “NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis,” Cell, vol. 145, no. 5, pp. 745–757, 2011. View at Publisher · View at Google Scholar · View at Scopus
  113. M. Levy, C. A. Thaiss, D. Zeevi et al., “Microbiota-modulated metabolites shape the intestinal microenvironment by regulating NLRP6 inflammasome signaling,” Cell, vol. 163, no. 6, pp. 1428–1443, 2015. View at Publisher · View at Google Scholar · View at Scopus
  114. S. Zeissig, C. Bojarski, N. Buergel et al., “Downregulation of epithelial apoptosis and barrier repair in active Crohn's disease by tumour necrosis factor α antibody treatment,” Gut, vol. 53, no. 9, pp. 1295–1302, 2004. View at Publisher · View at Google Scholar · View at Scopus
  115. A. Franke, DP. McGovern, JC. Barrett et al., “Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci,” Nat Genet, vol. 42, no. 12, pp. 1118–1125, 2010. View at Google Scholar
  116. K. Cadwell, J. Y. Liu, S. L. Brown et al., “A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal paneth cells,” Nature, vol. 456, no. 7219, pp. 259–263, 2008. View at Publisher · View at Google Scholar · View at Scopus
  117. M. A. McGuckin, R. D. Eri, I. Das, R. Lourie, and T. H. Florin, “ER stress and the unfolded protein response in intestinal inflammation,” American Journal of Physiology—Gastrointestinal and Liver Physiology, vol. 298, no. 6, pp. G820–G832, 2010. View at Publisher · View at Google Scholar · View at Scopus
  118. M. Schröder and R. J. Kaufman, “ER stress and the unfolded protein response,” Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, vol. 569, no. 1-2, pp. 29–63, 2005. View at Publisher · View at Google Scholar · View at Scopus
  119. A. Kaser, A. Lee, A. Franke et al., “XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease,” Cell, vol. 134, no. 5, pp. 743–756, 2008. View at Publisher · View at Google Scholar · View at Scopus
  120. C. G. Knutson, A. Mangerich, Y. Zeng et al., “Chemical and cytokine features of innate immunity characterize serum and tissue profiles in inflammatory bowel disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 26, pp. E2332–E2341, 2013. View at Publisher · View at Google Scholar · View at Scopus
  121. J. R. McDole, L. W. Wheeler, and K. G. McDonald, “Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine,” Nature, vol. 483, no. 7389, pp. 345–349, 2012. View at Publisher · View at Google Scholar · View at Scopus
  122. K. L. Wallace, L.-B. Zheng, Y. Kanazawa, and D. Q. Shih, “Immunopathology of inflammatory bowel disease,” World Journal of Gastroenterology, vol. 20, no. 1, pp. 6–21, 2014. View at Publisher · View at Google Scholar · View at Scopus
  123. M. F. Elshal, A. M. Aldahlawi, O. I. Saadah, and J. P. McCoy, “Reduced dendritic cells expressing CD200R1 in children with inflammatory bowel disease: correlation with Th17 and regulatory T cells,” International Journal of Molecular Sciences, vol. 16, no. 12, pp. 28998–29010, 2015. View at Publisher · View at Google Scholar · View at Scopus
  124. A. Geremia, P. Biancheri, P. Allan, G. R. Corazza, and A. di Sabatino, “Innate and adaptive immunity in inflammatory bowel disease,” Autoimmunity Reviews, vol. 13, no. 1, pp. 3–10, 2014. View at Publisher · View at Google Scholar · View at Scopus
  125. G. Zanello, D. Kevans, A. Goethel, M. Silverberg, A. Tyler, and K. Croitoru, “Genetics and innate and adaptive immunity in IBD,” Nestle Nutrition Institute Workshop Series, vol. 79, pp. 41–55, 2014. View at Publisher · View at Google Scholar · View at Scopus
  126. H. Shi, Y. Wang, X. Li et al., “NLRP3 activation and mitosis are mutually exclusive events coordinated by NEK7, a new inflammasome component,” Nature Immunology, vol. 17, no. 3, pp. 250–258, 2016. View at Publisher · View at Google Scholar · View at Scopus
  127. J. Dupaul-Chicoine, G. Yeretssian, K. Doiron et al., “Control of intestinal homeostasis, colitis, and colitis-associated colorectal cancer by the inflammatory caspases,” Immunity, vol. 32, no. 3, pp. 367–378, 2010. View at Publisher · View at Google Scholar · View at Scopus
  128. S. Hu, L. Peng, Y.-T. Kwak et al., “The DNA sensor AIM2 maintains intestinal homeostasis via regulation of epithelial antimicrobial host defense,” Cell Reports, vol. 13, no. 9, pp. 1922–1936, 2015. View at Publisher · View at Google Scholar · View at Scopus
  129. M. Wlodarska, C. A. Thaiss, R. Nowarski et al., “NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion,” Cell, vol. 156, no. 5, pp. 1045–1059, 2014. View at Publisher · View at Google Scholar · View at Scopus
  130. G. Gorfu, K. M. Cirelli, M. B. Melo et al., “Dual role for inflammasome sensors NLRP1 and NLRP3 in murine resistance to Toxoplasma gondii,” mBio, vol. 5, no. 1, Article ID e01117-13, 2014. View at Publisher · View at Google Scholar · View at Scopus
  131. P. K. Anand, R. K. S. Malireddi, J. R. Lukens et al., “NLRP6 negatively regulates innate immunity and host defence against bacterial pathogens,” Nature, vol. 488, no. 7411, pp. 389–393, 2012. View at Publisher · View at Google Scholar · View at Scopus
  132. A. Rubartelli and M. T. Lotze, “Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs) and redox,” Trends in Immunology, vol. 28, no. 10, pp. 429–436, 2007. View at Publisher · View at Google Scholar · View at Scopus
  133. T. Maslanik, L. Mahaffey, K. Tannura, L. Beninson, B. N. Greenwood, and M. Fleshner, “The inflammasome and danger associated molecular patterns (DAMPs) are implicated in cytokine and chemokine responses following stressor exposure,” Brain, Behavior, and Immunity, vol. 28, pp. 54–62, 2013. View at Publisher · View at Google Scholar · View at Scopus
  134. P. Fernandes, J. Macsharry, T. Darby et al., “Differential expression of key regulators of Toll-like receptors in ulcerative colitis and Crohn's disease: a role for Tollip and peroxisome proliferator-activated receptor gamma?” Clinical and Experimental Immunology, vol. 183, no. 3, pp. 358–368, 2016. View at Publisher · View at Google Scholar · View at Scopus
  135. A. Lahiri and C. Abraham, “Activation of pattern recognition receptors up-regulates metallothioneins, thereby increasing intracellular accumulation of zinc, autophagy, and bacterial clearance by macrophages,” Gastroenterology, vol. 147, no. 4, pp. 835–846, 2014. View at Publisher · View at Google Scholar · View at Scopus
  136. M. Scarpa, S. Kessler, T. Sadler et al., “The epithelial danger signal IL-1α is a potent activator of fibroblasts and reactivator of intestinal inflammation,” The American Journal of Pathology, vol. 185, no. 6, pp. 1624–1637, 2015. View at Publisher · View at Google Scholar · View at Scopus
  137. J. Däbritz, F. Friedrichs, T. Weinhage et al., “The functional -374T/A polymorphism of the receptor for advanced glycation end products may modulate Crohn's disease,” The American Journal of Physiology—Gastrointestinal and Liver Physiology, vol. 300, no. 5, pp. G823–G832, 2011. View at Publisher · View at Google Scholar · View at Scopus
  138. A. R. Neves, M. T. Castelo-Branco, V. R. Figliuolo et al., “Overexpression of ATP-activated P2X7 receptors in the intestinal mucosa is implicated in the pathogenesis of Crohn's disease,” Inflammatory Bowel Diseases, vol. 20, no. 3, pp. 444–457, 2014. View at Publisher · View at Google Scholar · View at Scopus
  139. R. Kalla, N. T. Ventham, N. A. Kennedy et al., “MicroRNAs: new players in IBD,” Gut, vol. 64, no. 3, pp. 504–517, 2015. View at Publisher · View at Google Scholar · View at Scopus
  140. J. S. Schaefer, T. Attumi, A. R. Opekun et al., “MicroRNA signatures differentiate Crohn's disease from ulcerative colitis,” BMC Immunology, vol. 16, no. 5, 2015. View at Publisher · View at Google Scholar · View at Scopus
  141. Y. Tay, J. Rinn, and P. P. Pandolfi, “The multilayered complexity of ceRNA crosstalk and competition,” Nature, vol. 505, no. 7483, pp. 344–352, 2014. View at Publisher · View at Google Scholar · View at Scopus
  142. S. Qu, Y. Zhong, R. Shang et al., “The emerging landscape of circular RNA in life processes,” RNA Biology, pp. 1–8, 2016. View at Publisher · View at Google Scholar · View at Scopus
  143. D. Iliopoulos, H. A. Hirsch, and K. Struhl, “An epigenetic switch involving NF-κB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation,” Cell, vol. 139, no. 4, pp. 693–706, 2009. View at Publisher · View at Google Scholar · View at Scopus
  144. G. Koukos, C. Polytarchou, J. L. Kaplan et al., “MicroRNA-124 regulates STAT3 expression and is down-regulated in colon tissues of pediatric patients with ulcerative colitis,” Gastroenterology, vol. 145, no. 4, pp. 842.e2–852.e2, 2013. View at Publisher · View at Google Scholar · View at Scopus
  145. J. R. Pekow, U. Dougherty, R. Mustafi et al., “MiR-143 and miR-145 are downregulated in ulcerative colitis: Putative regulators of inflammation and protooncogenes,” Inflammatory Bowel Diseases, vol. 18, no. 1, pp. 94–100, 2012. View at Publisher · View at Google Scholar · View at Scopus
  146. A. M. Zahm, N. J. Hand, D. M. Tsoucas, C. L. Le Guen, R. N. Baldassano, and J. R. Friedman, “Rectal microRNAs are perturbed in pediatric inflammatory bowel disease of the colon,” Journal of Crohn's and Colitis, vol. 8, no. 9, pp. 1108–1117, 2014. View at Publisher · View at Google Scholar · View at Scopus
  147. D. Chen, J. Liu, H.-Y. Zhao, Y.-P. Chen, Z. Xiang, and X. Jin, “Plasma long noncoding RNA expression profile identified by microarray in patients with Crohn's disease,” World Journal of Gastroenterology, vol. 22, no. 19, pp. 4716–4731, 2016. View at Publisher · View at Google Scholar · View at Scopus
  148. Z. Li and T. M. Rana, “Decoding the noncoding: prospective of lncRNA-mediated innate immune regulation,” RNA Biology, vol. 11, no. 8, pp. 979–985, 2014. View at Publisher · View at Google Scholar · View at Scopus
  149. M. Aguilera, T. Darby, and S. Melgar, “The complex role of inflammasomes in the pathogenesis of inflammatory bowel diseases—lessons learned from experimental models,” Cytokine & Growth Factor Reviews, vol. 25, no. 6, pp. 715–730, 2014. View at Publisher · View at Google Scholar · View at Scopus