Difference in Pathomechanism Between Crohn's Disease and Ulcerative Colitis Revealed by Colon Transcriptome.

BACKGROUND We aim to identify the differences in colonic mucosal transcriptome between Crohn's disease (CD) and ulcerative colitis (UC) for a better understanding of the molecular pathology. METHODS Differentially expressed genes (DEG) in the colonic mucosa of CD and UC were identified with a global gene expression microarray dataset generated from the colon biopsies of CD and UC patients and normal controls. The DEGs were then processed to identify altered pathways and modularized DEGs and pathways. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis with an independent cohort of samples was performed to validate the microarray data. RESULTS At the pathway level, virus infection and autoimmune pathways were upregulated in CD but not in UC when compared with controls. Some of the relevant DEGs (such as TAP1 and TAP2) were elevated in both CD and UC, with CD exhibiting more pronounced elevations. Gene expression levels in viral infection pathways were correlated with those of autoimmune pathways. In contrast, pattern recognition-mediated innate immune pathways (TLR4 and TLR2) were significantly elevated in UC but not in CD. Similar results were observed with an independent cohort by qRT-PCR. CONCLUSIONS Our data support the hypothesis that viral infection induced autoimmunity may represent a pathomechanism for IBD, especially CD. However, pattern recognition-mediated innate immunity targeting microbiome may play a more important role in UC compared with CD. Our findings identified different intervention targets for CD and UC, which may lead to more effective treatments for IBD patients.

[1]  M. Kamm,et al.  Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial , 2017, The Lancet.

[2]  J. Raes,et al.  Donor Species Richness Determines Faecal Microbiota Transplantation Success in Inflammatory Bowel Disease. , 2016, Journal of Crohn's & colitis.

[3]  Isabelle Cleynen,et al.  Strong Upregulation of AIM2 and IFI16 Inflammasomes in the Mucosa of Patients with Active Inflammatory Bowel Disease , 2015, Inflammatory bowel diseases.

[4]  Judy H. Cho,et al.  Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations , 2015, Nature Genetics.

[5]  M. Surette,et al.  Fecal Microbiota Transplantation Induces Remission in Patients With Active Ulcerative Colitis in a Randomized Controlled Trial. , 2015, Gastroenterology.

[6]  Abha Kaistha,et al.  Inflammatory bowel disease: the classic gastrointestinal autoimmune disease. , 2014, Current problems in pediatric and adolescent health care.

[7]  A. Kittai,et al.  Herpes simplex virus blepharitis in a patient with Crohn's colitis. , 2014, The American journal of medicine.

[8]  T. Lee,et al.  Herpes simplex virus duodenitis accompanying Crohn's disease. , 2013, The Korean journal of gastroenterology = Taehan Sohwagi Hakhoe chi.

[9]  Xavier Llor,et al.  Identification of Novel Predictor Classifiers for Inflammatory Bowel Disease by Gene Expression Profiling , 2013, PloS one.

[10]  A. Gasbarrini,et al.  Gut Microbial Flora, Prebiotics, and Probiotics in IBD: Their Current Usage and Utility , 2013, BioMed research international.

[11]  Sergey Brin,et al.  Reprint of: The anatomy of a large-scale hypertextual web search engine , 2012, Comput. Networks.

[12]  Michael D. Kappelman,et al.  Recent Trends in the Prevalence of Crohn’s Disease and Ulcerative Colitis in a Commercially Insured US Population , 2012, Digestive Diseases and Sciences.

[13]  Guangchuang Yu,et al.  clusterProfiler: an R package for comparing biological themes among gene clusters. , 2012, Omics : a journal of integrative biology.

[14]  C. Lees,et al.  Guidelines for the management of inflammatory bowel disease in adults , 2011, Gut.

[15]  P. Rutgeerts,et al.  Mucosal Gene Expression of Cell Adhesion Molecules, Chemokines, and Chemokine Receptors in Patients With Inflammatory Bowel Disease Before and After Infliximab Treatment , 2011, The American Journal of Gastroenterology.

[16]  Kristel Van Steen,et al.  Predictive value of epithelial gene expression profiles for response to infliximab in Crohn's disease‡ , 2010, Inflammatory bowel diseases.

[17]  R. Xavier,et al.  Virus-Plus-Susceptibility Gene Interaction Determines Crohn's Disease Gene Atg16L1 Phenotypes in Intestine , 2010, Cell.

[18]  N. Nowak,et al.  Role of Alcohol Metabolism in Non-Alcoholic Steatohepatitis , 2010, PloS one.

[19]  Isabelle Cleynen,et al.  Mucosal Gene Expression of Antimicrobial Peptides in Inflammatory Bowel Disease Before and After First Infliximab Treatment , 2009, PloS one.

[20]  G Van Assche,et al.  Mucosal gene signatures to predict response to infliximab in patients with ulcerative colitis , 2009, Gut.

[21]  R. Baldassano,et al.  CD68 expression is markedly different in Crohn's disease and the colitis associated with chronic granulomatous disease , 2009, Inflammatory bowel diseases.

[22]  Vasyl Pihur,et al.  RankAggreg, an R package for weighted rank aggregation , 2009, BMC Bioinformatics.

[23]  R. Baldassano,et al.  Effect of a Probiotic Preparation (VSL#3) on Induction and Maintenance of Remission in Children With Ulcerative Colitis , 2009, The American Journal of Gastroenterology.

[24]  K. Faber,et al.  Runt‐related transcription factor 3 is associated with ulcerative colitis and shows epistasis with solute carrier family 22, members 4 and 5 , 2008, Inflammatory Bowel Diseases.

[25]  L. Arckens,et al.  Anti-alpha-enolase antibodies in patients with inflammatory Bowel disease. , 2008, Clinical chemistry.

[26]  R. Xavier,et al.  Unravelling the pathogenesis of inflammatory bowel disease , 2007, Nature.

[27]  A. Gasbarrini,et al.  Efficacy of Lactobacillus GG in maintaining remission of ulcerative colitis , 2006, Alimentary pharmacology & therapeutics.

[28]  Thomas Lengauer,et al.  Dissection of the Inflammatory Bowel Disease Transcriptome Using Genome-Wide cDNA Microarrays , 2005, PLoS medicine.

[29]  R. Bibiloni,et al.  VSL#3 Probiotic-Mixture Induces Remission in Patients with Active Ulcerative Colitis , 2005, The American Journal of Gastroenterology.

[30]  M. Kamm,et al.  Characteristics of intestinal dendritic cells in inflammatory bowel diseases. , 2005, Gastroenterology.

[31]  K. Laupland,et al.  Herpes simplex virus type II infection of ileum mesothelium: a case report and review of the literature. , 2005, Canadian journal of gastroenterology = Journal canadien de gastroenterologie.

[32]  M. Stolte,et al.  Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine , 2004, Gut.

[33]  Jean YH Yang,et al.  Bioconductor: open software development for computational biology and bioinformatics , 2004, Genome Biology.

[34]  C. Fiocchi,et al.  Inflammatory Bowel Disease: Autoimmune or Immune-mediated Pathogenesis? , 2004 .

[35]  Jide Wang,et al.  Effects of probiotic on intestinal mucosa of patients with ulcerative colitis. , 2004, World journal of gastroenterology.

[36]  M. Kamm,et al.  The dendritic cell: its role in intestinal inflammation and relationship with gut bacteria , 2003, Gut.

[37]  T. Borody,et al.  Treatment of Ulcerative Colitis Using Fecal Bacteriotherapy , 2003, Journal of clinical gastroenterology.

[38]  C. J. Taylor,et al.  Matrix metalloproteinase levels are elevated in inflammatory bowel disease. , 1999, Gastroenterology.

[39]  G. Löwhagen,et al.  PCR detection of Epstein-Barr virus, herpes simplex virus and human papillomavirus from the anal mucosa in HIV-seropositive and HIV-seronegative homosexual men , 1999, International journal of STD & AIDS.

[40]  L. Biancone,et al.  Tropomyosin isoforms in intestinal mucosa: production of autoantibodies to tropomyosin isoforms in ulcerative colitis. , 1998, Gastroenterology.

[41]  H Cantor,et al.  Molecular mimicry by herpes simplex virus-type 1: autoimmune disease after viral infection. , 1998, Science.

[42]  D. Sachar,et al.  The Role of the Fecal Stream in Crohn's Disease: An Historical and Analytic Review , 1998, Inflammatory bowel diseases.

[43]  J. Strominger,et al.  Molecular mimicry in T cell-mediated autoimmunity: Viral peptides activate human T cell clones specific for myelin basic protein , 1995, Cell.

[44]  R. Hammer,et al.  The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats , 1994, The Journal of experimental medicine.

[45]  P. Rutgeerts,et al.  Effect of faecal stream diversion on recurrence of Crohn's disease in the neoterminal ileum , 1991, The Lancet.

[46]  J. Nelson,et al.  Is herpes simplex virus associated with peptic ulcer disease? , 1990, Journal of virology.

[47]  J. Bennet,et al.  TREATMENT OF ULCERATIVE COLITIS BY IMPLANTATION OF NORMAL COLONIC FLORA , 1989, The Lancet.

[48]  P. Matricardi,et al.  Raised serum levels of IgM-rheumatoid factor and anti-F(ab')2 autoantibodies in patients with active inflammatory bowel disease. , 1986, Journal of clinical & laboratory immunology.

[49]  C. Fiocchi,et al.  Sensitization to epithelial antigens in chronic mucosal inflammatory disease. Characterization of human intestinal mucosa-derived mononuclear cells reactive with purified epithelial cell-associated components in vitro. , 1985, The Journal of clinical investigation.

[50]  K. Holmes,et al.  Herpes simplex virus proctitis in homosexual men. Clinical, sigmoidoscopic, and histopathological features. , 1983, The New England journal of medicine.

[51]  D. Goldmeier.  Proctitis and herpes simplex virus in homosexual men. , 1980, The British journal of venereal diseases.

[52]  Brock Dj,et al.  Letter: Prospective diagnosis of spina bifida. , 1975 .

[53]  P. Perlmann,et al.  AUTOANTIBODIES IN HUMAN ULCERATIVE COLITIS , 1959, The Journal of experimental medicine.

[54]  K. Rosenthal,et al.  A block in glycoprotein processing correlates with small plaque morphology and virion targetting to cell-cell junctions for an oral and an anal strain of herpes simplex virus type-1 , 2005, Archives of Virology.