THEMATIC REVIEW SERIES ON GASTROENTEROLOGICAL DISEASES

Mechanisms of Disease: Inflammatory Bowel

Diseases
Guilherme Piovezani Ramos, MD, and Konstantinos A. Papadakis, MD

CME Activity
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AMA: Mayo Clinic College of Medicine and Science designates this journal- Dr Papadakis is a stock shareholder in Pfizer Inc, GlaxoSmithKline plc, and
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Learning Objectives: On completion of this article, you should be able to (1) Estimated Time: The estimated time to complete each article is approxi-
define key elements of the intestinal barrier responsible for maintaining intestinal mately 1 hour.
homeostasis, (2) understand the major mechanisms involved in the pathogenesis Hardware/Software: PC or MAC with Internet access.
of inflammatory bowel diseases (IBDs), (3) recognize the importance of genetic Date of Release: 1/1/2019
factors in the contribution to IBD development, (4) identify environmental factors, Expiration Date: 12/31/2020 (Credit can no longer be offered after it has
such as diet and medications, and their association with microbial dysbiosis and passed the expiration date.)
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Abstract

Inflammatory bowel diseases (IBDs), represented by Crohn disease and ulcerative colitis, are associated with
major morbidity in Western countries and with increasing incidence in the developing world. Although analysis
of the genome of patients with IBD, especially through genome-wide association studies, has unraveled multiple
pathways involved in IBD pathogenesis, only part of IBD heritability has been explained by genetic studies. This
finding has revealed that environmental factors also play a major role in promoting intestinal inflammation,
mostly through their effects in the composition of the microbiome. However, in order for microbial dysbiosis to
result in uncontrolled intestinal inflammation, the intestinal barrier formed by intestinal epithelial cells and the
innate immune system should also be compromised. Finally, activation of the immune system depends on the
working balance between effector and regulatory cells present in the intestinal mucosa, which have also been
found to be dysregulated in this patient population. Therefore, IBD pathogenesis is a result of the interplay of
genetic susceptibility and environmental impact on the microbiome that through a weakened intestinal barrier
will lead to inappropriate intestinal immune activation. In this article, we will review the mechanisms proposed
to cause IBD from the genetic, environmental, intestinal barrier, and immunologic perspectives.
ª 2018 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2019;94(1):155-165

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 MAYO CLINIC PROCEEDINGS

endoscopic findings observed in patients

I
nflammatory bowel diseases (IBDs), rep-
resented by Crohn disease (CD) and ul- with IBD (Figures 1 and 2). In this article,
cerative colitis (UC), are chronic and we will review the mechanisms proposed to
remitting disorders responsible for causing cause IBD from the genetic, environmental, in-
inflammation of the gastrointestinal tract. testinal barrier, and immunologic perspectives.
These conditions are associated with major
morbidity and mortality resulting in substan-
tial patient burden and costs to health care GENETIC FACTORS: HOST SUSCEPTIBILITY
systems. Approximately 1.6 million United Family aggregation of IBD has long been
States residents are affected by IBD, 785,000 recognized, but the inheritable component
with CD and 910,000 with UC.1 Prevalence seems to be stronger in CD than in UC, with
is higher in developed Western countries, a concordance rate in monozygotic twins of
with up to 2 million people with these condi- 30% to 58% in CD compared to 10% to 15%
tions in Europe.2 Interestingly, at the turn of in UC.5,7,8 The relative risk for disease devel-
the 21st century, newer epidemiological opment in first-degree relatives of patients
studies have revealed that the incidence of with IBD can be up to 5-fold higher than
IBD has been increasing in developing coun- that in unaffected individuals.9,10 The study
tries in South America, Asia, Africa, and of patients with very early-onset IBD, usually
Eastern Europe.1-3 The change in epidemio- with a family history of IBD and severe mani-
logical patterns in populations in which IBD festations of the disease, have helped identify
was not previously common raises again the rare genetic variants that may interfere with
question of important environmental factors pathways leading to intestinal inflamma-
that are involved in the development of these tion.11,12 For example, a rare mutation
chronic inflammatory disorders. affecting the regulatory function of the X-
The increased prevalence in specific pop- linked inhibitor of apoptosis (XIAP) gene
ulations around the world suggests an was found to result in early-onset IBD refrac-
important genetic component in the devel- tory to treatment in a 15-month old boy.13
opment of IBD, and the new epidemiological XIAP (X-linked inhibitor of apoptosis) is a
trends also reveal that environmental factors positive regulator of nucleotide-binding oligo-
play a critical role in the pathogenesis of CD merization domainecontaining protein 2
and UC. This change may be the result of
industrialization of developing countries.2,3
Most environmental triggers could mediate
GENETICS ENVIRONMENT
IBD pathogenesis through their impact on
the microbiome.3 However, in order for
Susceptibility Smoking
microbiome changes to result in inappro- Inheritance Diet
priate and continuing inflammation, the GWAS Medications
Noncoding variation Microbiota
integrity of the intestinal barrier separating
IBD
the lumen and the mucosa should also be Permeability Innate response
compromised.4,5 Finally, activation of the Goblet cells Cytokines
Paneth cells Effector cells
immune system, which would result in the Autophagy Regulatory cells
phenotypes seen in clinical practice, depends
on the working balance between effector and INTESTINAL IMMUNE
regulatory cells present in the intestinal mu- BARRIER RESPONSE
cosa, which have also been reported to be
dysregulated in this patient population.6 FIGURE 1. Mechanisms involved in the patho-
Therefore, it is the interplay of genetic sus- genesis of inflammatory bowel disease (IBD).
The pathogenesis of IBD is a result of the
ceptibility and environmental impact in the
interplay between genetic, environmental, in-
microbiome that through a weakened intesti-
testinal barrier, and immune response factors.
nal barrier will lead to inappropriate immune GWAS ¼ genome-wide association studies.
activation responsible for the clinical and
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MECHANISMS OF IBD

FIGURE 2. The intestinal mucosa in the normal bowel and in inflammatory bowel disease (IBD). On exposure to environmental
factors, patients with IBD have development of microbial dysbiosis with a decrease of short chain fatty acids (SCFA) producing
bacteria and an increase in Proteobacteria. Mechanisms that maintain the intestinal barrier are also disrupted in the IBD mucosa,
including down-regulation of epithelial cadherin (E-cadherin) in tight junctions; thickness of the mucus layer; abnormal goblet cell
function, including mucin 2 (Muc2) and resistin-like molecule b (RELMb) proteins; and dysfunctional Paneth celleassociated
mechanisms, including secretion of antimicrobial products, nucleotide-binding oligomerization domainecontaining protein 2
(NOD2), and autophagy-related 16-like 1 (ATG16L1) gene-associated functions. From the innate immune system perspective, the IBD
mucosa has been found to exhibit a decrease in colonic macrophages expressing CD14, defective CX3CR1 (C-X3-C motif che-
mokine receptor 1) antigen presentation by dendritic cells; and impaired autophagy. Lastly, although leukocyte migration via integrin
cellular adhesion molecule (CAM) interactions also occurs in the normal mucosa, the balance between effector and regulatory T cells
(T-reg) appears to be disturbed in the IBD mucosa, resulting in uncontrolled activation of different T-cell lineages that migrate to the
inflamed intestine. G ¼ goblet cells; IFNg ¼ interferon g; IL ¼ interleukin; NK-T ¼ natural killer T cell; P ¼ Paneth cells; Th ¼ T helper
cell; TGFb ¼ tumor growth factor b; TNFa ¼ tumor necrosis factor a.

(NOD2) function, which is compromised in childhood-onset IBD represents only 10% to

patients with IBD.14 Furthermore, mutations 25% of all IBD cases, and not all cases have
in the interleukin (IL)10 receptor (IL10RA) been associated with these types of genetic ab-
gene region, which can ultimately manifest normalities, suggesting that IBD is likely a
as early-onset IBD, have also been found to complex polygenic disease.16
be characterized by Medelian-like inheritance Most of the information related to the ge-
with highly penetrant variants.15 Nevertheless, netics of IBD has been obtained through

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 MAYO CLINIC PROCEEDINGS

genome-wide association studies polymorphisms within the autophagy-

(GWAS).5,8,17 The conceptual basis of related 16-like 1 (ATG16L1) gene, have
GWAS is that complex genetic disorders also revealed autophagy as an important
like IBD are polygenic, being driven by mul- pathogenic process in IBD.24-26 Further-
tiple common genetic polymorphisms.17 more, multiple IBD risk alleles acting at the
Meta-analysis combining GWAS data identi- IL-23 receptor (IL23R) loci suggested a role
fied 201 loci associated with IBD.18,19 of IL-23 signaling in CD, and this pathway
Among those, there are 41 CD-specific and is currently targeted by commercially avail-
30 UC-specific loci that may indicate some able drugs for the treatment of the
of the clinical, endoscopic, and histologic disease.27,28
differences seen in these patients.18,19 How- Up to 80% to 90% of GWAS-identified
ever, approximately 137 of the 201 loci loci, however, are confined to noncoding
(68%) are associated with both CD and variation that exerts its pathogenic effects
UC, indicating that these diseases share com- through modulation of gene expression.17
mon inflammatory pathways.19 Interestingly, Recent studies are focusing on small intranu-
around 70% of IBD loci are shared with clear molecules that can broadly regulate
other complex autoimmune and immunode- gene expression such as epigenetic markers,
ficiency diseases.19 Almost half of IBD- microRNAs, and noncoding RNAs, which
specific loci are associated with other have all been implicated in the pathogenesis
immune-mediated diseases, with strong of IBD through different pathways.
overlaps with ankylosing spondylitis and
psoriasis, which can often present as extrain- ENVIRONMENTAL FACTORS: THE ROLE OF
testinal manifestations of CD and UC.19,20 THE MICROBIOME
Genes implicated in the overlap between Despite the aforementioned advances, only
IBD and primary immunodeficiencies are about 25% of IBD heritability has been
associated with reduced levels of circulating explained by genetic studies.3,17 Further-
T cells or specific T-cell subsets, such as T more, new epidemiological trends of IBD in
helper (Th) 17 cells or regulatory T cells developing countries following industrializa-
(Tregs), again supporting an imbalance be- tion suggest that environmental factors may
tween effector and regulatory cells in the in- play an important role in promoting intesti-
testinal mucosa.6,19,21 nal inflammation in genetically susceptible
The benefit of identifying genes and ge- individuals.2,3
netic loci implicated in IBD is to understand Smoking has been one of the most stud-
disease-relevant biological pathways that are ied factors in the setting of IBD. Clinically,
crucial for the development of intestinal cigarette smoking has been found to be
inflammation.8,17,22 Biological processes harmful in patients with CD but protective
implicated by IBD-specific loci include bar- to those with UC.8 Different pathways have
rier function, epithelial restitution, microbial been hypothesized to explain these findings,
defense, innate immune regulation, reactive including impairments of autophagy, direct
oxygen species generation, autophagy, regu- toxicity to immune- and mucus-producing
lation of adaptive immunity, endoplasmic re- cells, and inducing changes in the micro-
ticulum stress, and metabolic pathways biome.29-31 Moreover, exposure to diets
associated with cellular hemostasis.8,22 For rich in saturated fatty acids and processed
example, NOD2, the first gene to be associ- meats has been reported to increase the
ated with IBD,23 recognizes the peptido- risk of IBD.32-34 Conversely, a high-fiber
glycan product muramyl dipeptide, which diet has been found to reduce the risk of
modulates both innate and adaptive immune CD by 40%.35 The metabolism of dietary fi-
responses.23 Identification of this molecule ber by colonic bacteria into light chain fatty
unraveled the role of the epithelial barrier acids that have anti-inflammatory properties
in maintaining mucosal hemostasis. NOD2 could potentially explain this protective
mutations, as well as others such as effect.36
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MECHANISMS OF IBD

The use of medications, most notably an- Furthermore, the number of mucolytic bacte-
tibiotics, has also been associated with ria seems to be increased in IBD, which
increased risk of IBD.37,38 This association consequently leads to a higher presence of
usually results from changes in the intestinal mucosa-associated bacteria in these pa-
microbiome after use of antibiotics during tients.55,56 Lastly, the number of sulfate-
early stages of life, when the microbiota reducing bacteria, such as Desulfovibrio, is
plays a critical role in shaping immune cell also increased in IBD, resulting in the produc-
39
development. Nonsteroidal anti- tion of hydrogen sulfate that damages the in-
inflammatory drugs, anticontraceptives, and testinal barrier and allows activation of
statins are other examples of medications mucosal inflammation.57
that have been associated with up to 2-
fold-increased risk for CD and UC.40-42 Early THE INTESTINAL BARRIER: EPITHELIUM
life events such as mode of delivery, breast- AND INNATE IMMUNITY
feeding, exposure to pets, and infections The intestinal mucosa exists in a functional
(“hygiene hypothesis”) are also factors asso- equilibrium with the luminal contents, and
ciated with considerable risk for develop- disturbance of this equilibrium can lead to
ment of IBD, mostly given influences in the diseases such as IBD. The intestinal barrier,
composition of the intestinal microbiota.43-46 consisting of intestinal epithelial cells
The intestinal microbiome has long been (IECs) and innate immune cells, maintains
recognized to establish the connection be- this balance between luminal contents and
tween the outside environment and the intes- the mucosa. The importance of the epithelial
tinal mucosa. Microbial dysbiosis, as a result barrier in IBD predisposition is supported by
of decreased diversity of the microbiome, the finding of abnormal intestinal perme-
has been described in patients with IBD.47,48 ability in patients with CD and some of their
Whether this is the cause or consequence of first-degree relatives.58-61 Furthermore, anal-
the observed intestinal inflammation, or ysis of intestinal biopsies from patients with
both, is yet to be determined.47 In patients CD has revealed down-regulation of the
with IBD, there is a decrease of bacteria junctional protein epithelial cadherin, which
with anti-inflammatory capacities and an in- comprises the tight junctions of this physical
crease of bacteria with inflammatory capac- barrier.62,63 Other studies have also associ-
ities compared with healthy individuals.48,49 ated IBD with several transcription factors
The most frequently observed changes involved in epithelial regeneration, such as
include a decrease of Firmicutes and an in- HNF4A (hepatocyte factor 4a) and NKX2-
crease in Proteobacteria and Bacteroidetes.4 3 (NK2 homeobox 3).64,65
The number of short chain fatty acids pro- Beyond just a promoting physical barrier
ducing bacteria (eg, Faecalibacterium praus- between lumen and mucosa, IECs of the in-
nitzii) has been reported to be decreased in testinal barrier consist of different cell types
patients with IBD, consequently affecting dif- that maintain the equilibrium of the lumen-
ferentiation and expansion of Tregs as well as mucosa through different mechanisms; these
growth of epithelial cells.50 Interestingly, the cells include enterocytes, goblet cells, neuro-
lower number of F praunitzii colonization endocrine cells, Paneth cells, and M cells
has been found to correlate with the risk of (Figure 2).66 Goblet cells produce the mucus
ileal CD after surgery and maintenance of matrix covering the epithelium, essential to
clinical remission in UC.51-53 In contrast, both mucosal defense and repair.67 Genetic
the increase in Proteobacteria, most notably deletion of Muc2 (mucin 2), a major goblet
Escherichia coli, with the ability to adhere to cellederived secretory mucin, results in
the intestinal epithelium affects the perme- spontaneous colitis in murine models.68
ability of the intestine, alters the diversity Resistin-like molecule b (RELMb), another
and composition of the microbiota, and in- goblet cellespecific protein, creates a bridge
duces inflammatory responses by regulating with the immune system by directing Th2
the expression of inflammatory genes.54 cell immunity and delivering luminal
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 MAYO CLINIC PROCEEDINGS

antigens to tolerogenic sets of dendritic have the capacity of producing anti-

cells.69,70 Disturbance of the RELMb gene re- inflammatory cytokines that promote regula-
duces the severity of colitis in murine tory T-cell differentiation and restrain Th1
models.71 cell and Th17 cell responses.80 Patients
Although Goblet cells seem to play a part with CD have defective innate immune re-
in protecting individuals from colitis devel- sponses, including attenuated macrophage
opment, defects in Paneth cell biology are activity in vitro and impaired neutrophil
associated with increased risk for CD.72,73 recruitment, facilitating microbe passage
Paneth cells reside at the base of small intes- through the mucosa.81 These patients also
tinal crypts and are responsible for crypt ho- present with another inflammatory macro-
meostasis, maintenance of intestinal stem phage population that expresses dendritic
cell niche, and secretion of antimicrobial cell markers, including CD14, and produce
effector cells that control the equilibrium be- large amounts of proinflammatory cytokines,
tween microbiota and mucosa.73 The path- such as tumor necrosis factor a and IL-6.82
ways of several key genetic risk factors for In contrast to phagocytic macrophages, den-
IBD impair Paneth cell function and lead to dritic cells constitute an interface for moni-
colitis, most notably NOD2 and autophagy. toring the environment and relaying signals
NOD2 is expressed by Paneth cells, dendritic to initiate appropriate adaptive responses.83
cells, macrophages, and absorptive IECs. Sampling of bacteria by resident dendritic
NOD2 risk variants are associated with lower cells is mediated in part by a CX3CR1 (C-
levels of a-defensins in Paneth cells leading X3-C motif chemokine receptor 1)edepen-
to impaired antimicrobial function.74 Not dent mechanism that permits direct den-
only through NOD2 but also via CD risk lo- dritic cell to microbe contact.84 Genetic
cus ATG16L1, Paneth cells’ function in auto- deletion of CX3CR1 results in decreased
phagy is compromised in patients with numbers of lamina propria macrophages
CD.25,75 Autophagy is an intracellular “self- and increased translocation of bacteria to
cannibalism” that involves degradation and mesenteric lymph nodes.85 Dendritic cells
recycling of cytosolic contents and organ- have been found to accumulate in the mu-
elles, as well as resistance against infection cosa of patients with IBD. Blockage of
and removal of intracellular microbes.76 Pa- CD40/CD40L interactions between dentritic
tients with ATG16L1 and NOD2 mutations, cell and effector T-cell populations, prevents
as well equivalent murine models, demon- experimental T cellemediated colitis.86,87
strate aberrancies in the secretory apparatus
of Paneth cells resulting in defects in anti- ADAPTIVE IMMUNE RESPONSE: EFFECTOR
bacterial autophagy.77 In dendritic cells, de- AND REGULATORY CELLS
fects in these genes also result in an Upon encounter with antigen and microbial
impaired ability to present exogenous anti- products that gain access through the intes-
gens to T cells.26 tinal barrier, dendritic cells and other
Dendritic cells, macrophages, innate antigen-presenting cells (APCs) initiate a
lymphoid cells, and neutrophils complement cascade of proinflammatory and anti-
the physical and functional barrier of IECs as inflammatory signals to activate different
the first line of defense of a well-developed subsets of local and circulating lymphocytes
mucosal innate immune system. In the to migrate to effector sites where inflamma-
healthy human gut, intestinal macrophages, tion takes place. Migration of leukocytes to
which are characterized by lack of CD14 the inflamed intestine occurs via binding of
expression, exist in a state of hyporespon- integrin molecules located on leukocyte sur-
siveness, showing attenuated proliferation face to cellular adhesion molecules
and chemotactic activity in response to expressed on the surface of endothelial
either microbial ligands or host cytokines cells.88 These endothelial cells, as a reflex
while retaining the phagocytic and bacteri- of inflammatory signals in the mucosa, can
cidal function.78,79 Furthermore, they also also produce chemokines to attract
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MECHANISMS OF IBD

leukocytes to sites where inflammation is production of IL-12, IL-18, IL-23, and trans-
taking place.89 The integrins aLb2, a4b1, forming growth factor b by APCs and macro-
a4b7, and aEb7 are heterodimeric receptors phages. In turn, Th1 and Th17 cells secrete
expressed on the surface of circulating leu- the proinflammatory cytokines IL-17, inter-
kocytes capable of interacting with different feron g, and tumor necrosis factor a that
adhesion molecules for specific leukocyte feed into a self-sustaining amplification cycle
trafficking to the intestine.88 Currently, mul- whereby they stimulate APCs, macrophages,
tiple commercially available drugs are suc- fibroblasts, and endothelial cells to produce
cessfully used in clinical practice to target tumor necrosis factor a, IL-1, IL-6, IL-8,
these molecules in order to prevent leuko- IL-12, and IL-18.5,22,98 Studies have found
cyte migration to the intestine and control that mice deficient in IL-12 p40 subunit
inflammation in patients with IBD.90,91 and IL-23 are resistant to experimentally
New therapies that control inflammation in induced colitis, suggesting that these cyto-
patients with CD and UC target endothelial kines are in the center of the CD inflamma-
cell cellular adhesion molecules or preven- tory pathway.99,100 Therapeutic agents
tion of lymphocyte egression from lymph targeting the shared p40 subunit between
nodes are currently under evaluation in clin- IL-12 and IL-23 are currently used in clinical
ical trials.89,92,93 practice to control intestinal inflammation,
The disturbed balance between anti- and new therapies targeting the IL-
inflammatory and proinflammatory signals 23especific p19 subunit are currently under
with consequent migration of leukocytes to clinical evaluation.101,102 Conversely, drugs
the intestinal mucosa results in and is perpet- directed to the Th17 cellespecific cytokine
uated by an exaggerated T-cell immune IL-17A may worsen the inflammation in pa-
response, which is seen in both CD and UC tients with CD.103 In addition to secretion of
(Figure 2). The T cells involved in immune effector cytokines, Th17 cells also fulfill
responses in these diseases, however, seem important homeostatic functions in the in-
to be different, which may explain phenotypic testine, which may explain these conflicting
differences seen in clinical practice as well as results. In this scenario, IL-17A may also
response to new targeted therapies. Whereas play a role in protecting barrier integrity
the intercalated transmural inflammation of and Treg function, which are crucial to con-
CD results from an excessive Th1 cell and trolling immune activation and limiting in-
Th17 cell response, the uniform mucosal flammatory responses.104
inflammation seen in UC is secondary to a Tregs and Th17 cells have opposing ac-
Th2 celletype-like cytokine profile.22 In UC, tivities but arise from a common precursor
increased secretion of the Th2 cellespecific on transforming growth factor b (TGF-b)
cytokine IL-5 is associated with more efficient stimulation. The abundance of TGF-b in in-
activation of B cells and the induction of im- testinal tissues contributes to normal ho-
mune responses compared with the Th1 cell meostasis by promoting Treg differentiation
response seen in CD.22,94 Interestingly, UC- in naive lamina propria CD4þ T cells.105 In
specific Th cells show only low levels of IL- inflammatory states such as IBD, Th17-cell
4 production, which suggests they do not differentiation is promoted instead as a com-
display all the features of classic Th2 cells.94,95 bination of mucosal TGF-b with other sig-
Instead, UC is associated with the presence of nals, including cytokine, metabolite, and
CD1d-restricted nonclassic natural killer T microbial signals.106 Therefore, the gut may
cells that produce IL-13, which is increased use TGF-b pathways to promote T cells to
in the lamina of patients with UC but not in carry out both proinflammatory and anti-
those with CD.22,95 AntieIL-13 inhibitors inflammatory programs depending on the
have had conflicting results in treating pa- local presence of cytokines and microbial
tients with UC in clinical trials.96,97 products that may consequently affect initia-
In CD, the differentiation of Th cell types tion, persistence, and relapses in human IBD.
1 and 17 occurs in response to the Many of the genes required for Treg and
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 MAYO CLINIC PROCEEDINGS

Th17-cell differentiation have been impli- in controlling inflammation in refractory

cated in IBD pathogenesis.8 In experimental UC.113
models, inflammation driven by Th17 cells
leads to colitis and can be suppressed by
Tregs. In this setting, Tregs have an impor- FUTURE PERSPECTIVES: TARGETED
tant function not only in restraining effector EVALUATION AND THERAPY
T-cell populations but also in controlling Understanding the mechanisms that lead to
innate inflammatory mechanisms.107 Loss- IBD pathogenesis is crucial in order to find
of-function mutations in the key Treg tran- new therapeutic strategies to improve patient
scription factor FOXP3 (forkhead box P3) therapies. Beyond identifying new pathways
results in IPEX (immune dysregulation, pol- amendable for therapeutic intervention, new
yendocrinopathy, enteropathy, X-linked syn- genomic studies should also aim to assist
drome), which can be accompanied by with risk stratification and possibly under-
intestinal inflammation.108 Tregs are standing different responses to available ther-
expanded in both inflamed and noninflamed apies and the development of more
UC and could have a critical role in modu- personalized medicine. Aiming for this tar-
lating the clinical spectrum of the disease.109 geted evaluation from an environmental
Therefore, the use of Tregs has been pro- perspective, studies should attempt to charac-
posed as an alternative strategy to control terize the composition of the microbiome,
excessive inflammation in IBD.110 both quantitatively and functionally (metabo-
lome), in order to assess how it interferes
New immunotherapies currently in
with outcomes of intestinal inflammation
development and clinical trials aim to reduce
and response to therapy. Modulation of the
the inflammatory response of IBD by block-
microbiome has already had promising re-
ing downstream signaling pathways associ-
sults in small trials of fecal microbiota trans-
ated with different cytokines. Janus kinases
plant, mostly in patients with UC.114
(JAKs) are a family of tyrosine kinases
Furthermore, the use of cell-based therapies,
(JAK1, JAK2, JAK3, and TYK2 [tyrosine ki-
most notably stem cells, is in the horizon of
nase 2]) that working in pairs mediate intra-
individualized IBD therapy with the purpose
cellular communication between cytokine
of assisting with mucosal healing, recovery
receptors and nuclear signals.111 These mol-
of the intestinal barrier, and control of aber-
ecules act as a bridge between cytokine re-
rant immune responses.115 Lastly, with a va-
ceptors and intranuclear proteins, most
riety of immunotherapies approaching
notably signal transducer and activator of
clinical practice, future studies should
transcription factors (STATs). The 7
consider an individualized treatment
different members of the STAT family
approach based on specific features of each
(STAT1, STAT2, STAT3, STAT4, STAT5A,
individual’s inflammatory response, because
STAT5B, and STAT6) combine in pairs
inflammatory responses vary from patient to
with different JAKs in order to mediate intra-
patient as well as over time in a single patient.
cellular effects of specific cytokine pathways
and are, therefore, potential therapeutic tar-
Abbreviations and Acronyms: APC = antigen-presenting
gets in the modulation of inflammation.112
cell; CD = Crohn disease; GWAS = genome-wide associa-
In the case of IL-12 and IL-23, which are tion studies; IBD = inflammatory bowel disease; IEC = in-
important cytokines in the pathogenesis of testinal epithelial cell; IL = interleukin; JAK = Janus kinase;
CD, JAK2 and TYK are activated by the STAT = signal transducer and activator of transcription; Th
= T helper; Treg = regulatory T cell; UC = ulcerative colitis
membrane receptors and will consequently
recruit STAT3 and STAT4 to deliver intranu- Grant Support: Dr Papadakis is supported by National Insti-
clear signals associated with controlling Th1/ tutes of Health grant 1R03AI131011-01A1.
Th17 cell responses seen in these pa-
Potential Competing Interests: Dr Papadakis is a stock
tients.100,111 Recent studies have also re- shareholder in Pfizer Inc, GlaxoSmithKline plc, and Amgen
ported promising results of JAK inhibitors Inc. Dr Ramos reports no competing interests.

n n
162 Mayo Clin Proc. January 2019;94(1):155-165 https://doi.org/10.1016/j.mayocp.2018.09.013
www.mayoclinicproceedings.org
MECHANISMS OF IBD

The Thematic Review Series on Gastroenterological and highlight shared genetic risk across populations. Nat
Diseases will continue in an upcoming issue. Genet. 2015;47(9):979-986.
19. Jostins L, Ripke S, Weersma RK, et al. Host-microbe interac-
Correspondence: Address to Konstantinos A. Papadakis, tions have shaped the genetic architecture of inflammatory
MD, Division of Gastroenterology and Hepatology, Mayo bowel disease. Nature. 2012;491(7422):119-124.
Clinic, 200 First St SW, Rochester, MN 55905 (Papadakis. 20. Hindorff LA, Sethupathy P, Junkins HA, et al. Potential etio-
logic and functional implications of genome-wide association
[email protected]).
loci for human diseases and traits. Proc Natl Acad Sci U S A.
2009;106(23):9362-9367.
Individual reprints of this article and a bound reprint of the 21. International Union of Immunological Societies Expert Commit-
entire Thematic Review on Gastroenterological Diseases tee on Primary Immunodeficiencies, Notarangelo LD, Fischer A,
will be available for purchase from our website www. Geha RS, et al. Primary immunodeficiencies: 2009 update [pub-
mayoclinicproceedings.org. lished correction appears in J Allergy Clin Immunol. 2010;125(3):
771-773]. J Allergy Clin Immunol. 2009;124(6):1161-1178.
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