Immune and microbial mechanisms in the pathogenesis of inflammatory bowel disease

INTRODUCTION — The immune response has long been implicated in the pathogenesis of inflammatory bowel disease (IBD), including both ulcerative colitis and Crohn disease. A vast body of literature has identified roles for both host and microbial factors in the pathogenesis of IBD, ultimately leading to inappropriate immune responses to microbes residing in the intestinal lumen [1].

This topic review will focus on our expanding understanding of the immune, microbial, and genetic factors involved in both the initiation and maintenance of IBD. The epidemiology, risk factors, clinical manifestations, diagnosis of IBD are discussed separately:

●(See "Definitions, epidemiology, and risk factors for inflammatory bowel disease".)

●(See "Clinical manifestations, diagnosis, and prognosis of Crohn disease in adults".)

●(See "Clinical manifestations, diagnosis, and prognosis of ulcerative colitis in adults".)

The management of IBD (Crohn disease, ulcerative colitis) is discussed separately:

●(See "Overview of the medical management of mild (low risk) Crohn disease in adults".)

●(See "Medical management of moderate to severe Crohn disease in adults".)

●(See "Medical management of low-risk adult patients with mild to moderate ulcerative colitis".)

●(See "Management of the hospitalized adult patient with severe ulcerative colitis".)

●(See "Management of moderate to severe ulcerative colitis in adults".)

THE MUCOSAL IMMUNE SYSTEM — In the process of carrying out the absorption of essential nutrients, the human intestine must discriminate between innocuous food antigens and infectious or toxic agents. To protect the host from the latter, the intestine relies upon an effective barrier and an innate and an acquired immune system (figure 1):

●The effective barrier depends upon an intact intestinal epithelium, with its overlying surface mucus secreted by goblet cells, normal peristalsis, and the secretion of numerous protective factors (eg, antimicrobial proteins, growth factors). Studies have shown that, in addition to their role in producing mucus, goblet cells actively participate in the delivery of antigens from the intestinal lumen to cells in the intestinal lamina propria [2].

●The innate immune system is comprised of myeloid-derived cells (neutrophils, monocytes, dendritic cells, and macrophages), natural killer cells, and innate lymphoid cells. These cells, in addition to epithelial cells, endothelial cells, and stromal cells, express pattern recognition receptors, which bind stereotypic microbial products. In combination, these cells provide the initial response to either pathogenic or commensal microorganisms.

●The adaptive immune system is comprised primarily of B and T lymphocytes, which confer specific immunity. The acquired immune system is designed to respond to foreign antigens displayed by "professional" antigen-presenting cells (APCs) (eg, dendritic cells and macrophages) in association with molecules of the major histocompatibility complex (MHC).

Both humoral and cell-mediated mechanisms are involved in the acquired immune system. Humoral immunity is mediated by B cells within the gut, which secrete antibodies largely of the immunoglobulin (Ig) A class. (See "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis".)

Cellular immunity is mediated by T lymphocytes, which can be functionally divided into CD4⁺ helper T cells (Th), CD8⁺ T cells (cytotoxic), and regulatory T cells. CD4⁺ T cells respond to processed antigen on professional APCs in association with MHC class II molecules. CD8⁺ T cells respond to processed antigen on all cell types in association with MHC class I molecules.

CD4⁺ Th cells can be further subdivided functionally into various T-cell subsets that are, in part, defined by the cytokines they produce. Examples of these include Th1 cells, Th2 cells, Th9 cells, Th17 cells, T follicular helper cells, tissue resident memory T cells, and regulatory T cells.

●Th1 cells secrete predominantly interferon gamma (IFN-gamma), tumor necrosis factor (TNF)-alpha, and interleukin (IL)-2. IL-12 (consisting of the heterodimer p35/p40) is secreted by APCs and is critical for the generation of Th1 cells.

●Th2 cells are induced by IL-4 and inhibited by IL-12. Th2 cells regulate B-cell differentiation by secreting predominantly IL-4, IL-5, and IL-13.

●Th17 cells are a lineage of helper T cells that have a critical role in regulating the inflammatory process and responses at mucosal surfaces and may have a central role in immune-mediated diseases. Th17 cells secrete predominantly IL-17, IL-21, IL-22, and granulocyte-macrophage colony-stimulating factor (GM-CSF) [3,4]. These cells are somewhat heterogeneous, such that subsets of Th17 cells also can secrete IFN-gamma, TNF-alpha, or IL-10; the repertoire of combined cytokines help determine the behavior of Th17 cells at mucosal surfaces. The IL-12-related molecule, IL-23 (consisting of the heterodimer p19/p40), is important for maintenance of Th17 cells [3]. Mutations in the IL-23 receptor have been associated with susceptibility to inflammatory bowel disease (IBD) [5-7]. Furthermore, targeting of both the p19 subunit (unique to IL-23) and the p40 subunit (common to both IL-12 and IL-23) has demonstrated efficacy in clinical trials for treatment of IBD [8-10], thereby highlighting the importance of these cytokines in IBD pathogenesis; anti-IL-12p40 therapy has been approved for both Crohn disease and ulcerative colitis. Selective anti-IL23p19 therapy is being studied in ongoing clinical trials. (See "Medical management of moderate to severe Crohn disease in adults".)

In contrast, clinical trials blocking IL-17 in Crohn disease patients showed no efficacy, and, in fact, some patients developed worse disease [11]. Data have suggested that, in addition to pro-inflammatory activities, IL-17 has important roles in intestinal epithelial cell functions, which may have hindered clinical efficacy with anti-IL-17 targeted therapies [12,13].

●Tissue resident CD4⁺ memory (TRM) T cells (defined as non-circulating, memory CD4 T cells) are retained locally in specific tissue sites and have the potential to rapidly express cytokines in response to antigen. In human intestine, these cells express CD69 and CD154, produce IFN-gamma and IL-17, and are broadly reactive to commensal organisms [14].

●Regulatory T cells consist of various subsets including Th3, type 1 regulatory (Tr1), and CD4⁺CD25⁺ (mediated at least in part by the expression of the forkhead box P3 transcription factor [FOXP3]). They block or downregulate Th1, Th2, and Th17 cells either by production of specific cytokines (IL-10 and transforming growth factor (TGF)-beta) or via cell-cell contact mechanisms [15].

Immune cells, when located in the intestine, are collectively known as the gut-associated lymphoid tissue (GALT) and are distributed throughout the lamina propria, between epithelial cells, and in discrete lymphoid structures. Epithelial cells, "professional" APCs, and other leukocytes within the GALT also secrete a variety of soluble protein mediators (cytokines), which serve to regulate responses to foreign antigens. In addition, alterations in the intestinal microcirculation, trafficking molecules, and neuronal afferents can modify the composition and effector function of both immune and non-immune cells within the GALT.

KEY CONCEPTS EMERGING IN THE MUCOSAL IMMUNE SYSTEM

●The immune response components must be properly balanced. As such, either too strong a response or an inadequate immune response to microbes in the intestinal lumen can ultimately result in intestinal inflammation.

●The various arms of the intestinal immune system cooperate to defend against microbiota that gain access to intestinal tissues.

●Given the high density of resident microbes in the intestinal lumen, the intestinal immune system has developed mechanisms to control excessive responses to these microbes. Cells in the intestinal immune system exhibit unique characteristics that are, in part, conditioned through the local intestinal environment. Examples of unique phenotypes of macrophages, dendritic cells, and T cells within intestinal tissues include:

•Relative to the peripheral immune system, macrophages in the intestinal lamina propria do not produce high levels of proinflammatory cytokines upon exposure to microbial components but are more effective in clearing bacteria [16]. These combined characteristics likely contribute to eliminating bacteria in a manner that minimizes tissue injury. Intestinal macrophages also demonstrate anti-inflammatory characteristics [17,18].

•Intestinal dendritic cells express high levels of retinoic acid-metabolizing enzymes. Retinoic acid, in turn, leads to expression of molecules that lead to enriched T-cell trafficking to intestinal tissues and regulatory T-cell function [19-24].

•Mechanisms exist in intestinal tissues to eliminate T cells reactive to luminal bacteria [25] and to differentiate T cells into regulatory T-cell subsets.

●While many distinct, differentiated intestinal immune cell subsets have been identified, a number of these same cells demonstrate plasticity. For example, Th17 cells can undergo transition to IL-10-producing regulatory T cells and Th2 cells, Th1 cells to Th2 cells, and Treg cells can transition to pathogenic IL-17-producing and IFN-gamma-producing T cells [26-29]. This has implications for therapy in IBD. On the one hand, it indicates that, when considering cell therapy with transfer of regulatory T-cell subsets for inhibiting inflammation, these cells may transition to pathogenic T cells rather than function in the protective manner intended. On the other hand, it provides possibilities for therapeutically inducing transition of pathogenic T cells to T cells with regulatory function. In addition, single-cell analysis technologies are allowing for more refined insight into the broad spectrum of cell subsets and how these cell subsets might transition during health and disease and with therapeutic interventions [30-35].

●Conditions in the intestinal environment can influence the manner in which immune cells differentiate, with inflammation, secreted mediators, microbiota, metabolic products, dietary factors, and prior infectious exposures all able to influence these differentiation outcomes [26,27,36-44].

●The enteric nervous system (ENS) can modulate the mucosal immune system and is comprised of both sympathetic and parasympathetic nerve fibers originating from the central nervous system. In addition, the intrinsic ENS is the network of neurons and glia that reside along the intestine and interact with the gastrointestinal tract by receiving and delivering modulating signals [30,45-47].

IMMUNE DYSREGULATION AND IBD — Many studies support the concept that inflammatory bowel disease (IBD) results from a dysregulated response by the mucosal immune system to the microbiota that reside within the intestinal lumen. This dysregulation can be both due to excessive immune reactivity and to inadequate immune responses to intestinal microbiota, highlighting the importance of a balanced immune response. The following describe alterations in the immune responses observed in IBD.

Dysregulation at the epithelial barrier — Alterations in intestinal mucus, high numbers of bacteria within mucus, and increased intestinal permeability have been associated with IBD [48-55]. Studies have revealed that mice with defects in epithelial barrier function can develop spontaneous colitis and/or demonstrate increased susceptibility to experimental models of colitis [56-59]. Epithelial cells can express some receptors also expressed on immune cells and can present antigens, similar to classical antigen-presenting cells [60-65]. Some studies have shown that abnormal antigen presentation by epithelial cells and/or interaction with intraepithelial lymphocytes is associated with IBD [66-69]. Moreover, abnormalities in the manner in which epithelial cells (in particular, highly secretory cells such as Paneth cells) handle unfolded intracellular proteins, a process that is associated with "stress" on the endoplasmic reticulum, has been associated with IBD [70-72]. Other abnormalities in Paneth cells have been identified in association with various immune pathway perturbations observed in IBD, which in some cases result in dysregulation in production of antimicrobial proteins [73,74].

Dysregulation in immune cells — Excessive immune cell recruitment and activation has been detected in multiple immune cell subsets. Myeloid cells with an "inflammatory" phenotype that produce increased levels of cytokines are present in the lamina propria of IBD patients [36,75-77]. Natural killer (NK) cells subsets are altered [78]. Mononuclear cells isolated from lesions of patients with IBD display numerous activation markers and cytokines [34,79]. T cells isolated from IBD mucosa may show increased proliferation and cytokine production to antigens in vitro, suggesting that they may respond abnormally to resident antigens [80]. Whether IBD results from an altered response by T cells to single or few antigens remains an unanswered question since some, but not all, studies have found a restricted T-cell receptor repertoire [52,81-86]. Innate lymphoid cells have also been found to be dysregulated in IBD [87].

The findings of increased numbers of mucosal and circulating B cells and plasma cells, autoantibodies (atypical perinuclear antineutrophil cytoplasmic antibodies [P-ANCA]), and increased antibodies to microbial components and cytokines (eg, anti-granulocyte-macrophage colony-stimulating factor) in patients with IBD suggest that abnormal B-cell regulation may also be involved in the pathogenesis of this disorder [53,54,88-94]. However, studies have not shown that antibody production is directly involved in the pathogenesis of IBD. As an example, the B-cell-depleting medication rituximab was not effective for treating ulcerative colitis [94]. Colonic-resident plasma cells are retained in the colonic mucosa of treated patients, which may contribute to the lack of efficacy [95].

Some inflammatory cells, such as neutrophils, found within diseased mucosa in IBD are not usually present in the lamina propria and therefore must be recruited from the blood vessels. This process, called "homing," requires several coordinated steps. Leukocytes "roll" along the endothelium, and chemokines secreted from the tissues activate adhesion molecules, thereby resulting in firm adhesion. Once adherent, leukocytes traverse the endothelium (a process called "diapedesis") [22,96]. Enhanced expression of adhesion molecules on leukocytes and endothelial cells, increased chemokines, and increased leukocyte binding to vascular endothelial cells in patients with IBD have been described [55,97-99]. There is an increasing focus on stromal cell contributions to immune cell recruitment into intestinal tissues and intestinal inflammation, in addition to their known role in fibrosis [100,101]. Therapeutic strategies to block mucosal homing of leukocytes are in use as described below, with additional strategies under investigation.

One approach to reduce lymphocyte trafficking to the intestine is with vedolizumab, an antibody directed specifically against the alpha-4 beta-7 integrin heterodimer mediating lymphocyte trafficking to the lamina propria [63,64,102,103]. Other approaches have included modulators of the S1P/S1PR1 axis such as ozanimod [104], which blocks the egress of lymphocytes from lymph nodes, thereby reducing the number of circulating lymphocytes. Defining the integrins, chemokines, and other pathways regulating the homing of various distinct cell subsets to intestinal tissues remains an area of active investigation.

Dysregulation in secreted mediators — In addition to the dysregulated cell populations, abnormal levels of immunoregulatory and inflammatory cytokines correlate with active IBD [65,68].

CD4⁺ T lymphocytes isolated from patients with Crohn disease secrete large amounts of interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha, cytokines with a marked proinflammatory effect, thereby implicating Th1 cells in the pathogenesis of IBD. These findings are consistent with observations in several mouse models of chronic colitis [105-110]. These studies have led to therapeutic strategies using anti-TNF-alpha antibodies for Crohn disease [111]. The secretion of interleukin (IL)-4, IL-5, and IL-13 by Th2 cells suppresses Th1-mediated responses, but also leads to the infiltration of eosinophils and can contribute to intestinal inflammation, shown in both human IBD and mouse colitis studies [69,72,112-115]. Cytokines associated with Th17 cells are also observed in the intestinal mucosa of IBD patients [116-123]. IL-23-dependent signaling and secretion of cytokines by Th17 cells may account, at least in part, for some of the aberrant cytokine secretion previously attributed to Th1 cells [4,124-130]. Importantly, Th17 cells are heterogenous in nature and the conditioning of Th17 cells by IL-23 leads to Th17 cells that are more pathogenic in nature [131-133]. Ongoing studies are investigating optimal approaches for targeting the IL-12/IL-23 axis given its critical role in the generation of Th1/Th17 cells [8-10].

As noted above, mice and humans also exhibit subsets of regulatory CD4⁺ T cells, including CD4⁺ CD25⁺ Tregs (forkhead box P3 transcription factor [FOXP3] expressing), Th3 and Tr1 cells, which can act as "suppressor" cells, in part through the secretion of inhibitory IL-10 and TGF-beta cytokines. While some regulatory cells are generated in the thymus, other "induced" or "adaptive" regulatory cells can be generated in situ in the gut-associated lymphoid tissue (GALT). CD8⁺ T cells also secrete IL-10 and TGF-beta, which suppress inflammatory responses. Although aberrant regulatory cell function has not yet been implicated in IBD, therapeutic strategies to induce or enhance regulatory T cells are under active investigation [15,134].

The TL1A (TNFSF15)/DR3 axis has also been implicated in Crohn disease [135-137]. TL1A is a TNF-like cytokine that is increased in Crohn disease and interacts with the death domain receptor (DR3). Several studies have implicated the TL1A/DR3 axis in animal models of colitis [138-140], with studies suggesting that TL1A can lead to induction of cytokines from Th1, Th2, and Th17 cells; NK cells; myeloid cells; and innate lymphoid cells [137,138,140-144]. As noted below, TNFSF15 is a well-established susceptibility locus in Crohn disease [145-150].

In addition to protein mediators, several other biological products have been implicated in IBD pathogenesis when found in excess. Examples include arachidonic acid and its byproducts and reactive oxygen and nitrogen products (table 1).

ROLE OF MICROBES — The distal ileum and colon contain high concentrations of microbes. Bidirectional host-microbe interactions in the intestine can be mutually beneficial or have adverse effects that contribute to intestinal inflammation. On the one hand, intestinal microbial colonization is essential to nutrition, energy metabolism, and proper "conditioning" of the intestinal and peripheral immune systems. On the other hand, the intestinal lumen can contain microbiota and microbial-derived factors that may promote inflammatory bowel disease (IBD) in the context of an underlying genetic immune defect.

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 [151]. Yet another important measure beyond the composition of intestinal microbiota is the manner in which intestinal microbiota modulate microbial functions such as energy metabolism [152,153]. Studies in mice have shown that intestinal microbiota and the ability of the host to recognize and respond to these microbiota are important in the generation and optimal function of intestinal antimicrobial proteins, epithelial cells, innate lymphoid cells, natural killer T cells, macrophages, interleukin(IL)-17-producing T cells, intestinal and peripheral regulatory T cells (Tregs), and immunoglobulin A (IgA) [42,154-170].

At the same time, the host immune system and various host conditions (eg, obesity) can influence intestinal microbial communities [57,171-176]. The microbial community alterations can, in turn, modulate intestinal inflammatory outcomes [71,172,173]. Environmental factors can also influence intestinal microbiota, including dietary factors [176-179], helminth exposure [180], and antibiotic usage. Changes in these environmental factors have likely contributed to the increased prevalence of IBD during the past century. For example, the increased use of antibiotics in early childhood has been associated with an increased likelihood of developing IBD [181-184].

In patients with IBD, alterations in both the diversity and density of bacteria, in specific bacteria directly associated with the mucosa, and in the functions of the bacteria present (eg, oxidative stress, nutritional regulation) have been described [185-190]. These alterations in microbial communities have been identified even at the time of initial diagnosis in children [189]. Whether these microbial alterations are primary drivers of IBD or secondary to the underlying intestinal inflammation observed with IBD is not yet clear. Interestingly, select communities of bacteria from ulcerative colitis patients can induce Th17 responses when transferred into mice [191,192], thereby demonstrating that these bacteria can contribute to the dysregulated T cell responses observed in patients. No single agent has been shown to have a consistent relationship to IBD. The prevailing hypothesis at this time is that changes in communities of intestinal bacteria can contribute to the initiation and/or perpetuation of inflammation associated with IBD.

Consistent with this hypothesis is the observation of immune responses directed against particular microbial components. For example, antibodies to the DNA segment (I2) in affected mucosa is observed in 54 percent of patients with Crohn disease compared with 4 to 10 percent of controls [193], and antibodies to bacterial flagellin are observed in complicated Crohn disease patients [194,195]. In general, the immunoreactivity to microbial antigens correlates with more aggressive IBD [196,197]. It has been unclear if these increased antibodies are in response to the enhanced exposure to intestinal bacteria due to epithelial barrier perturbations and/or to increased immune reactivity of intestinal immune cells in the context of inflammation, or if these antibodies also contribute to the pathogenesis of IBD.

The role of microbiota is also being examined in patients who have undergone an ileal pouch-anal anastomosis surgery for ulcerative colitis. Correlations have been identified between microbiota, mucosal gene expression, and clinical outcomes (eg, pouchitis) [198-200]. (See "Pouchitis: Epidemiology, pathogenesis, clinical features, and diagnosis", section on 'Etiopathogenesis'.)

In contrast to our limited understanding in human IBD, the importance of microbes in the protection, induction, and/or maintenance of disease has been demonstrated more clearly in murine models of IBD. As an example, various rodent models of colitis develop intestinal inflammation in the presence of a normal microflora, but not in germ-free conditions [196,201,202]. In some cases, bacteria from mice with colitis have been shown to promote intestinal inflammation when transferred from one animal to another [172,173]. In other cases, select bacteria result in inflammation specifically when combined with an underlying genetic defect [203]. There are numerous efforts underway to better identify these inflammation-promoting bacteria. As one such example, IgA-coated intestinal bacteria preferentially drive intestinal inflammation [204]. Moreover, certain combinations of bacteria (eg, probiotics, Clostridia) can mediate protection from inflammation through such mechanisms as inducing Treg cells [205] or modulating growth factors that promote epithelial restitution [206]. Beyond their ability to regulate colitis, studies in mice have shown that intestinal microbiota can modulate the development of other diseases such as metabolic syndrome, diabetes, and autism [207-209].

Additional analyses have revealed that specific microbial components, such as the polysaccharide A component of the resident intestinal microbe Bacteroides fragilis, and microbial-derived products, such as short-chain fatty acids, are mechanisms through which intestinal microbiota can modulate both intestinal immune system development and intestinal inflammation [210-215].

The microbial alterations in IBD have extended to those beyond bacteria. For example, changes in intestinal viruses have also been described in patients with IBD [216]. Further supporting contributions from intestinal viral communities are studies that have shown that in mice with alterations in genes associated with IBD, colonization with norovirus leads to intestinal abnormalities [217]. Fungi have also been shown to modulate intestinal inflammation in mouse studies [218], and studies are ongoing to determine how fungi may be altered in human IBD [219].

Genetic studies have identified susceptibility loci that regulate innate responses to the microbial flora. They provide further evidence for the role of microbes in the pathogenesis of IBD. (See 'Genetic susceptibility' below.)

GENETIC SUSCEPTIBILITY — Over 240 distinct susceptibility loci for inflammatory bowel disease (IBD) have been identified, with some contributing to unique risk and others contributing to combined risk for Crohn disease and ulcerative colitis [145,150,220,221]. In fact, approximately 70 percent of the genes are shared between Crohn disease and ulcerative colitis, thereby highlighting significant genetic overlap in these disease entities [145]. Many of the variants are located in intronic regions of the gene, such that they do not alter the amino acids within the proteins encoded by these genes, but rather likely modulate the expression of the proteins. This expression modulation is generally mild in degree, consistent with the fact that each of the susceptibility loci confers a slight increase in disease risk. A subset of the pathways associated with IBD susceptibility also contribute to very early-onset IBD when associated with genetic variants that result in more dramatic disruption of the same pathway [222]. A high percentage of the IBD-associated pathways are associated with other immune-mediated diseases and/or confer risk for immunodeficiencies and for susceptibility to mycobacterial diseases [145].

The IBD genetic discoveries have provided insight into pathways that contribute to IBD pathogenesis and that might ultimately be targeted in IBD. Studies are ongoing to define the specific genes within the identified susceptibility loci, the functional consequences of the variants within these genes, and the specific manner in which the associations are contributing to IBD pathogenesis. In many cases, the proteins encoded by the genes are expressed in multiple different cell subsets and thereby contribute to disease through distinct and cooperative mechanisms in these various cells. The following are illustrative of the range of findings:

●Innate immune pathways – The first susceptibility gene identified in association with Crohn disease encodes for the protein NOD2 [223,224]. Of the genes identified to date, NOD2 confers the greatest risk of developing Crohn disease. The wild-type NOD2 protein responds to bacterial peptidoglycan, which then activates signaling pathways that lead to cytokine production and clearance of bacteria [225]. The variants associated with Crohn disease result in a loss of these various functional outcomes. Mice deficient in NOD2 are susceptible to enteric pathogens and have changes in their intestinal luminal bacteria [226,227]. The loss-of-function in NOD2 also leads to an impaired ability to instruct cells to ultimately downregulate inflammatory pathways in conditions that simulate the intestinal environment [228,229]. NOD2 is expressed in a variety of cell types, including intestinal epithelial cells, macrophages, dendritic cells, endothelial cells, and stromal cells [225], thereby highlighting the many different levels at which NOD2 contributes to intestinal immune function. Further, experimental model systems have demonstrated that the adverse consequences of impaired NOD2 function can be more severe when combined with additional genetic or environmental triggers [54,230].

An individual inheriting one mutant NOD2 allele has a 1.5- to 3.7-fold increase in risk of developing Crohn disease, while an individual inheriting two mutant NOD2 alleles has a 17- to 40-fold increase in risk [231-234]. Penetrance of Crohn disease in carriers of one mutant NOD2 allele is 0.54 percent and two mutant NOD2 alleles is 4.9 percent, compared with 0.18 percent for wild-type NOD2 carriers [234]. In contrast to the risk conferred to European populations, studies including populations from East Asia have not found an association between the common NOD2 variants and Crohn disease [150,235,236].

The variants in NOD2 confer susceptibility to developing Crohn disease at an earlier age, to ileal and fibrostenosing Crohn disease, and to worse outcomes following ileal pouch-anal anastomosis for ulcerative colitis [231,232,237-241]. A meta-analysis that included 49 studies with 8893 Crohn disease patients found that patients with NOD2 mutations were at increased risk for complicated disease (relative risk [RR] 1.17, 95% CI 1.10-1.24) and surgery (RR 1.58, 95% CI 1.38-1.80) compared with those without mutations [242].

In addition to NOD2, a number of other IBD-associated gene variants have been shown to modulate innate pathways. Interestingly, innate cells from healthy individuals demonstrate dramatic variation in responses upon exposure to microbial products. This variation between individuals is in part genetically determined and contributes to the balance in susceptibility to infectious diseases and to immune-mediated diseases. Various studies have examined innate cells from individuals carrying IBD risk variants. In some cases, the common risk variants that confer IBD risk have been shown to increase innate pathway responses (eg, IRF5, TNFSF15, TPL2, JAK2, STAT1/STAT4, STAT3/STAT5), thereby increasing cytokine production in the presence of microbial products [143,243-251]. In other cases, the variants decrease innate pathway responses (eg, ICOSLG, INAVA, LACC1, RNF186) [252-259], which may ultimately lead to less effective bacterial clearance mechanisms. These genetic findings once again highlight the need to balance bacterial clearance with tightly controlled immune responses in the intestinal environment.

●Microbial clearance pathways – Defects in autophagy Related 16-Like 1 (ATG16L1) and immunity-related GTPase M (IRGM) proteins have been associated with Crohn disease [146,147,260-266]. These proteins are involved in promoting autophagy, a process that contributes to elimination of intracellular pathogens. Consequences of the mutation in ATG16L1 associated with Crohn disease include changes in Paneth cells and goblet cells, a decreased ability to clear bacteria, and an increased secretion of cytokines in studies in both mice and IBD patients [73,74,267,268]. In addition to loss-of-function variants in proteins promoting autophagy, gain-of-function variants in MTMR3, an inhibitor of autophagy, are associated with Crohn disease [220]. This, in turn, also leads to impaired autophagy [269].

Variants in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase genes that regulate the generation of reactive oxygen species, which contribute to microbial clearance, are observed in both very early-onset IBD [270,271] and adult-onset IBD [145]. As above, there are also IBD-associated genetic variants leading an impaired induction of the microbial pathways observed with the activation of pattern recognition receptors. Given the numerous examples in mouse studies wherein host immune function can modulate microbiota within the intestinal lumen, studies are ongoing to determine how various IBD risk variants modulate human intestinal microbiota [272]. One such example is the alterations in colonic microbiota at both the compositional and functional levels observed in FUT2 IBD risk carriers [273].

●Cytokine pathways – Consistent with the very important role of cytokines in mediating the inflammation observed in IBD, a variety of IBD genetic associations have been identified in pathways both leading to the production of and the response to cytokines. Below are examples of these associations:

•Th17/IL-23 pathway – Certain noncoding variants of the IL-23 receptor have been associated with both Crohn disease and ulcerative colitis [5-7,145,147]. By contrast, an uncommon coding variant confers an approximately two- to threefold protection against the risk of IBD. As noted above, IL-23 is a proinflammatory cytokine that is important for the stabilization of Th17 cells, and in particular for conditioning more pathogenic Th17 cells. Individuals carrying the protective IL23R risk variant have less circulating Th17 cells, and their T cells signal less in response to IL-23 [274-276]. Interestingly, loci containing STAT3, JAK2, and TYK2 (signaling molecules downstream of IL-23-dependent signaling); IL12B (the p40 subunit that is contained within both IL-12 and IL-23); and RORC (a transcription factor associated with Th17 cells) are associated with IBD risk [145-147,262], thereby highlighting the convergence of multiple genes in the same pathway. Colonic tissues from STAT3 risk-variant IBD patients have increased expression of cytokines and chemokines [277], and myeloid cells from STAT3 IBD risk-variant individuals also demonstrate increased cytokines in response to microbial components [251].

•IL-10 pathway – IL-10 functions to inhibit a broad array of inflammatory outcomes [278-282]. Interestingly, common IL-10 variants are associated with the common form of IBD [145]; rare loss-of-function IL-10 and IL-10 receptor mutations are associated with very early-onset IBD [283-285]; and IL-10 and IL-10 receptor deficient mice develop spontaneous colitis [105,110]. These provide examples of both common and rare variants in human disease, as well as convergence of human and mouse models in a single critical regulatory pathway. Interestingly, one of the inflammatory outcomes which IL-10 inhibits is the IL-1 beta pathway. As such, very early-onset IBD patients with mutations leading to IL-10 deficiency have demonstrated improvement upon therapy with IL-1 beta pathway blockade [286].

•TNFSF15 pathway – Variants associated with IBD [145,147,287] that result in increased TNFSF15 (TL1A) expression enhance innate cell responses to microbial products [143,249]. In addition to European-ancestry IBD, TNFSF15 variants are strongly associated with IBD in Asian-ancestry individuals [148-150], providing an important example of an IBD risk gene that is shared across populations. As above, TNFSF15 is increased in intestinal tissues from IBD patients, and several studies have implicated the TNFSF15/DR3 axis in animal models of colitis and in the fibrosis observed in these models [138-140,288].

•IL18R/IL1R pathways – Genetic variants in a region that includes a cluster of cytokine receptors from the IL1 receptor and IL18 receptor family are associated with both Crohn disease and ulcerative colitis [145]. The IBD risk variants lead to decreased expression of IL18RAP, IL18R1, and IL1R1 on innate cells. This decreased expression leads to decreased responses to IL-18 and IL-1beta and to the IL-18 and IL-1beta amplification of signaling and cytokines observed upon exposure to microbial products [289].

●Adaptive immune pathways – The innate immune system is continuously interacting with the adaptive immune system. As a result, a number of the IBD gene variants that regulate innate immune responses will likely also modulate adaptive immune responses through both direct and indirect mechanisms. Examples of IBD risk variants that directly regulate adaptive immune pathways include those in IRF5 [290], IL23R, PTPN2 and PTPN22. Crohn disease patients who carry the IBD risk PTPN2 variants show increased Th1 and Th17 cell but decreased Treg markers in serum and intestinal tissues [291].

●Epithelial pathways – Several susceptibility loci include genes that regulate epithelial cell functions. For example, X-box binding protein 1 (XBP1) and ORMDL3 are proteins that regulate the unfolded protein response, which is a critical cellular process by which highly secretory cells like epithelial cells handle endoplasmic reticulum stress. This process also regulates the process of autophagy described above [70]. Additional IBD susceptibility genes that can regulate outcomes in epithelial cells include ATG16L1, PTPN2, INAVA, RNF186, and A20; in some cases, these outcomes are particularly observed when alterations in these IBD-associated genes are combined with environmental triggers (eg, smoking, viruses) or other IBD-associated gene alterations [74,217,292-296].  

LESSONS FROM ANIMAL MODELS OF IBD — The availability of various animal models of inflammatory bowel disease (IBD) has facilitated investigation into the mechanisms essential for maintaining a well-balanced intestinal immune system, the underlying defects in the gut-associated lymphoid tissue (GALT) that can induce inflammation, and the essential factors required for the maintenance of disease. Numerous murine strains develop intestinal inflammation as a result of genetic manipulation or "knock out" of genes that affect immune function within the mucosal immune system [56,105,106,260,297-307]. The elimination of these genes from selection cell subsets has allowed for further refining of our understanding of the differential regulation of pathways in distinct cells subsets. This more refined understanding might ultimately allow for selectively targeting implicated IBD-associated pathways in pertinent cell subsets, while leaving the pathway(s) intact in cell subsets where maintained function might be important.  

Major themes have emerged from these animal models, including:

●The absence or impaired function of diverse proteins (or cell types) involved in regulating the innate or adaptive mucosal immune system and epithelial cell function can result in mucosal inflammation or can enhance susceptibility to experimental models of colitis.

●The presence of luminal bacteria is generally required for development of colitis.

●There is continuous cross-talk between the host and intestinal microbes, which ultimately influences both protection and susceptibility to intestinal inflammation.

Importantly, these animal models provide a foundation for future investigation into the mechanisms responsible for IBD. They further provide a means for developing and testing therapeutic interventions for IBD, which will hopefully result in the future availability of novel therapeutic regimens.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ulcerative colitis in adults" and "Society guideline links: Crohn disease in adults".)

SUMMARY AND RECOMMENDATIONS

●A vast body of evidence indicates that the pathogenesis of inflammatory bowel disease (IBD) arises from dysregulated immune responses to luminal bacteria and/or their products. (See 'Immune dysregulation and IBD' above.)

●Multiple lines of evidence suggest that patients with IBD have alterations in both the composition and function of intestinal microbiota. (See 'Role of microbes' above.)

●Numerous genetic variations have been implicated in the pathogenesis of IBD, which provide insight into pathways important in regulating intestinal inflammation. (See 'Genetic susceptibility' above.)

●Therapies targeting immune dysregulation, alterations in intestinal microbiota, and pathways identified through genetic studies are in active development. (See 'Immune dysregulation and IBD' above and 'Role of microbes' above and 'Genetic susceptibility' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Daniel Podolsky, MD, who contributed to an earlier version of this topic review, and E Richard Stiehm, MD, who contributed as a Section Editor to an earlier version of this topic review.

The UpToDate editorial staff also acknowledges Paul Rutgeerts, MD (deceased), who contributed as a section editor for UpToDate in Gastroenterology.