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Inflammatory bowel disease: between genetics and microbiota

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Abstract

Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disease that can involve any part of the gastrointestinal tract. It includes two main disorders: Crohn’s disease (CD) and Ulcerative colitis (UC). CD and UC often share a similar clinical presentation; however, they affect distinct parts of the GI Tract with a different gut wall inflammatory extent. Ultimately, IBD seems to emanate from an uncontrollably continuous inflammatory process arising against the intestinal microbiome in a genetically susceptible individual. It is a multifactorial disease stemming from the impact of both environmental and genetic components on the intestinal microbiome. Furthermore, IBD genetics has gained a lot of attention. Around 200 loci were identified as imparting an increased risk for IBD. Few of them were heavily investigated and determined as highly linked to IBD. These genes, as discussed below, include NOD2, ATG16L1, IRGM, LRRK2, PTPN2, IL23R, Il10, Il10RA, Il10RB, CDH1 and HNF4α among others. Consequently, the incorporation of a genetic panel covering these key genes would markedly enhance the diagnosis and evaluation of IBD.

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Data Availability

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Abbreviations

IBD:

Inflammatory bowel disease

CD:

Crohn’s disease

UC:

Ulcerative Colitis

NSAIDs:

Nonsteroidal anti-inflammatory drugs

DC:

Dendritic cell

TLR:

Toll-like receptor

NOD:

Nucleotide-binding oligomerization domain-like receptor

NK:

Natural killer cell

NKT:

Natural killer T cell

sIgA:

Secretory IgA

GWAS:

Genome-wide association studies

NOD2:

Nucleotide-binding oligomerization domain-containing protein 2

ATG16L1:

Autophagy-related 16-like 1 protein

IRGM:

Immunity-related guanosine triphosphate M

LRRK2:

Leucine-rich repeat kinase 2 proteins

PTPN2:

Protein tyrosine phosphatase non-receptor type 2

HLA:

Human leukocyte antigen

Il23R:

Interleukin 23 receptor

Il10R:

Interleukin 10 receptor

VEO-IBD:

Very Early-Onset IBD

CDH1:

Cadherin 1

HNF4-α:

Hepatocyte nuclear factor 4-alpha

WGS:

Whole genome sequencing

WES:

Whole exome sequencing

References

  1. Ferguson LR, Shelling AN, Browning BL, Huebner C, Petermann I (2007) Genes, diet and inflammatory bowel disease. Mutat Res Mol Mech Mutagen 622(1–2):70–83

    CAS  Google Scholar 

  2. Harris KG, Chang EB (2018) The intestinal microbiota in the pathogenesis of inflammatory bowel diseases: new insights into complex disease. Clin Sci (Lond) 132(18):2013–2028

    CAS  Google Scholar 

  3. Zuo T, Kamm MA, Colombel J-F, Ng SC (2018) Urbanization and the gut microbiota in health and inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 15(7):440–452

    PubMed  Google Scholar 

  4. Ye Y, Pang Z, Chen W, Ju S, Zhou C (2015) The epidemiology and risk factors of inflammatory bowel disease. Int J Clin Exp Med 8(12):22529–22542

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Inflammatory bowel disease (IBD)—Symptoms and causes—Mayo Clinic [Internet]. https://www.mayoclinic.org/diseases-conditions/inflammatory-bowel-disease/symptoms-causes/syc-20353315. Accessed 21 Oct 2018

  6. Damman CJ, Miller SI, Surawicz CM, Zisman TL (2012) The microbiome and inflammatory bowel disease: is there a therapeutic role for fecal microbiota transplantation? Am J Gastroenterol 107(10):1452–1459

    PubMed  Google Scholar 

  7. Klein A, Eliakim R (2010) Non steroidal anti-inflammatory drugs and inflammatory bowel disease. Pharmaceuticals (Basel) 3(4):1084–1092

    CAS  Google Scholar 

  8. Khor B, Gardet A, Xavier RJ (2011) Genetics and pathogenesis of inflammatory bowel disease. Nature 474(7351):307–317

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Vavricka SR, Schoepfer A, Scharl M, Lakatos PL, Navarini A, Rogler G (2015) Extraintestinal manifestations of inflammatory bowel disease. Inflamm Bowel Dis 21(8):1982–1992

    PubMed  Google Scholar 

  10. Podolsky DK (2002) Inflammatory bowel disease. N Engl J Med 347(6):417–429

    CAS  PubMed  Google Scholar 

  11. Waugh N, Cummins E, Royle P, Kandala N-B, Shyangdan D, Arasaradnam R, Clar C, Johnston R (2013) Faecal calprotectin testing for differentiating amongst inflammatory and non-inflammatory bowel diseases: systematic review and economic evaluation. Health Technol Assess 17(55):xv–xix, 1–211

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Lichtenstein GR (2017) Depression and inflammatory bowel disease. Gastroenterol Hepatol (N Y) 13(3):143

    Google Scholar 

  13. Bannaga AS, Selinger CP (2015) Inflammatory bowel disease and anxiety: links, risks, and challenges faced. Clin Exp Gastroenterol 8:111–117

    PubMed  PubMed Central  Google Scholar 

  14. Desai D (2018) Psychiatric morbidity in inflammatory bowel disease: time to screen all the patients. Indian J Gastroenterol 37(4):281–283

    PubMed  Google Scholar 

  15. Santos MPC, Gomes C, Torres J (2018) Familial and ethnic risk in inflammatory bowel disease. Ann Gastroenterol 31(1):14–23

    PubMed  Google Scholar 

  16. Ananthakrishnan AN, Khalili H, Higuchi LM, Bao Y, Korzenik JR, Giovannucci EL et al (2012) Higher predicted vitamin D status is associated with reduced risk of Crohn’s disease. Gastroenterology 142(3):482–489

    CAS  PubMed  Google Scholar 

  17. Abegunde AT, Muhammad BH, Bhatti O, Ali T (2016) Environmental risk factors for inflammatory bowel diseases: evidence based literature review. World J Gastroenterol 22(27):6296–6317

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Khalili H (2016) Risk of inflammatory bowel disease with oral contraceptives and menopausal hormone therapy: current evidence and future directions. Drug Saf 39(3):193–197

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Kronman MP, Zaoutis TE, Haynes K, Feng R, Coffin SE (2012) Antibiotic exposure and IBD development among children: a population-based cohort study. Pediatrics 130(4):e794–803

    PubMed  PubMed Central  Google Scholar 

  20. Dolan KT, Chang EB (2017) Diet, gut microbes, and the pathogenesis of inflammatory bowel diseases. Mol Nutr Food Res 61(1):1600129

    Google Scholar 

  21. Ghaly S, Kaakoush NO, Lloyd F, McGonigle T, Mok D, Baird A et al (2018) High Dose Vitamin D supplementation alters faecal microbiome and predisposes mice to more severe colitis. Sci Rep 8(1):11511

    PubMed  PubMed Central  Google Scholar 

  22. Sardi C, Luchini P, Emanuelli A, Giannoni A, Martini E, Manara LM et al (2017) Three months of Western diet induces small intestinal mucosa alteration in TLR KO mice. Microsc Res Tech 80(6):563–569

    CAS  PubMed  Google Scholar 

  23. Imhann F, Vich Vila A, Bonder MJ, Fu J, Gevers D, Visschedijk MC et al (2018) Interplay of host genetics and gut microbiota underlying the onset and clinical presentation of inflammatory bowel disease. Gut 67(1):108–119

    CAS  PubMed  Google Scholar 

  24. Talley NJ, Abreu MT, Achkar J-P, Bernstein CN, Dubinsky MC, Hanauer SB et al (2011) An evidence-based systematic review on medical therapies for inflammatory bowel disease. Am J Gastroenterol 106:S2–S25

    CAS  PubMed  Google Scholar 

  25. Nell S, Suerbaum S, Josenhans C (2010) The impact of the microbiota on the pathogenesis of IBD: lessons from mouse infection models. Nat Rev Microbiol 8(8):564–577

    CAS  PubMed  Google Scholar 

  26. Knights D, Lassen KG, Xavier RJ (2013) Advances in inflammatory bowel disease pathogenesis: linking host genetics and the microbiome. Gut 62(10):1505–1510

    CAS  PubMed  Google Scholar 

  27. Stecher B (2015) The roles of inflammation, nutrient availability and the commensal microbiota in enteric pathogen infection. Microbiol Spectr. https://doi.org/10.1128/microbiolspec.MBP-0008-2014

    Article  PubMed  Google Scholar 

  28. Lane ER, Zisman TL, Suskind DL (2017) The microbiota in inflammatory bowel disease: current and therapeutic insights. J Inflamm Res 10:63–73

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Walker AW, Sanderson JD, Churcher C, Parkes GC, Hudspith BN, Rayment N et al (2011) 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 11(1):7

    PubMed  PubMed Central  Google Scholar 

  30. Manichanh C, Rigottier-Gois L, Bonnaud E, Gloux K, Pelletier E, Frangeul L et al (2006) Reduced diversity of faecal microbiota in Crohn’s disease revealed by a metagenomic approach. Gut 55(2):205–211

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Sokol H, Pigneur B, Watterlot L, Lakhdari O, Bermúdez-Humarán LG, Gratadoux JJ et al (2008) Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci USA 105(43):16731–16736

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Wright EK, Kamm MA, Teo SM, Inouye M, Wagner J, Kirkwood CD (2015) Recent advances in characterizing the gastrointestinal microbiome in Crohn’s disease: a systematic review. Inflamm Bowel Dis 21(6):1219–1228

    PubMed  Google Scholar 

  33. Khan RR, Lawson AD, Minnich LL, Martin K, Nasir A, Emmett MK et al (2009) Gastrointestinal norovirus infection associated with exacerbation of inflammatory bowel disease. J Pediatr Gastroenterol Nutr 48(3):328–333

    PubMed  Google Scholar 

  34. Cadwell K, Patel KK, Maloney NS, Liu TC, Ng ACY, Storer CE et al (2010) Virus-plus-susceptibility gene interaction determines crohn’s disease gene Atg16L1 phenotypes in intestine. Cell 141(7):1135–1145

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Li Q, Wang C, Tang C, He Q, Li N, Li J (2014) Dysbiosis of gut fungal microbiota is associated with mucosal inflammation in crohn’s disease. J Clin Gastroenterol 48(6):513–523

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Turpin W, Goethel A, Bedrani L, Croitoru K (2018) Determinants of IBD Heritability: genes, Bugs, and More. Inflamm Bowel Dis 24:1133–1148

    PubMed  PubMed Central  Google Scholar 

  37. Schippa S, Conte MP (2014) Dysbiotic events in gut microbiota: impact on human health. Nutrients 6:5786–5805

    PubMed  PubMed Central  Google Scholar 

  38. Matricon J, Barnich N, Ardid D (2010) Immunopathogenesis of inflammatory bowel disease. Self Nonself 1(4):299–309

    PubMed  PubMed Central  Google Scholar 

  39. Pedersen G (2015) Development, validation and implementation of an in vitro model for the study of metabolic and immune function in normal and inflamed human colonic epithelium. Dan Med J 62(1):B4973

    PubMed  Google Scholar 

  40. Geremia A, Biancheri P, Allan P, Corazza GR, Di Sabatino A (2014) Innate and adaptive immunity in inflammatory bowel disease. Autoimmun Rev 13(1):3–10

    CAS  PubMed  Google Scholar 

  41. MacDermoit RP (1996) Alterations of the mucosal immune system in inflammatory bowel disease. J Gastroenterol 31(6):907–916

    Google Scholar 

  42. Kim DH, Cheon JH (2017) Pathogenesis of inflammatory bowel disease and recent advances in biologic therapies. Immune Netw 17(1):25–40

    PubMed  PubMed Central  Google Scholar 

  43. Abraham C, Cho JH (2009) Inflammatory bowel disease. N Engl J Med 361(21):2066–2078

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Campos N, Magro F, Castro AR, Cabral J, Rodrigues P, Silva R et al (2011) Macrophages from IBD patients exhibit defective tumour necrosis factor-α secretion but otherwise normal or augmented pro-inflammatory responses to infection. Immunobiology 216(8):961–970

    CAS  PubMed  Google Scholar 

  45. Vazeille E, Buisson A, Bringer M-A, Goutte M, Ouchchane L, Hugot J-P et al (2015) Monocyte-derived Macrophages from Crohn’s disease patients are impaired in the ability to control intracellular adherent-invasive Escherichia coli and exhibit disordered cytokine secretion profile. J Crohn’s Colitis 9(5):410–420

    Google Scholar 

  46. Smith AM, Rahman FZ, Hayee B, Graham SJ, Marks DJB, Sewell GW et al (2009) Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn’s disease. J Exp Med 206(9):1883–1897

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Sanchez-Munoz F, Dominguez-Lopez A, Yamamoto-Furusho J-K (2008) Role of cytokines in inflammatory bowel disease. World J Gastroenterol 14(27):4280–4288

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Hart AL, Al-Hassi HO, Rigby RJ, Bell SJ, Emmanuel AV, Knight SC et al (2005) Characteristics of intestinal dendritic cells in inflammatory bowel diseases. Gastroenterology 129(1):50–65

    CAS  PubMed  Google Scholar 

  49. Steinbach EC, Plevy SE (2014) The role of macrophages and dendritic cells in the initiation of inflammation in IBD. Inflamm Bowel Dis 20(1):166–175

    PubMed  Google Scholar 

  50. Baumgart DC, Carding SR (2007) Inflammatory bowel disease: cause and immunobiology. Lancet 369(9573):1627–1640

    CAS  PubMed  Google Scholar 

  51. Cho JH, Brant SR (2011) Recent insights into the genetics of inflammatory bowel disease. Gastroenterology 140(6):1704–1712

    CAS  PubMed  Google Scholar 

  52. Niess JH (2008) Role of mucosal dendritic cells in inflammatory bowel disease. World J Gastroenterol 14(33):5138–5148

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Lord JD (2015) Promises and paradoxes of regulatory T cells in inflammatory bowel disease. World J Gastroenterol 21(40):11236

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Műzes G, Molnár B, Sipos F (2012) Regulatory T cells in inflammatory bowel diseases and colorectal cancer. World J Gastroenterol 18(40):5688

    PubMed  PubMed Central  Google Scholar 

  55. Yamada A, Arakaki R, Saito M, Tsunematsu T, Kudo Y, Ishimaru N (2016) Role of regulatory T cell in the pathogenesis of inflammatory bowel disease. World J Gastroenterol 22(7):2195–2205

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Ishikawa D, Okazawa A, Corridoni D, Jia LG, Wang XM, Guanzon M et al (2013) Tregs are dysfunctional in vivo in a spontaneous murine model of Crohn’s disease. Mucosal Immunol 6(2):267–275

    CAS  PubMed  Google Scholar 

  57. Badr-El-Din S, Trejdosiewicz LK, Heatley RV, Losowsky MS (1988) Local immunity in ulcerative colitis: evidence for defective secretory IgA production. Gut 29(8):1070–1075

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Macpherson A, Khoo UY, Forgacs I, Philpott-Howard J, Bjarnason I (1996) Mucosal antibodies in inflammatory bowel disease are directed against intestinal bacteria. Gut 38(3):365–375

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Coskun M (2014) Intestinal epithelium in inflammatory bowel disease. Front Med 1:24

    Google Scholar 

  60. Naser SA, Arce M, Khaja A, Fernandez M, Naser N, Elwasila S et al (2012) Role of ATG16L, NOD2 and IL23R in Crohn’s disease pathogenesis. World J Gastroenterol 18(5):412–424

    CAS  PubMed  PubMed Central  Google Scholar 

  61. White JR, Phillips F, Monaghan T, Fateen W, Samuel S, Ghosh S et al (2018) Review article: novel oral-targeted therapies in inflammatory bowel disease. Aliment Pharmacol Ther 47(12):1610–1622

    CAS  PubMed  Google Scholar 

  62. Coskun M, Vermeire S, Nielsen OH (2017) Novel targeted therapies for inflammatory bowel disease. Trends Pharmacol Sci 38(2):127–142

    CAS  PubMed  Google Scholar 

  63. Ye BD, McGovern DPB (2016) Genetic variation in IBD: progress, clues to pathogenesis and possible clinical utility. Expert Rev Clin Immunol 12(10):1091–1107

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Loddo I, Romano C (2015) Inflammatory bowel disease: genetics, epigenetics, and pathogenesis. Front Immunol 6:551

    PubMed  PubMed Central  Google Scholar 

  65. Liu JZ, van Sommeren S, Huang H, Ng SC, Alberts R, Takahashi A et al (2015) Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet 47(9):979–986

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Bianco AM, Girardelli M, Tommasini A (2015) Genetics of inflammatory bowel disease from multifactorial to monogenic forms. World J Gastroenterol 21(43):12296–12310

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Iida T, Yokoyama Y, Wagatsuma K, Hirayama D, Nakase H (2018) Impact of autophagy of innate immune cells on inflammatory bowel disease. Cells 8(1):7

    PubMed Central  Google Scholar 

  68. Prescott NJ, Lehne B, Stone K, Lee JC, Taylor K, Knight J et al (2015) Pooled sequencing of 531 genes in inflammatory bowel disease identifies an associated rare variant in BTNL2 and implicates other immune related genes. PLoS Genet 11(2):e1004955

    PubMed  PubMed Central  Google Scholar 

  69. Ponder A, Long MD (2013) A clinical review of recent findings in the epidemiology of inflammatory bowel disease. Clin Epidemiol 5:237–247

    PubMed  PubMed Central  Google Scholar 

  70. Saxena A, Lopes F, Poon KKH, McKay DM (2017) Absence of the NOD2 protein renders epithelia more susceptible to barrier dysfunction due to mitochondrial dysfunction. Am J Physiol Liver Physiol 313(1):G26–38

    Google Scholar 

  71. Uniken Venema WT, Voskuil MD, Dijkstra G, Weersma RK, Festen EA (2017) The genetic background of inflammatory bowel disease: from correlation to causality. J Pathol 241(2):146–158

    PubMed  Google Scholar 

  72. Negroni A, Pierdomenico M, Cucchiara S, Stronati L (2018) NOD2 and inflammation: current insights. J Inflamm Res 11:49–60

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Caruso R, Warner N, Inohara N, Núñez G (2014) NOD1 and NOD2: signaling, host defense, and inflammatory disease. Immunity 41(6):898–908

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Wehkamp J, Salzman NH, Porter E, Nuding S, Weichenthal M, Petras RE et al (2005) Reduced paneth cell -defensins in ileal Crohn’s disease. Proc Natl Acad Sci 102(50):18129–18134

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Wehkamp J, Harder J, Weichenthal M, Schwab M, Schäffeler E, Schlee M et al (2004) NOD2 (CARD15) mutations in Crohn’s disease are associated with diminished mucosal-defensin expression. Gut 53(11):1658–1664

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Salem M, Seidelin JB, Eickhardt S, Alhede M, Rogler G, Nielsen OH (2015) Species-specific engagement of human nucleotide oligomerization domain 2 (NOD)2 and Toll-like receptor (TLR) signalling upon intracellular bacterial infection: role of Crohn’s associated NOD2 gene variants. Clin Exp Immunol 179(3):426–434

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Cadwell K, Liu JY, Brown SL, Miyoshi H, Loh J, Lennerz JK et al (2008) A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature [Internet] 456(7219):259–263

    CAS  Google Scholar 

  78. Salas A, Panés J (2009) Defects in autophagy induce alterations in the secretory pathway and proinflammatory signaling of paneth cells. Gastroenterology 137(4):1527–1529

    PubMed  Google Scholar 

  79. Salem M, Ammitzboell M, Nys K, Seidelin JB, Nielsen OH (2015) ATG16L1: a multifunctional susceptibility factor in Crohn disease. Autophagy 11(4):585–594

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Yin H, Wu H, Chen Y, Zhang J, Zheng M, Chen G et al (2018) The therapeutic and pathogenic role of autophagy in autoimmune diseases. Front Immunol 9:1512

    PubMed  PubMed Central  Google Scholar 

  81. Cadwell K (2016) Crosstalk between autophagy and inflammatory signalling pathways: balancing defence and homeostasis. Nat Rev Immunol 16(11):661–675

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Dikic I, Elazar Z (2018) Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol 19(6):349–364

    CAS  PubMed  Google Scholar 

  83. Mizushima N (2007) Autophagy: process and function. Genes Dev 21(22):2861–2873

    CAS  PubMed  Google Scholar 

  84. Campoy E, Colombo MI (2009) Autophagy in intracellular bacterial infection. Biochim Biophys Acta - Mol Cell Res 1793(9):1465–1477

    CAS  Google Scholar 

  85. Glick D, Barth S, Macleod KF (2010) Autophagy: cellular and molecular mechanisms. J Pathol 221(1):3–12

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Kabat AM, Harrison OJ, Riffelmacher T, Moghaddam AE, Pearson CF, Laing A et al (2016) The autophagy gene Atg16l1 differentially regulates Treg and TH2 cells to control intestinal inflammation. Elife 5:e12444

    PubMed  PubMed Central  Google Scholar 

  87. Fowler EV, Doecke J, Simms LA, Zhao ZZ, Webb PM, Hayward NK et al (2008) ATG16L1 T300A shows strong associations with disease subgroups in a large australian IBD population: further support for significant disease heterogeneity. Am J Gastroenterol 103(10):2519–2526

    CAS  PubMed  Google Scholar 

  88. Iida T, Onodera K, Nakase H (2017) Role of autophagy in the pathogenesis of inflammatory bowel disease. World J Gastroenterol 23(11):1944–1953

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Prescott NJ, Fisher SA, Franke A, Hampe J, Onnie CM, Soars D et al (2007) A nonsynonymous SNP in ATG16L1 predisposes to ileal Crohn’s disease and is independent of CARD15 and IBD5. Gastroenterology 132(5):1665–1671

    CAS  PubMed  Google Scholar 

  90. Glas J, Konrad A, Schmechel S, Dambacher J, Seiderer J, Schroff F et al (2008) The ATG16L1 Gene Variants rs2241879 and rs2241880 (T300A) Are strongly associated with susceptibility to crohn’s disease in the german population. Am J Gastroenterol 103(3):682–691

    CAS  PubMed  Google Scholar 

  91. Van Limbergen J, Radford-Smith G, Satsangi J (2014) Advances in IBD genetics. Nat Rev Gastroenterol Hepatol 11(6):372–385

    PubMed  Google Scholar 

  92. Takagawa T, Kitani A, Fuss I, Levine B, Brant SR, Peter I et al (2018) An increase in LRRK2 suppresses autophagy and enhances Dectin-1-induced immunity in a mouse model of colitis. Sci Transl Med 10(444):eaan8162

    PubMed  PubMed Central  Google Scholar 

  93. Takagawa T, Nakamura S, Fuss IJ, Strober W (2016) Su1890 LRRK2, a susceptibility gene of IBD suppresses autophagy through beclin-1 inactivation. Gastroenterology 150(4):S581

    Google Scholar 

  94. Chauhan S, Mandell MA, Deretic V (2015) IRGM governs the core autophagy machinery to conduct antimicrobial defense. Mol Cell 58(3):507–521

    CAS  PubMed  PubMed Central  Google Scholar 

  95. McCarroll SA, Huett A, Kuballa P, Chilewski SD, Landry A, Goyette P et al (2008) Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn’s disease. Nat Genet 40(9):1107–1112

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Prescott NJ, Dominy KM, Kubo M, Lewis CM, Fisher SA, Redon R et al (2010) Independent and population-specific association of risk variants at the IRGM locus with Crohn’s disease. Hum Mol Genet 19(9):1828–1839

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Spalinger MR, McCole DF, Rogler G, Scharl M (2016) Protein tyrosine phosphatase non-receptor type 2 and inflammatory bowel disease. World J Gastroenterol 22(3):1034

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Scharl M, Wojtal KA, Becker HM, Fischbeck A, Frei P, Arikkat J et al (2012) Protein tyrosine phosphatase nonreceptor type 2 regulates autophagosome formation in human intestinal cells. Inflamm Bowel Dis 18(7):1287–1302

    PubMed  Google Scholar 

  99. Spalinger MR, McCole DF, Rogler G, Scharl M (2015) Role of protein tyrosine phosphatases in regulating the immune system. Inflamm Bowel Dis 21(3):645–655

    PubMed  Google Scholar 

  100. Scharl M, Rogler G (2012) The role for protein tyrosine phosphatase nonreceptor type 2 in regulating autophagosome formation. Ann N Y Acad Sci 1257(1):93–102

    CAS  PubMed  Google Scholar 

  101. Spalinger MR, Manzini R, Hering L, Riggs JB, Gottier C, Lang S et al (2018) PTPN2 regulates inflammasome activation and controls onset of intestinal inflammation and colon cancer. Cell Rep 22(7):1835–1848

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Scharl M, Mwinyi J, Fischbeck A, Leucht K, Eloranta JJ, Arikkat J et al (2012) Crohnʼs disease-associated polymorphism within the PTPN2 gene affects muramyl-dipeptide-induced cytokine secretion and autophagy. Inflamm Bowel Dis 18(5):900–912

    PubMed  Google Scholar 

  103. Spalinger MR, Kasper S, Chassard C, Raselli T, Frey-Wagner I, Gottier C et al (2015) PTPN2 controls differentiation of CD4+ T cells and limits intestinal inflammation and intestinal dysbiosis. Mucosal Immunol 8(4):918–929

    CAS  PubMed  Google Scholar 

  104. Han B, Akiyama M, Kim K-K, Oh H, Choi H, Lee CH et al (2018) Amino acid position 37 of HLA-DRβ1 affects susceptibility to Crohn’s disease in Asians. Hum Mol Genet 27(22):3901–3910

    CAS  PubMed  Google Scholar 

  105. Mahdi BM (2015) Role of HLA typing on Crohn’s disease pathogenesis. Ann Med Surg 4(3):248–253

    Google Scholar 

  106. Venkateswaran S, Prince J, Cutler DJ, Marigorta UM, Okou DT, Prahalad S et al (2018) Enhanced contribution of HLA in pediatric onset ulcerative colitis. Inflamm Bowel Dis 24(4):829–838

    PubMed  PubMed Central  Google Scholar 

  107. Ahmad T, Marshall S-E, Jewell D (2006) Genetics of inflammatory bowel disease: the role of the HLA complex. World J Gastroenterol 12(23):3628–3635

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Arimura Y, Isshiki H, Onodera K, Nagaishi K, Yamashita K, Sonoda T et al (2014) Characteristics of Japanese inflammatory bowel disease susceptibility loci. J Gastroenterol 49(8):1217–1230

    PubMed  Google Scholar 

  109. McGovern D, Powrie F (2007) The IL23 axis plays a key role in the pathogenesis of IBD. Gut 56(10):1333–1336

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Peng L-L, Wang Y, Zhu F-L, Xu W-D, Ji X-L, Ni J (2017) IL-23R mutation is associated with ulcerative colitis: a systemic review and meta-analysis. Oncotarget 8(3):4849–4863

    PubMed  Google Scholar 

  111. Xu W-D, Xie Q-B, Zhao Y, Liu Y (2016) Association of Interleukin-23 receptor gene polymorphisms with susceptibility to Crohn’s disease: a meta-analysis. Sci Rep 5(1):18584

    Google Scholar 

  112. Liu Z, Yadav PK, Xu X, Su J, Chen C, Tang M et al (2011) The increased expression of IL-23 in inflammatory bowel disease promotes intraepithelial and lamina propria lymphocyte inflammatory responses and cytotoxicity. J Leukoc Biol 89(4):597–606

    CAS  PubMed  Google Scholar 

  113. Kobayashi T, Okamoto S, Hisamatsu T, Kamada N, Chinen H, Saito R et al (2008) IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn’s disease. Gut 57(12):1682–1689

    CAS  PubMed  Google Scholar 

  114. Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ et al (2006) A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314(5804):1461–1463

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Bilsborough J, Targan SR, Snapper SB (2016) Therapeutic targets in inflammatory bowel disease: current and future. Am J Gastroenterol Suppl 3(3):27–37

    CAS  Google Scholar 

  116. Sands BE, Chen J, Feagan BG, Penney M, Rees WA, Danese S et al (2017) Efficacy and safety of MEDI2070, an antibody against interleukin 23, in patients with moderate to severe crohn’s disease: a phase 2a study. Gastroenterology 153(1):77–86.e6

    CAS  PubMed  Google Scholar 

  117. Feagan BG, Sandborn WJ, D’Haens G, Panés J, Kaser A, Ferrante M et al (2017) Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn’s disease: a randomised, double-blind, placebo-controlled phase 2 study. Lancet 389(10080):1699–1709

    CAS  PubMed  Google Scholar 

  118. Lin Z, Wang Z, Hegarty JP, Lin TR, Wang Y, Deiling S et al (2017) Genetic association and epistatic interaction of the interleukin-10 signaling pathway in pediatric inflammatory bowel disease. World J Gastroenterol 23(27):4897–4909

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Kotlarz D, Beier R, Murugan D, Diestelhorst J, Jensen O, Boztug K et al (2012) Loss of Interleukin-10 Signaling and Infantile Inflammatory Bowel Disease: implications for Diagnosis and Therapy. Gastroenterology 143(2):347–355

    CAS  PubMed  Google Scholar 

  120. Uhlig HH, Schwerd T, Koletzko S, Shah N, Kammermeier J, Elkadri A et al (2014) The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology 147(5):990–1007.e3

    PubMed  Google Scholar 

  121. Saraiva M, O’Garra A (2010) The regulation of IL-10 production by immune cells. Nat Rev Immunol 10(3):170–181

    CAS  PubMed  Google Scholar 

  122. Glocker E-O, Kotlarz D, Boztug K, Gertz EM, Schäffer AA, Noyan F et al (2009) Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med 361(21):2033–2045

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Kühn R, Löhler J, Rennick D, Rajewsky K, Müller W (1993) Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75(2):263–274

    PubMed  Google Scholar 

  124. Shouval DS, Biswas A, Goettel JA, McCann K, Conaway E, Redhu NS et al (2014) Interleukin-10 Receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function. Immunity 40(5):706–719

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Moran CJ, Klein C, Muise AM, Snapper SB (2015) Very early-onset inflammatory bowel disease: gaining insight through focused discovery. Inflamm Bowel Dis 21(5):1166–1175

    PubMed  Google Scholar 

  126. McCole DF (2014) IBD candidate genes and intestinal barrier regulation. Inflamm Bowel Dis 20(10):1829–1849

    PubMed  Google Scholar 

  127. Muise AM, Walters TD, Glowacka WK, Griffiths AM, Ngan B-Y, Lan H et al (2009) Polymorphisms in E-cadherin (CDH1) result in a mis-localised cytoplasmic protein that is associated with Crohn’s disease. Gut 58(8):1121–1127

    CAS  PubMed  Google Scholar 

  128. van Sommeren S, Visschedijk MC, Festen EAM, de Jong DJ, Ponsioen CY, Wijmenga C et al (2011) HNF4α and CDH1 are associated with ulcerative colitis in a Dutch cohort. Inflamm Bowel Dis 17(8):1714–1718

    PubMed  Google Scholar 

  129. Barrett JC, Lee JC, Lees CW, Prescott NJ, Anderson CA, Phillips A et al (2009) Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region. Nat Genet 41(12):1330–1334

    CAS  PubMed  Google Scholar 

  130. Babeu J-P, Boudreau F (2014) Hepatocyte nuclear factor 4-alpha involvement in liver and intestinal inflammatory networks. World J Gastroenterol 20(1):22–30

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Battle MA, Konopka G, Parviz F, Gaggl AL, Yang C, Sladek FM et al (2006) Hepatocyte nuclear factor 4alpha orchestrates expression of cell adhesion proteins during the epithelial transformation of the developing liver. Proc Natl Acad Sci USA 103(22):8419–8424

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Chellappa K, Deol P, Evans JR, Vuong LM, Chen G, Briançon N et al (2016) Opposing roles of nuclear receptor HNF4α isoforms in colitis and colitis-associated colon cancer. Elife 5:e10903

    PubMed  PubMed Central  Google Scholar 

  133. Parkes M, Barrett JC, Prescott NJ, Tremelling M, Anderson CA, Fisher SA et al (2007) Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn’s disease susceptibility. Nat Genet 39(7):830–832

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Hui KY, Fernandez-Hernandez H, Hu J, Schaffner A, Pankratz N, Hsu N-Y et al (2018) Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease. Sci Transl Med 10(423):eaai7795

    PubMed  PubMed Central  Google Scholar 

  135. Wellcome Trust Case Control Consortium TWTCC (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447(7145):661–678

    Google Scholar 

  136. Glas J, Wagner J, Seiderer J, Olszak T, Wetzke M, Beigel F et al (2012) PTPN2 gene variants are associated with susceptibility to both Crohn’s disease and ulcerative colitis supporting a common genetic disease background. PLoS ONE 7(3):e33682

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Zhu H, Lei X, Liu Q, Wang Y (2013) Interleukin-10-1082A/G polymorphism and inflammatory bowel disease susceptibility: a meta-analysis based on 17,585 subjects. Cytokine 61(1):146–153

    CAS  PubMed  Google Scholar 

  138. Moran CJ, Walters TD, Guo C-H, Kugathasan S, Klein C, Turner D et al (2013) IL-10R polymorphisms are associated with very-early-onset ulcerative colitis. Inflamm Bowel Dis 19(1):115–123

    PubMed  Google Scholar 

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  1. Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Cairo Street, Beirut, Lebanon

    Nour Younis, Rana Zarif & Rami Mahfouz

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  1. Nour Younis
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NY and RZ were involved in the major literature search and write-up of manuscript. RM edited the final version of the manuscript.

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Younis, N., Zarif, R. & Mahfouz, R. Inflammatory bowel disease: between genetics and microbiota. Mol Biol Rep 47, 3053–3063 (2020). https://doi.org/10.1007/s11033-020-05318-5

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