Inflammatory Bowel Disease and Colitis: New Concepts From the Bench and the Clinic
Séverine Vermeire; Gert Van Assche; Paul Rutgeerts
Curr Opin Gastroenterol. 2011;27(1):32-37. © 2011 Lippincott Williams & Wilkins
Abstract and Introduction
Abstract
Purpose of review The previous 18 months have shown important progress in unravelling the causes of inflammatory bowel disease (IBD) and in improving its management for the patients.
Recent findings More genome-wide association studies and meta-analyses of these have been published and have identified more than 100 confirmed genes for IBD, and highlighted a number of novel pathways. Two of the genes, NOD2/CARD15 and the autophagy gene ATG16L1 have recently been linked into one functional pathway of bacterial sensing, invasion and elimination. From the clinical side, the previous year has been dominated mainly by the results of the SONIC study, comparing efficacy and safety of azathioprine, infliximab and the combination of azathioprine and infliximab, in patients with active Crohn's disease, naive to these drugs. International consensus guidelines on infection prevention were released last year by the European Crohn's and Colitis Organisation.
Summary The recent findings in IBD include the increasing number of IBD susceptibility genes, the demonstration that NOD2 and ATG16L1 are linked in one functional pathway and the role of IL-33/ST2 in colitis. From the bedside, the novelties have been the results of SONIC and selecting the right patient for intensified treatment with immunomodulators and anti-tumor necrosis factor, and appropriate counselling regarding risk of infections and vaccinations.
Introduction
The successful integration of basic, translational and clinical research for several years already has resulted in major advances in understanding Crohn's disease and ulcerative colitis. The last 18 months have again been characterized by several landmark studies from both bench as well as bedside. We have selected a number of studies in this overview with respect to their relevance for the patient with IBD and the treating physician.
Inflammatory Bowel Disease Pathogenesis: Gene–Environment Interactions
Since 2006, the technique of genome-wide association scanning (GWAS) has been applied in the hunt for the genes underlying complex diseases such as rheumatoid arthritis, psoriasis, hypertension, Crohn's disease and ulcerative colitis. Besides the multiple GWAS published in adult inflammatory bowel disease (IBD), a GWAS in early-onset IBD was performed on 3426 children and 11 963 genetically matched controls recruited through international collaborations in Europe and North America.[1] At least five new regions were identified, including 16p11 near the cytokine gene IL27, but also 22q12, 10q22, 2q37 and 19q13.11. A large proportion of loci previously implicated in adult-onset Crohn's disease and ulcerative colitis were also identified in pediatric-onset IBD, highlighting the close pathogenetic relationship between early-onset and adult-onset IBD. Given the increasing amount of GWAS data, an updated meta-analysis of the Crohn's disease GWAS scans and an ulcerative colitis meta-analysis were performed by the analysts of the International IBD Genetics Consortium and have brought the total number of confirmed IBD loci to more than 100. The results will be published soon.
IBD genetics has highlighted a number of important pathways. The pathway of bacterial sensing with the pattern recognition receptor NOD2/CARD15 is most known without doubt but also the pathway of autophagy has received a lot of attention following the discovery of IRGM and ATG16L1. Autophagy is a physiological process important for cellular homeostasis but has also a role in the defence against intracellular bacteria. Given that both NOD2 and ATG16L1 are implicated in defence against bacteria, researchers hypothesized that both pathways could be linked. Two independent studies were able to demonstrate this. Travassos et al. [2] showed that Nod1 and Nod2 are critical for the autophagy response to invasive bacteria by recruiting ATG16L1 to the plasma membrane at the bacterial entry site. In cells that were homozygous for the Crohn's disease-associated NOD2 fs1001insC mutation, ATG16L1 could not be recruited to the plasma membrane and encapsulation of invading bacteria by autophagosomes was impaired. The NOD2-mediated autophagy is also required for generation of MHC class II antigen-specific CD4+ T cell responses in dendritic cells as shown by Cooney et al. [3] Dendritic cells from Crohn's disease patients with NOD2 or ATG16L1 risk alleles are defective in autophagy induction, bacterial trafficking and antigen presentation. Both studies have therefore linked these two Crohn's disease-associated susceptibility genes in a single functional pathway and show defects in dendritic cells that could lead to bacterial persistence via impaired autophagy.
Despite the progress in the field of genetics, it is clear that only a small proportion of individuals carrying disease susceptibility genes will effectively develop overt Crohn's disease or ulcerative colitis. Studies on gene–environment interactions have been limited so far. Cadwell et al. [4••] demonstrated in a recent issue of Cell that an interaction between murine norovirus (MNV) infection and a mutation in the Atg16L1 gene induces intestinal inflammation in mice. Noroviruses are RNA viruses responsible for the majority of epidemic nonbacterial gastroenteritis in humans. In their study, Atg16L1HM mice infected with MNV for 1 week prior to dextran sulfate sodium treatment showed ileocolonic inflammation and anorectal abnormalities with transmural inflammation and fibrosis as observed in human Crohn's disease. This study shows how an infection triggers Paneth cell abnormalities and leads to persistent infection in genetically predisposed mice, and for the first time in IBD, shows how multiple hits or triggers may induce disease in susceptible organisms.
Séverine Vermeire; Gert Van Assche; Paul Rutgeerts
Curr Opin Gastroenterol. 2011;27(1):32-37. © 2011 Lippincott Williams & Wilkins
Abstract and Introduction
Abstract
Purpose of review The previous 18 months have shown important progress in unravelling the causes of inflammatory bowel disease (IBD) and in improving its management for the patients.
Recent findings More genome-wide association studies and meta-analyses of these have been published and have identified more than 100 confirmed genes for IBD, and highlighted a number of novel pathways. Two of the genes, NOD2/CARD15 and the autophagy gene ATG16L1 have recently been linked into one functional pathway of bacterial sensing, invasion and elimination. From the clinical side, the previous year has been dominated mainly by the results of the SONIC study, comparing efficacy and safety of azathioprine, infliximab and the combination of azathioprine and infliximab, in patients with active Crohn's disease, naive to these drugs. International consensus guidelines on infection prevention were released last year by the European Crohn's and Colitis Organisation.
Summary The recent findings in IBD include the increasing number of IBD susceptibility genes, the demonstration that NOD2 and ATG16L1 are linked in one functional pathway and the role of IL-33/ST2 in colitis. From the bedside, the novelties have been the results of SONIC and selecting the right patient for intensified treatment with immunomodulators and anti-tumor necrosis factor, and appropriate counselling regarding risk of infections and vaccinations.
Introduction
The successful integration of basic, translational and clinical research for several years already has resulted in major advances in understanding Crohn's disease and ulcerative colitis. The last 18 months have again been characterized by several landmark studies from both bench as well as bedside. We have selected a number of studies in this overview with respect to their relevance for the patient with IBD and the treating physician.
Inflammatory Bowel Disease Pathogenesis: Gene–Environment Interactions
Since 2006, the technique of genome-wide association scanning (GWAS) has been applied in the hunt for the genes underlying complex diseases such as rheumatoid arthritis, psoriasis, hypertension, Crohn's disease and ulcerative colitis. Besides the multiple GWAS published in adult inflammatory bowel disease (IBD), a GWAS in early-onset IBD was performed on 3426 children and 11 963 genetically matched controls recruited through international collaborations in Europe and North America.[1] At least five new regions were identified, including 16p11 near the cytokine gene IL27, but also 22q12, 10q22, 2q37 and 19q13.11. A large proportion of loci previously implicated in adult-onset Crohn's disease and ulcerative colitis were also identified in pediatric-onset IBD, highlighting the close pathogenetic relationship between early-onset and adult-onset IBD. Given the increasing amount of GWAS data, an updated meta-analysis of the Crohn's disease GWAS scans and an ulcerative colitis meta-analysis were performed by the analysts of the International IBD Genetics Consortium and have brought the total number of confirmed IBD loci to more than 100. The results will be published soon.
IBD genetics has highlighted a number of important pathways. The pathway of bacterial sensing with the pattern recognition receptor NOD2/CARD15 is most known without doubt but also the pathway of autophagy has received a lot of attention following the discovery of IRGM and ATG16L1. Autophagy is a physiological process important for cellular homeostasis but has also a role in the defence against intracellular bacteria. Given that both NOD2 and ATG16L1 are implicated in defence against bacteria, researchers hypothesized that both pathways could be linked. Two independent studies were able to demonstrate this. Travassos et al. [2] showed that Nod1 and Nod2 are critical for the autophagy response to invasive bacteria by recruiting ATG16L1 to the plasma membrane at the bacterial entry site. In cells that were homozygous for the Crohn's disease-associated NOD2 fs1001insC mutation, ATG16L1 could not be recruited to the plasma membrane and encapsulation of invading bacteria by autophagosomes was impaired. The NOD2-mediated autophagy is also required for generation of MHC class II antigen-specific CD4+ T cell responses in dendritic cells as shown by Cooney et al. [3] Dendritic cells from Crohn's disease patients with NOD2 or ATG16L1 risk alleles are defective in autophagy induction, bacterial trafficking and antigen presentation. Both studies have therefore linked these two Crohn's disease-associated susceptibility genes in a single functional pathway and show defects in dendritic cells that could lead to bacterial persistence via impaired autophagy.
Despite the progress in the field of genetics, it is clear that only a small proportion of individuals carrying disease susceptibility genes will effectively develop overt Crohn's disease or ulcerative colitis. Studies on gene–environment interactions have been limited so far. Cadwell et al. [4••] demonstrated in a recent issue of Cell that an interaction between murine norovirus (MNV) infection and a mutation in the Atg16L1 gene induces intestinal inflammation in mice. Noroviruses are RNA viruses responsible for the majority of epidemic nonbacterial gastroenteritis in humans. In their study, Atg16L1HM mice infected with MNV for 1 week prior to dextran sulfate sodium treatment showed ileocolonic inflammation and anorectal abnormalities with transmural inflammation and fibrosis as observed in human Crohn's disease. This study shows how an infection triggers Paneth cell abnormalities and leads to persistent infection in genetically predisposed mice, and for the first time in IBD, shows how multiple hits or triggers may induce disease in susceptible organisms.
