Crohn’s disease (CD) and ulcerative colitis (UC), the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry with rising prevalence in other populations1. Genome-wide association studies (GWAS) and subsequent meta-analyses of CD and UC2,3 as separate phenotypes implicated previously unsuspected mechanisms, such as autophagy4, in pathogenesis and showed that some IBD loci are shared with other inflammatory diseases5. Here we expand knowledge of relevant pathways by undertaking a meta-analysis of CD and UC genome-wide association scans, with validation of significant findings in more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional and balancing selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe striking overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

The inflammatory bowel diseases Crohn's disease and ulcerative colitis are common, chronic disorders that cause abdominal pain, diarrhea, and gastrointestinal bleeding. To identify genetic factors that might contribute to these disorders, we performed a genome-wide association study.

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Chronic mucosal inflammation and tissue damage predisposes patients to the development of colorectal cancer (CRC)1. This association could be explained by the hypothesis that the same factors and pathways important for wound healing also promote tumorigenesis. A sensor of tissue damage should induce these factors to promote tissue repair and regulate their action to prevent development of cancer. IL-22, a cytokine of the IL-10 superfamily, plays an important role for colonic epithelial cell repair, and is increased in the blood and intestine of IBD patients2, 3. This cytokine can be neutralized by the soluble IL-22 receptor, known as the IL-22 binding protein (IL-22BP, IL-22RA2), however the significance of endogenous IL-22BP in vivo and the pathways that regulate this receptor are unknown4, 5. We describe herein that IL-22BP plays a crucial role in controlling tumorigenesis and epithelial cell proliferation in the colon. IL-22BP is highly expressed by dendritic cells (DC) in the colon in steady state conditions. Sensing of intestinal tissue damage via the NLRP3 or NLRP6 inflammasomes led to an IL-18-dependent down regulation of IL-22BP, thereby increasing the ratio of IL-22/IL-22BP. IL-22, which is induced during intestinal tissue damage, exerted protective properties during the peak of damage, but promoted tumor development if uncontrolled during the recovery phase.Thus the IL-22-IL-22BP axis critically regulates intestinal tissue repair and tumorigenesis in the colon.

The intestinal immune system defends against pathogens and entry of excessive intestinal microbes; simultaneously, a state of immune tolerance to resident intestinal microbes must be maintained. Perturbation of this balance is associated with intestinal inflammation in various mouse models and is thought to predispose humans to inflammatory bowel disease (IBD). The innate immune system senses microbes; dendritic cells, macrophages, and epithelial cells produce an initial, rapid response. The immune system continuously monitors resident microbiota and utilizes constitutive antimicrobial mechanisms to maintain immune homeostasis. associations between IBD and genes that regulate microbial recognition and innate immune pathways, such as nucleotide oligomerization domain 2 (Nod2), genes that control autophagy (eg, ATG16L1, IRGM), and genes in the interleukin-23–T helper cell 17 pathway indicate the important roles of host-microbe interactions in regulating intestinal immune homeostasis. There is increasing evidence that intestinal microbes influence host immune development, immune responses, and susceptibility to human diseases such as IBD, diabetes mellitus, and obesity. Conversely, host factors can affect microbes, which in turn modulate disease susceptibility. We review the cell populations and mechanisms that mediate interactions between host defense and tolerance and how the dysregulation of host-microbe interactions leads to intestinal inflammation and IBD.

Background & Aims-Inflammatory bowel disease (IBD) is a multifactorial disease thought to be caused by alterations in epithelial function, innate and adaptive immunity, and luminal microbiota. The specific role of epithelial barrier function remains undefined, although increased activity of intestinal epithelial myosin light chain kinase (MLCK), which is the primary mechanism of tumor necrosis factor (TNF)-induced barrier dysfunction, occurs in human IBD. We aimed to determine whether in an intact epithelium, primary dysregulation of the intestinal epithelial barrier by pathophysiologically relevant mechanisms can contribute to development of colitis.

Rotavirus, a leading cause of severe gastroenteritis and diarrhoea in young children, accounts for around 215,000 deaths annually worldwide1. Rotavirus specifically infects the intestinal epithelial cells in the host small intestine and has evolved strategies to antagonize interferon and NF-κB signalling2–5, raising the question as to whether other host factors participate in antiviral responses in intestinal mucosa. The mechanism by which enteric viruses are sensed and restricted in vivo, especially by NOD-like receptor (NLR) inflammasomes, is largely unknown. Here we uncover and mechanistically characterize the NLR Nlrp9b that is specifically expressed in intestinal epithelial cells and restricts rotavirus infection. Our data show that, via RNA helicase Dhx9, Nlrp9b recognizes short double-stranded RNA stretches and forms inflammasome complexes with the adaptor proteins Asc and caspase-1 to promote the maturation of interleukin (Il)-18 and gasdermin D (Gsdmd)-induced pyroptosis. Conditional depletion of Nlrp9b or other inflammasome components in the intestine in vivo resulted in enhanced susceptibility of mice to rotavirus replication. Our study highlights an important innate immune signalling pathway that functions in intestinal epithelial cells and may present useful targets in the modulation of host defences against viral pathogens.

BACKGROUND & AIMS Tight junction dysregulation and epithelial damage contribute to barrier loss in patients with inflammatory bowel disease (IBD). However, the mechanisms that regulate these processes and their relative contributions to disease pathogenesis are incompletely understood. We investigated these processes using colitis models in mice. METHODS We induced colitis by adoptive transfer of CD4+CD45RBhi cells or administration of dextran sulfate sodium (DSS) to mice, including those deficient in tumor necrosis factor receptor (TNFR) 1, TNFR2, or the long isoform of myosin light chain kinase (MLCK). Intestinal tissues and isolated epithelial cells were analyzed by immunoblot, immunofluorescence, ELISA, and real-time PCR assays. RESULTS Induction of immune-mediated colitis by CD4+CD45RBhi adoptive transfer increased intestinal permeability; epithelial expression of claudin-2, the long isoform of MLCK, and TNFR2 (but not TNFR1); and phosphorylation of the myosin II light chain (MLC). Long MLCK upregulation, MLC phosphorylation, barrier loss, and weight loss were attenuated in TNFR2−/−, but not TNFR1−/−, recipients of wildtype CD4+CD45RBhi cells. Similarly, long MLCK−/− mice had limited increases in MLC phosphorylation, claudin-2 expression, and intestinal permeability and delayed onset of cell transfer-induced colitis. However, coincident with onset of epithelial apoptosis, colitis ultimately developed. This indicates that disease progresses via apoptosis in the absence of MLCK-dependent tight junction regulation. In support of this conclusion, long MLCK−/− mice were not protected from epithelial apoptosis-mediated, damage-dependent DSS colitis. CONCLUSIONS In immune-mediated IBD models, TNFR2 signaling increases long MLCK expression, resulting in tight junction dysregulation, barrier loss and induction of colitis. At advanced stages, colitis progresses by apoptosis and mucosal damage that results in tight junction- and MLCK-independent barrier loss. Therefore, barrier loss in immune-mediated colitis occurs via two temporally and morphologically distinct mechanisms. Differential targeting of these mechanisms may lead to improved IBD therapies.