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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
N Engl J Med. Author manuscript; available in PMC 2012 November 7.
Published in final edited form as:
PMCID: PMC3491806

Inflammatory Bowel Disease

Clara Abraham, M.D. and Judy H. Cho, M.D.

The idiopathic inflammatory bowel diseases comprise two types of chronic intestinal disorders: Crohn’s disease and ulcerative colitis. Accumulating evidence suggests that inflammatory bowel disease results from an inappropriate inflammatory response to intestinal microbes in a genetically susceptible host. Genetic studies highlight the importance of host–microbe interactions in the pathogenesis of these diseases.1-13 Prominent among these genetic findings are genomic regions containing nucleotide oligomerization domain 2 (NOD2),14 autophagy genes,4,7,8,10 and components of the interleukin-23–type 17 helper T-cell (Th17) pathway.2 The NOD2 protein is an intracellular sensor of bacterial peptidoglycan, and autophagy enables cells to regulate and degrade diverse intracellular components, including pathogens.15 The autophagy gene, ATG16L1, has been associated with Crohn’s disease but not, thus far, with ulcerative colitis. The interleukin-23–Th17 pathway mediates microbial defense and intestinal inflammation.16,17 Multiple genes regulating this pathway have been associated with both Crohn’s disease and ulcerative colitis. This review summarizes recent progress in studies of intestinal immunity and genetics in inflammatory bowel disease.

Inflammatory bowel disease affects approximately 1.4 million Americans, and its peak onset is in persons 15 to 30 years of age.18 Crohn’s disease generally involves the ileum and colon, but it can affect any region of the intestine, often discontinuously. Ulcerative colitis involves the rectum and may affect part of the colon or the entire colon (pancolitis) in an uninterrupted pattern. In Crohn’s disease the inflammation is often transmural, whereas in ulcerative colitis the inflammation is typically confined to the mucosa. Crohn’s disease can be associated with intestinal granulomas, strictures, and fistulas, but these are not typical findings in ulcerative colitis. Cigarette smoking affects these two diseases differently: smokers are at increased risk for Crohn’s disease and tend to have more severe disease, whereas former smokers and nonsmokers are at greater risk for ulcerative colitis. Patients with inflammatory bowel disease are at risk for primary sclerosing cholangitis, ankylosing spondylitis, and psoriasis.19

Familial clustering of cases and twin studies have established a role for genetic factors, which are likely to play a more prominent role in Crohn’s disease than in ulcerative colitis.14 The observation that cases of both these diseases can occur within the same family suggests that some of the genes may be common to both disorders. As with other complex genetic disorders, inflammatory bowel disease entails the interaction of genetic and nongenetic factors. Changes in diet, antibiotic use, and intestinal colonization (e.g., the eradication of intestinal helminths) have probably contributed to the increased prevalence of inflammatory bowel disease during the past century.20,21

Our current knowledge of inflammatory bowel disease is based on a combination of gene association studies, clinical investigations, and laboratory experiments in mice. In this review, we first describe homeostasis of the intestinal immune system in health and then focus on advances in our understanding of how genetic alterations in this system contribute to the development of inflammatory bowel disease.

The Intestinal Immune System

The Intestinal Microbiome and Inflammatory Bowel Disease

The intestinal microbiome consists of the microorganisms that inhabit the gut. The intraluminal microbiota affects the development of the intestinal immune system, supplies key nutrients, and modulates energy metabolism.22 The intestinal microbiota is acquired at birth but changes rapidly during the first year of life. In adults, each person’s unique population of fecal microbiota is fairly stable over time, but fluctuations occur in response to environmental and developmental factors and in disease.21,23,24

Host–microbiome interactions can be mutually beneficial or can be deleterious, inciting intestinal inflammation. Observations in patients with inflammatory bowel disease and in animal models point to the role of bacteria in such inflammation. For example, antibiotics are effective in some patients with inflammatory bowel disease, and most mouse models of colitis require intestinal bacteria for inflammation to occur.25 Bacteria that can adhere to and invade the intestinal mucosa may be particularly important, as in the case of Escherichia coli.26 Although a number of specific pathogens have been incriminated in the development of inflammatory bowel disease, none have been confirmed as causal; rather, microbial antigens that are normally present in the intestinal lumen seem to drive inflammation in the gut. As compared with control subjects, patients with Crohn’s disease and those with ulcerative colitis have depletion and reduced diversity of members of the mucosa-associated phyla Firmicutes and Bacteroidetes.21,27 Whether these alterations contribute to the disease or merely reflect secondary changes caused by the inflammation is not known.

The Intestinal Epithelium

The intestinal epithelium at the interface between the intestinal microbiome and the lymphoid tissue associated with the gastrointestinal system plays a critical role in shaping the mucosal immune response. Intestinal epithelial cells are a physical barrier against excessive entry of bacteria and other antigens from the intestinal lumen into the circulation. An intact mucosal barrier depends on intercellular junctions, which help to seal the space between adjacent epithelial cells (the paracellular space), and tight junctions, which are the key elements of the seal.28 In inflammatory bowel disease, the paracellular space has increased permeability, and the regulation of tight junctions is defective.28 These abnormalities may be due to a primary defect in barrier function or may be an outcome of inflammation.28-32

Additional defenses against bacterial invasion consist of specialized epithelial cells, including goblet cells and Paneth cells. Goblet cells regulate the production of mucus and factors that contribute to epithelial repair and regulation of inflammation.33,34 Paneth cells secrete antimicrobial peptides such as α-defensins. Intestinal mucus overlies the epithelium, thereby limiting contact between bacteria and epithelial cells. Epithelial regeneration and repair serve to control and ultimately resolve the inflammatory response to injury. In inflammatory bowel disease, however, the inflammatory response often results in continued epithelial injury, which causes erosions, ulcerations, and a decrease in the production of defensin.35,36 The result is increased exposure to intestinal microbiota and amplification of the inflammatory response.

In mouse models of inflammatory bowel disease, several types of epithelial dysfunction can cause intestinal inflammation. These include defects in epithelial-cell development or proliferation, barrier function, cell-matrix adhesion, endoplasmic reticulum stress, and epithelial restitution after injury.28,37,38 Prostaglandin E receptor 4 (EP4) contributes to mucosal repair and barrier function; in mice that are deficient in EP4, the colitis that develops in response to chemical injury is more severe than that in wild-type animals.39 Polymorphisms in proximity to the gene encoding EP4 (PTGER4) were recently implicated in Crohn’s disease in humans6 (Table 1). In mice in which the gene encoding MUC2, a major mucin component, has been deleted, intestinal inflammation develops41; moreover, a variant in a genomic region that includes the gene encoding MUC19 has been associated with Crohn’s disease.2 Endoplasmic reticulum stress (a cellular response to various environmental changes) is increased in inflamed intestinal epithelial cells,42 and deletion from murine intestinal epithelium of the XBP1 gene, which encodes X-box binding protein 1, a key component of the endoplasmic reticulum stress response, results in inflammation in the small intestine.38

Table 1
Genetic Associations with Crohn’s Disease and Ulcerative Colitis.*

The Inflammatory Response in Inflammatory Bowel Disease

The intestinal lamina propria contains a complex population of immune cells that balance the requirement for immune tolerance of luminal microbiota with the need to defend against pathogens, the excessive entry of luminal microbiota, or both (Fig. 1 and and2A).2A). The hallmark of active inflammatory bowel disease is a pronounced infiltration into the lamina propria of innate immune cells (neutrophils, macrophages, dendritic cells, and natural killer T cells) and adaptive immune cells (B cells and T cells). Increased numbers and activation of these cells in the intestinal mucosa elevate local levels of tumor necrosis factor α (TNF-α), interleukin-1β, interferon-γ, and cytokines of the interleukin-23–Th17 pathway (Fig. 2B).

Figure 1
The Intestinal Immune System
Figure 2
The Intestinal Immune System in Health and Disease

The initial immune response to intestinal microbiota is tightly regulated, and this regulation determines whether immune tolerance or a defensive inflammatory response ensues. Disturbance of the balance of these responses can lead to inflammatory bowel disease: in mouse models, perturbation of the proteins essential to immune function can incite intestinal inflammation.25 In experimental colitis, some intestinal lymphocytes respond to microbial antigens, but the extent to which specific intestinal microbial antigens drive intestinal lymphocytes in inflammatory bowel disease is unknown.

Innate Immune Recognition

The innate arm of the immune system provides an initial, rapid response to microbes. Cells of the innate system display receptors that recognize general microbial patterns (pattern-recognition receptors), in contrast to antigen-specific recognition by receptors of the adaptive immune system. The intestinal epithelial layer expresses various types of innate immune receptors (Fig. 1) that mediate defenses against luminal microbiota but also condition epithelial and antigen-presenting cells for inducing the tolerance mechanisms that maintain immune homeostasis in the intestine.43-46 The expression of plasma-membrane toll-like receptors — either intracellularly or basolaterally — and the down-regulation of the expression and responses of pattern-recognition receptors limit activation of intestinal epithelial cells by luminal microbes.45,47-50

Continual sampling of intestinal microbiota is important in regulating the intestinal immune response. In laboratory animals, microbial sampling occurs by translocation of microbes across epithelial cells and the M cells of the epithelium of Peyer’s patches, by immunoglobulins,51 and by dendritic cells52,53 (Fig. 1). Activated antigen-presenting cells, notably dendritic cells, then present peptide antigens to T cells in secondary lymphoid organs of the gut, such as Peyer’s patches, mesenteric lymph nodes, and isolated lymphoid follicles54,55 (Fig. 1). This interaction initiates an adaptive immune response, after which memory lymphocytes develop. One characteristic of adaptive immunity is a rapid and robust response to subsequent challenge by antigen — that is, immunologic memory.

CD4+ T Cells

Certain helper T cells (Th1, Th2, and Th17) and regulatory T cells (e.g., forkhead box P3 [Foxp3+] Treg), which are subgroups of CD4+ T cells, secrete characteristic types of cytokines (Fig. 1). Regulation of these subgroups must be continually fine-tuned to maintain intestinal immune homeostasis.56,57 Effector subgroups (Th1, Th2, and Th17 cells) are critical for defenses against pathogens and excessive entry of luminal microbiota (Fig. 2A), but expansion and overactivity of these cells relative to the regulatory CD4+ T cells can lead to intestinal inflammation (Fig. 2B).25,57-64 Studies of inflammatory bowel disease in mice and humans implicate dysregulation of intestinal CD4+ T-cell subgroups in the pathogenesis of these diseases. In Crohn’s disease, for example, there is increased production in the intestinal mucosa of the Th17 cytokine interleukin-17 and the Th1 cytokines interferon-γ and TNF-α.60,65 In ulcerative colitis, by contrast, there is usually an increase in interleukin-17 and Th2 cytokines.60,65,66 The interleukin-23 pathway is central to the function of Th17 cells. Polymorphic variants of multiple genes involved in this pathway and in Th17 cell function have been associated with both Crohn’s disease and ulcerative colitis.2

B Cells

The role of B cells in inflammatory bowel disease has not been as extensively studied as that of T cells. Intestinal B cells produce IgA antibodies, which contribute to immune protection without provoking inflammation. In animal models of colitis, both antiinflammatory67 and proinflammatory68 roles of B cells have been described. The presence of circulating antimicrobial antibodies in patients with inflammatory bowel disease (e.g., anti-flagellin antibodies and anti–Saccharomyces cerevisiae antibodies)69 but not in healthy controls indicates B-cell reactivity.

Intestinal Vasculature and Leukocyte Migration

The intestinal vasculature and endothelium regulate the entry of leukocytes into the gut and maintain an adequate blood flow. Entry of cells into intestinal tissues is modulated by adhesion molecules (selectins, integrins) and chemokines (secreted cell attractants). T cells that become activated in mesenteric lymph nodes and Peyer’s patches become “gut-tropic” cells by expressing the integrin α4β7 and the chemokine receptor CCR970,71; this change requires retinoic acid.72 The relative specificity in cellular migration to the intestine is the basis for targeting these molecules for the treatment of inflammatory bowel disease.

An accumulation of leukocytes in intestinal tissues is characteristic of inflammatory bowel disease. Leukocyte adherence and recruitment are increased in the microvessels in chronic disease,73 mediated in part by up-regulation of adhesion molecules on vascular endothelial cells by TNF-α and interleukin-1. Moreover, increased levels of tissue-specific and inflammatory chemokines enhance leukocyte migration.74 Abnormalities in microvascular function probably contribute to inflammation, ischemia, and impaired mucosal healing.73 Ischemia causes local tissue hypoxia, which in turn regulates factors that contribute to both intestinal injury and protection.75,76

Innate-Immune-Response Genes and Crohn’s Disease

NOD2 and Crohn’s Disease

The importance of responses to intestinal bacteria in inflammatory bowel disease is highlighted by the association between Crohn’s disease and the NOD2 gene77 (Table 1), which encodes an intracellular sensor of peptidoglycan, a component in bacterial cell walls.78,79 The association includes three NOD2 polymorphisms that change the amino acids in NOD2, each impairing responses to peptidoglycan. These three polymorphisms occur with increased frequency in persons of European ancestry but are not present in Asian patients and are significantly less frequent in African Americans with Crohn’s disease.14 Approximately 30% of patients of European ancestry have at least one of the three polymorphisms. NOD2 carriers are more likely than noncarriers to have ileal involvement and complications related to fibrostenosis and to require intestinal resection.80 Heterozygosity for a polymorphism confers an increased risk of Crohn’s disease (by a factor of 1.75 to 4), whereas homozygosity confers a much greater risk (by a factor of 11 to 27)81; these are the highest relative risks observed for any of the genes associated with this disease. NOD2 polymorphisms alone, however, are not sufficient to cause Crohn’s disease, which is indicative of the complexities of a multifactorial disorder.

Epithelial cells, Paneth cells, macrophages, dendritic cells, and endothelial cells all express NOD2.77 The activation of the NOD2 protein by bacterial peptidoglycan activates the nuclear factor κB (NF-κB) and mitogen-activated protein (MAP) kinase signaling pathways, which leads to the production of cytokines (e.g., TNF and interleukin-1β) and antimicrobial peptides.77,82 Decreased secretion of proinflammatory cytokines and decreased activation of NF-κB on acute stimulation of NOD2 with bacterial peptidoglycan components have been detected in NOD2 carriers.77 Intestinal inflammation does not develop in NOD2-deficient mice, as is the case with most human NOD2 risk-allele carriers.82 Normally, secretion of proinflammatory cytokines by intestinal antigen-presenting cells is minimal,55,83 yet bacterial killing occurs, implying that the intestinal immune system can defend against luminal microbiota while minimizing tissue injury.83 In contrast, the gut in inflammatory bowel disease contains an increased number of antigen-presenting cells that secrete proinflammatory cytokines.84 Various factors within the intestinal environment contribute to the down-regulation of proinflammatory cytokines by intestinal antigen–presenting cells. These include inhibitory cytokines (transforming growth factor β [TGF-β] and interleukin-10) and chronic stimulation through pattern-recognition receptors, such as chronic peptidoglycan stimulation through NOD2.85,86 The NOD2-mediated mechanisms that down-regulate proinflammatory cytokines during chronic NOD2 stimulation are defective in carriers of genetic variants that impair NOD2 function.85 How loss-of-function NOD2 polymorphisms increase susceptibility to Crohn’s disease is unknown, but most likely this outcome reflects the myriad functions of NOD2 and the unique features of the intestinal environment.

Autophagy Genes and Crohn’s Disease

Associations with Crohn’s disease have been established for ATG16L1 and immunity-related GTPase M protein (IRGM)4,7,8,10 (Table 1), two genes involved in autophagy. Autophagy is a mechanism for clearing intracellular components, including organelles, apoptotic bodies, and microbes.15 In mice with low expression of ATG16L1, the morphologic features and gene expression of Paneth cells are abnormal.87 ATG16L1 carriers with Crohn’s disease also have abnormal Paneth-cell morphology.87 In mice, ATG16L1 appears to regulate secretion of interleukin-1β and inhibit intestinal inflammation.88

Adaptive Immunity and Inflammatory Bowel Disease

Alterations in T-Cell Tolerance

The inhibitory cytokines interleukin-10 and TGF-β in Peyer’s patches, mesenteric lymph nodes, and lamina propria are involved in T-cell tolerance in the intestine.25 Regulatory T cells can differentiate in Peyer’s patches and mesenteric lymph nodes through the actions of TGF-β and retinoic acid.89 Defects in the development and function of regulatory T cells, or alterations in the ability to respond to them, can result in intestinal inflammation in mice.56,90 The autophagy pathway contributes to T-cell tolerance at multiple levels, which suggests that polymorphisms of autophagy genes associated with Crohn’s disease could increase a patient’s susceptibility to intestinal inflammation through defects in T-cell tolerance.15,91 Moreover, there is a genetic association between the inhibitory cytokine interleukin-10 and ulcerative colitis.11 This association corresponds with animal models showing that interleukin-10 participates in down-regulating intestinal inflammation; for example, colitis and intestinal dysplasia develop spontaneously in interleukin-10–deficient mice.25 The central importance and sufficiency of defective interleukin-10 signaling in the mediation of intestinal inflammation are further highlighted by the finding that uncommon, recessive loss-of-function mutations in either the IL10RA or the IL10RB component of the interleukin-10 receptor result in Crohn’s disease.92

Th17 Cells and Interleukin-23 Signaling in Inflammatory Bowel Disease

Interleukin-23 signaling is mediated through the engagement of heterodimeric interleukin-23 (comprising p19 and p40 subunits) with its heterodimeric receptor (comprising interleukin-23R and interleukin-12RB1). The engagement activates the JAK-STAT (Janus-associated kinase–signal transducers and activators of transcription) signaling pathway, which regulates the transcription of several genes. The importance of interleukin-23 signaling in mediating inflammation has been shown in animal models.17,59,61,64,65,93 Moreover, reports of highly significant genetic associations between IL23R and inflammatory bowel disease,3 psoriasis,94 and ankylosing spondylitis95 indicate that inflammatory bowel disease shares genetic associations with certain other autoimmune diseases. Interleukin-23, secreted by macrophages and dendritic cells, may contribute to TR17 proliferation, survival, or both.96 Interleukin-23 also contributes to intestinal inflammation through Th17-independent pathways.93 Levels of interleukin-23 and Th17 cytokines are elevated in the colonic mucosa in both Crohn’s disease and ulcerative colitis.58,60,63

Multiple independent associations within the IL23R gene region have been found in inflammatory bowel disease, most notably for an Arg381Gln variant of the gene: carriers of this uncommon glutamine allele are less likely to have inflammatory bowel disease, by a factor of 2 to 3, than persons who carry only the common arginine allele.3 The effect of the IL23R polymorphisms on interleukin-23R function has not been defined. In addition to IL23R, associations with Crohn’s disease have been observed in genomic regions encompassing multiple genes involved in interleukin-23–Th17 signaling2 (Fig. 2 and Table 1).

Comparative Gene Association Studies in Crohn’s Disease and Ulcerative Colitis

It is estimated that known genetic associations account for only about 20% of the genetic variance underlying susceptibility to inflammatory bowel disease; the remaining genetic factors have not been identified. Consistent with predictions inferred from epidemiologic studies, genomewide association studies have identified loci associated solely with Crohn’s disease or ulcerative colitis and other loci associated with both disorders (Table 1). For example, multiple genes along the interleukin-23 signaling pathway — notably IL23R, JAK2, STAT3, and p40 — have been associated with both these diseases.2,11,40,97 Genomic associations with Crohn’s disease alone include NOD2 and the autophagy gene, ATG16L1,2 but a number of well-powered studies have not shown associations between these genes and ulcerative colitis. Given the broad functional contributions of autophagy, a more general role in either Crohn’s disease or ulcerative colitis may eventually be established. Significant associations between ulcerative colitis and a region on chromosome 12q15 encompassing the interferon-γ and interleukin-26 genes have been observed, but no such associations with Crohn’s disease have thus far been reported.40 In the initial genomewide association studies in ulcerative colitis, a highly significant association was observed for a common polymorphism in a region on chromosome 1q32 containing the IL10 gene, with only a very modest association observed in Crohn’s disease.11 However, the intriguing finding that complete, loss-of-function mutations in the interleukin-10 receptor92 result in a Crohn’s disease–predominant phenotype highlights the complex phenotypic overlap between these two diseases.

Associations within the major histocompatibility complex class II region near HLA-DRA (alpha chain) are the most significant observed in genomewide association studies of ulcerative colitis.11,40,97 Distinct HLA-DRB1 (beta-chain) alleles have been associated with both diseases.97

Therapeutic Implications

Treatment of inflammatory bowel disease includes lifestyle alterations (e.g., smoking cessation for patients with Crohn’s disease), medical management, and surgical interventions. A seminal advance was the introduction of treatment with an anti–TNF-α monoclonal antibody, which is particularly effective in Crohn’s disease. The efficacy of this therapy alone probably reflects the pleiotropic effects of TNF; however, the therapy is often limited by a loss of efficacy, underscoring the need for novel therapies.

Anti-p40 monoclonal antibodies have been reported to be effective in psoriasis98 and Crohn’s disease.99,100 The p40 cytokine subunit is common to both interleukin-23 and interleukin-12, and monoclonal antibodies against p40 inhibit both pathways. Selective blockade of interleukin-23 can be achieved by targeting the p19 subunit, and this approach has been reported to be effective in many,59,64 although not all,101 animal models of inflammatory bowel disease. Selective inhibition of interleukin-23 may, however, deregulate other, cross-regulated pathways and T-cell subgroups, with unintended consequences.100 Moreover, some Th17 cytokines may also have protective features; for example, interleukin-22 ameliorates disease in an animal model of colitis.102 A major question that remains to be resolved is whether selective interleukin-23 blockade will be more or less effective than combined interleukin-12–interleukin-23 blockade in the treatment of inflammatory bowel disease.

Other treatments under investigation include the infusion of interleukin-10–producing T cells and the administration of interleukin-10–producing bacteria.103,104 Certain bacterial components, commensal bacteria, and “probiotic” bacteria more generally are also being investigated.48,105 The increased levels of tissue-specific and inflammatory chemokines that enhance intestinal leukocyte migration74 are the basis for targeting these molecules in inflammatory bowel disease.104,106 With the development of new, potent antiinflammatory agents, one must consider balancing therapeutic benefit with side effects resulting from an increased risk of infection or reactivation of infections (JC virus–induced multifocal leukoencephalopathy in the case of natalizumab107 and tuberculosis in the case of anti-TNF-α monoclonal antibody108). Future progress in disease monitoring and therapy will depend on the development of a more refined and integrated understanding of the mechanisms mediating intestinal immune homeostasis.


Supported by grants from the National Institutes of Health (DK P30-34989, to Drs. Abraham and Cho; R01DK077905, to Dr. Abraham; and R01DK072373, U01 DK62429, U01 DK062422, and UL1 RR024139, to Dr. Cho), the Burroughs Wellcome Medical Foundation (to Dr. Cho), the Bohmfalk Funds for Medical Research (to Dr. Cho), and the Crohn’s and Colitis Foundation of America (to Drs. Abraham and Cho).

Dr. Cho reports being listed as a coinventor on a patent for NOD2 polymorphisms owned by Prometheus Labs and receiving lecture fees from Millennium Pharmaceuticals.

We thank Graeme Bell, Eric Elton, Fred Gorelick, and Cathy Nagler for reviewing an earlier version of the manuscript.


No other potential conflict of interest relevant to this article was reported.


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