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com/esps/ World J Gastroenterol 2014 January 7; 20(1): 91-99

bpgoffice@wjgnet.com ISSN 1007-9327 (print) ISSN 2219-2840 (online)
doi:10.3748/wjg.v20.i1.91 © 2014 Baishideng Publishing Group Co., Limited. All rights reserved.

TOPIC HIGHLIGHT

WJG 20th Anniversary Special Issues (3): Inflammatory bowel disease

Inflammatory bowel disease: Pathogenesis

Yi-Zhen Zhang, Yong-Yu Li

Yi-Zhen Zhang, Yong-Yu Li, Department of Pathophysiology, a major role in the pathogenesis of IBD, as new studies
Tongji University School of Medicine, Shanghai 200092, China in immunology and genetics have clarified that the in-
Author contributions: Zhang YZ and Li YY have substantial nate immune response maintains the same importance
contributions to conception and design, and acquisition of data; in inducing gut inflammation. Recent progress in un-
Zhang YZ drafted the article; Li YY revised the manuscript
derstanding IBD pathogenesis sheds lights on relevant
critically for important intellectual content; Zhang YZ and Li
YY worked together for the final approval of the version to be disease mechanisms, including the innate and adaptive
published. immunity, and the interactions between genetic factors
Supported by grants from the National Natural Science Foun- and microbial and environmental cues. In this review,
dation of China, No. 81270477 we provide an update on the major advances that have
Correspondence to: Yong-Yu Li, MD, Department of Patho- occurred in above areas.
physiology, Tongji University School of Medicine, Siping Road
1239, Shanghai 200092, China. liyongyu@tongji.edu.cn © 2014 Baishideng Publishing Group Co., Limited. All rights
Telephone: +86-21-65981021  Fax: +86-21-65987071 reserved.
Received: September 29, 2013 Revised: November 5, 2013
Accepted: November 28, 2013
Key words: Inflammatory bowel disease; Ulcerative
Published online: January 7, 2014
colitis; Crohn’s disease; pathogenesis; Genetics; Micro-
bial factors; Immune responses

Core tip: Inflammatory bowel disease (IBD) includes

Abstract Crohn’s disease and ulcerative colitis. Recent research
Inflammatory bowel disease (IBD), including Crohn’s indicated that the individual’s genetic susceptibility,
disease and ulcerative colitis, is characterized by chronic external environment, intestinal microbial flora and im-
relapsing intestinal inflammation. It has been a world- mune responses are all involved and functionally inte-
wide health-care problem with a continually increasing grated in the pathogenesis of IBD. The main purpose
incidence. It is thought that IBD results from an aber- of this review is to offer an update that have occurred
rant and continuing immune response to the microbes in each of the above four areas, and to highlight the
in the gut, catalyzed by the genetic susceptibility of the future work to find a clear understanding of IBD patho-
individual. Although the etiology of IBD remains largely genesis.
unknown, it involves a complex interaction between
the genetic, environmental or microbial factors and
the immune responses. Of the four components of IBD Zhang YZ, Li YY. Inflammatory bowel disease: Pathogenesis.
pathogenesis, most rapid progress has been made in World J Gastroenterol 2014; 20(1): 91-99 Available from: URL:
the genetic study of gut inflammation. The latest inter- http://www.wjgnet.com/1007-9327/full/v20/i1/91.htm DOI:
nationally collaborative studies have ascertained 163 http://dx.doi.org/10.3748/wjg.v20.i1.91
susceptibility gene loci for IBD. The genes implicated in
childhood-onset and adult-onset IBD overlap, suggest-
ing similar genetic predispositions. However, the fact
that genetic factors account for only a portion of overall
INTRODUCTION
disease variance indicates that microbial and environ-
mental factors may interact with genetic elements in Inflammatory bowel disease (IBD) has been a global
the pathogenesis of IBD. Meanwhile, the adaptive im- healthcare problem with a sustained increasing inci-
mune response has been classically considered to play dence[1]. It includes two major forms, Crohn’s disease (CD)

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 Zhang YZ et al . Pathogenesis of IBD

and ulcerative colitis (UC), which are distinct chronic immunity-related GTPase family. CD-associated poly-
bowel-relapsing inflammatory disorders. CD can cause morphisms in IRGM lead to reduced protein expression.
transmural inflammation and affect any part of the gas- Epithelial cells and dendritic cells containing ATG16L1
trointestinal tract (most commonly, the terminal ileum or and NOD2 variants show defects in antibacterial autoph-
the perianal region) in a non-continuous type. Unlike UC, agy[12,20].
CD is commonly associated with complications such as With the widespread use of GWAS and SNPs, a sig-
abscesses, fistulas and strictures. In contrast, UC is typi- nificant association between IBD and the IL23R gene
fied by mucosal inflammation and limited to the colon[2]. has recently been described[21]. The IL23R gene encodes
Although the etiology of IBD remains largely unknown, a subunit of the receptor for the pro-inflammatory
recent research indicated that the individual’s genetic sus- cytokine interleukin (IL)-23, a peptide involved in the
ceptibility, external environment, intestinal microbial flora generation of Th17 cells. The Th17 and IL-23 pathway
and immune responses are all involved and function- is well established in the pathogenesis of IBD, with sus-
ally integrated in the pathogenesis of IBD[3-5]. The main ceptibility gene loci IL23R, IL12B, JAK2, and STAT3
purpose of this review is to offer an update that have having been identified in both UC and CD[22,23]. Variants
occurred in each of the above four areas, and to highlight in IL12B, which encodes the p40 subunit of IL-12 and
the future work to find a clear understanding of IBD IL-23, have been associated with IBD and other immune
pathogenesis. disorders. Defects in the function of IL-10 have also
been associated with CD and UC[24]. Other susceptibility
genes that regulate immune function include CARD9,
GENETICS IL1R2, REL, SMAD3 and PRDM1.
Over the past decades, there have been huge advances Recent progress in the genetics of IBD holds several
in our understanding of genetic contributions to IBD[6]. key messages in regard to the underlying mechanism
This is due to the technological advances in DNA analy- of the disease. On one hand, the expanding number
sis and sequencing and the use of huge multinational of susceptibility gene loci described in IBD indicates
databases[7]. Advances in genetic testing and analyzing that genetic influences are critical components of the
technologies have allowed for the completion of many disease pathogenesis; while on the other hand, explain-
genome-wide association studies (GWAS) which identify able susceptibility loci discovered so far account for only
single nucleotide polymorphisms (SNPs). Recent studies 20%-25% of the heritability found in the above-men-
have brought the number of IBD-associated gene loci to tioned studies. This is not only true for IBD, but also true
163, of which 110 are associated with both diseases, 30 for many other polygenetic diseases, and the phenom-
CD specific and 23 UC specific[8]. Studies of gene loci enon has been called “the mystery of missing heritability
shared by UC and CD may provide new way to find their of common traits” or “genetic vacuum”[25]. This issue is
common pathogenesis. further proved by GWAS that has failed to add new sus-
The era of modern IBD genetic research began in ceptibility gene loci to fill the “genetic vacuum”[26,27]. The
2001 with the discovery of NOD2 (nucleotide-binding possibility was then proposed that, instead of missing
oligomerization domaincontaining 2), the first suscepti- genes, the interactions among genes and their products
bility gene for CD[9]. The NOD2 gene codes for a protein could explain much of the apparent vacuum and account
that was originally described as an intracellular receptor for a considerable number of IBD[25]. These new insights
recognizing the muramyl dipeptide (MDP), a conserved into genetics and heritability of IBD implicate that future
motif present in peptidoglycan from both Gram-positive explorations of gene-gene interactions, gene-pathway in-
and -negative bacteria[10]. MDP stimulation induces au- teractions and gene-environment interactions are likely to
tophagy which controls bacterial replication and antigen give us more insights into IBD pathogenesis than finding
presentation[11,12], and modulates both innate and adap- new rare variants.
tive immune responses[13]. NOD2 participates in distinct
MDP-independent pathways such as the regulation of
the T-cell response[14]. The association between CD and ENVIRONMENT
NOD2 has already been replicated at the genome-wide There is no doubt that environmental factors play an im-
significance level[15]. portant role in the pathogenesis of IBD. A large number
Genetic analyses have shown an indispensable role of environmental factors are considered risk factors for
for autophagy in immune responses in IBD, and re- IBD, including smoking, diet, drugs, geography, social
ported two autophagy-related genes named ATG16L1 stress, and psychological element[28]. Among them, smok-
and IRGM[16-18]. Autophagy is involved in intracellular ing remains the most widely studied and replicated en-
homeostasis, contributing to the degradation and recy- vironmental prompter for IBD. Since the first described
cling of cytosolic contents and organelles, as well as to inverse association between UC and smoking in 1982,
the resistance against infection and removal of intracel- subsequent studies have confirmed the protective effect
lular microbes[19]. ATG16L1 is essential for all forms of of heavy smoking on the development of UC with a
autophagy, and the coding mutation T300A is associated lower rate of relapse[29-31]. Contrary to its effect on UC,
with an increased risk of CD. IRGM belongs to the p47 smoking increases the risk of CD and is associated with a

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 Zhang YZ et al . Pathogenesis of IBD

higher rate of postoperative disease[32]. proximately 1150 bacterial species, with each individual
Traditional conception for vitamin D’s role is concen- host having roughly 160 species[50]. Gut microbiome is
trated in calcium metabolism and bone health. Nowadays, established within the first 2 wk of life and then usually
there has been increasing recognition of the immuno- remains remarkably stable thereafter. Although it is only
logic role of vitamin D[33]. Recent literature suggests that possible to culture 20%-30% of the gut microbiome, the
the role of vitamin D is multifarious and associated with association between the changes in the microbiome and
diverse diseases including IBD. Leslie et al[34] found that IBD has been established[51]. Many studies have examined
vitamin D deficiency had been common in diagnosed the gut flora in CD and UC in both inflamed and non-
IBD patients and pointed out that low vitamin D had inflamed segments, and found that there is a significantly
contributed to the increased risk of IBD. In mouse mod- reduced biodiversity in faecal microbiome in IBD patients
els, vitamin D deficiency is associated with an increased compared to that in healthy controls[52]. Other research
susceptibility to dextran sodium sulfate-induced colitis has also found that the microbiota in IBD patients is un-
and 1,25(OH)2D3 supplementation ameliorates the sever- stable than that in healthy individual[53]. In healthy intes-
ity of intestinal inflammation[35]. tine, the Firmicutes and Bacteroidetes phyla predominate,
The effect of aspirin and nonsteroidal anti-inflamma- and contribute to the production of epithelial metabolic
tory drugs (NSAIDs) in the gastrointestinal tract is well substrates. In contrast, the microbiota is characterized by
recognized. However, limited high quality evidence is a relative lack of Firmicutes and Bacteroidetes, and an
available to support the notion that aspirin and NSAIDs over-representation of enterobacteria in CD; meanwhile,
have an effect in triggering onset or relapse of IBD. An- a reduction in Clostridium spp. and an increase in Esch-
anthakrishnan et al[36] found no association between the erichia coli (E. coli) have been reported in UC[54].
dose, duration, or frequency of aspirin use and the risk In healthy colon, there is a continuous mucus coating
for CD or UC; but the high dose, prolonged using dura- consisting of two layers of sub-structures: the outer is a
tion, and frequent use of NSAIDs had been associated loosely adherent layer, good for bacterial growth; while
with an increased risk of CD and UC. A recent study has the inner is a tightly adherent layer, normally sterile. In
found that the use of antibiotics is an important environ- IBD, particularly CD, there is a marked increase in bacte-
mental factor, influencing the risk of IBD through their ria associated with the colonic adherent mucus layer[55,56].
effect on the microbiome. Antibiotic use within the first In CD, a consistent increase in mucosa-associated E. coli
year of life is more common among pediatric IBD cases and reduction in Firmicutes are reported[57,58]. There is
compared to controls[37]. strong evidence for an increase in mucosa-associated E.
Stress has long been proposed to play a role in the coli in both the ileum and colon, and their presence within
pathogenesis of CD and UC[38-40]. Bitton et al[41] suggested the granulomas in CD implicates a primary pathogenic
that individuals with lower levels of stress had a reduced role[59]. An adherent and invasive E. coli (AIEC) pheno-
risk of the disease onset. Mood components of perceived type has been found in CD, which is typified by bacterial
stress, including depression and anxiety, may play a strong invasion into epithelial cells and replication within mac-
role in mediating the deterioration of IBD[42]. A retro- rophages[60]. AIEC has also been shown to induce granu-
spective study by Goodhand et al[43] found a reduction loma in vitro and granulomatous colitis in Boxer dogs[61].
in the number of symptomatic relapses in participants,
and the antidepressants beneficially impact the course of
IBD. However, a Cochrane review shows no benefit of IMMUNOLOGICAL FACTORS
psychological interventions in IBD[44]. The investigation of IBD pathogenesis has been domi-
Recent ecological and epidemiologic evidence sug- nated for a long time by the studies of mucosal immunity,
gests that air pollution may contribute to the risk of CD especially the T cell response. Available evidence suggests
and UC. The rising incidence of CD and UC in develop- that the dysfunctions of innate and adaptive immune
ing countries parallels the development of industrializa- pathways contribute to the aberrant intestinal inflamma-
tion[45]. Elevated air pollution is associated with an aug- tory response in patients with IBD. Most studies in the
ment in circulating polymorphonuclear leukocytes and last two decades have focused on the role of abnormal
plasma cytokines[46,47]. Kaplan et al[48] using The Health adaptive immune responses in the pathogenesis of IBD.
Improvement Network Database in the United King- The focus on the adaptive immune response has ulti-
dom, found that high levels of NO2 and SO2 correlate mately led to the notion that the two main types of IBD
with the increased risk of CD and UC. In another study, represent clearly distinct forms of gut inflammation: CD
total pollutant emission has been linked to increased rates has long been considered to be driven by a Th1 response
of hospitalizations for both CD and UC, suggesting that and UC has been associated with a non-conventional
ambient air pollution may also influence these established Th2 response[62,63]. The newly described Th17 cells are
diseases[49]. also involved in the gut inflammatory response in IBD[64].
Immunological studies have recently focused on the mu-
cosal innate immune responses, such as epithelial barrier
MICROBIAL FACTORS integrity, innate microbial sensing, autophagy and un-
The whole human gut microbiome consists of ap- folded protein response.

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 Zhang YZ et al . Pathogenesis of IBD

Innate immunity may also contribute to IBD pathogenesis. This response

The innate immune response represents our first line of is induced by endoplasmic reticulum stress and finally in-
defense against pathogens. It is non-specific, allowing the duces apoptotic cell death and causes IBD[74].
body to quickly respond to stimuli often within minutes In addition, defective epithelial barrier and increased
or hours. The innate immune response is mediated by intestinal permeability have long been observed in IBD
a large variety of different cell types including epithelial patients[75]. The first physical barrier that intestinal bacte-
cells, neutrophils, dendritic cells, monocytes, macrophages ria and food antigens encounter on the mucosal surface is
and natural killer cells[65]. This form of immunity is initi- represented by the mucous layer that covers the intestinal
ated by the recognition of microbial antigens, which is epithelium. The importance of mucus in the prevention
mediated by pattern recognition receptors including toll- of bacterial break-through and intestinal inflammation
like receptors (TLRs) on the cell surface and NOD-like has been proved by many studies[76]. The second line
receptors in the cytoplasm[66]. Recent studies have found of defense against bacterial invasion is formed by the
that the behavior of the cells mediating innate immu- intestinal epithelium which consists of enterocytes and
nity and the expression and function of both TLRs and specialized epithelial cells, such as goblet cells and Paneth
NOD proteins are altered significantly in individuals with cells. Besides forming a physical barrier against bacteria,
IBD. epithelial cells can secrete a number of antimicrobial pep-
A British study shows that mucosal neutrophil accu- tides. Defective expression of antimicrobial peptides has
mulation and production of IL-1β and IL-8 in response been observed in patients with CD[77].
to trauma are selectively reduced in CD patients but not
in UC patients[67]. GWAS reveal that the NOD2 muta- Adaptive immunity
tions most commonly associated with CD induce a defec- As opposed to the innate immune response, the adaptive
tive ability of the gut to respond to LPS, and this defect immunity is highly specific, often takes several days to
may contribute to disease susceptibility[68]. Although the respond and depends on the type and number of T cells.
functional role of NOD2 mutations is still controversial, Th1 cells, induced by IL-12, produce a high amount of
available evidence suggests that they represent loss-of- IFN-γ, whereas Th2 cells release IL-4, IL-5 and IL-13[78].
function mutations that lead to reduced activation of NF- An abnormal Th1 immune response is thought to cause
[69]
κB . This inadequate response might result in reduced intestinal inflammation in CD, and it has been observed
antibacterial agent production and pathogenic microbial that mucosal T cells from CD patients produce higher
invasion[70]. Other studies suggest that the loss of func- amounts of IL-2 and IFN-γ than T cells from UC pa-
tion of NOD2 may result in the lack of inhibition of tients or controls do[79]. It has also been shown that in
TLR2 stimulation, leading to activation of inflammatory UC, atypical NK T cells release higher amounts of the
pathways and excessive Th-1 responses[71]. Furthermore, Th2 cytokine IL-13 than T cells from controls or CD
NOD2 also contributes to immune tolerance. These ef- patients do[80,81]. Therefore, CD has been thought to be
fects are impaired in cells from patients with NOD2 mu- characterized by a Th1 immune response, while UC has
tation 3020insC[72]. been considered as a Th2-mediated disease[82]. However,
IL-23 is a key cytokine both in innate and adaptive there have also been different observations about mu-
immunity and possesses a central role in driving early cosal Th1 and Th2 cytokines in IBD. Both UC and CD
responses against microbes. IL23R polymorphisms have biopsies cultured in vitro release high and comparable
been associated with both CD and UC, suggesting that amounts of IFN-γ[83]. Lower levels of IL-13 are found in
IL-23 may represent a shared inflammatory molecule the colonic mucosa of UC patients compared to those
in chronic intestinal inflammation. Recent studies have in CD patients and subjects of the control group. Recent
shown that, besides its activity on Th17 cells, IL-23 can studies on experimental colitis have suggested an anti-
also act on cells of the innate immune system. IL-23 has inflammatory effect of IL-13 in the gut[84,85]. It has been
been shown to induce Th17 cytokine production by in- also observed that IL-13 levels in the supernatants of
nate lymphoid cells (ILCs) that share the phenotype of intestinal biopsies cultured in vitro are lower than IFN-γ
lymphoid tissue-induced cells[73]. concentration and the concentrations are comparable
CD has also been associated with ATG16L1 and among CD, UC and control groups[86]. Similar observa-
IRGM genes, which are involved in autophagy. ATG16L1 tions have been reported by Bernardo et al[87] who have
is essential for all forms of autophagy, and the coding described the presence of a mixed cytokine profile with
mutation T300A is associated with an increased risk of predominance of IL-6 and the absence of IL-13 in su-
CD. Autophagy is one of the mechanisms for maintain- pernatants of UC biopsies cultured in vitro. Collectively,
ing cellular homeostasis and considered very important these data should lead us to reconsider the Th1/Th2
for host defense against intracellular microorganisms. paradigm in CD and UC[82], but the conception that UC
Normally, autophagy is induced by bactericidal effects is a Th2-mediated disease remains controversial.
and presentation of endogenous antigens, and these pro- Th17 cells are a T cell subset characterized by the
cesses are impaired in patients with mutations in NOD2 production of large amounts of IL-17A, IL-17F, IL-21
or Atg16L1. Closely relating to autophagy and innate im- and IL-22. They are induced by a combination of IL-6
munity, dysregulation of the unfolded protein response and transforming growth factor (TGF)-β, and their ex-

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 Zhang YZ et al . Pathogenesis of IBD

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P- Reviewers: Manguso F, Osawa S S- Editor: Ma YJ

L- Editor: Wang TQ E- Editor: Zhang DN

WJG|www.wjgnet.com 99 January 7, 2014|Volume 20|Issue 1|

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