Genetic and Epigenetic Etiology of Inflammatory Bowel Disease: An Update

Abstract

Inflammatory bowel disease (IBD) is a chronic disease with periods of exacerbation and remission of the disease. The etiology of IBD is not fully understood. Many studies point to the presence of genetic, immunological, environmental, and microbiological factors and the interactions between them in the occurrence of IBD. The review looks at genetic factors in the context of both IBD predisposition and pharmacogenetics.

Full text

Citation: Jarmakiewicz-Czaja, S.;
Zieli´nska, M.; Sokal, A.; Filip, R.
Genetic and Epigenetic Etiology of
Inflammatory Bowel Disease: An
Update. Genes 2022,13, 2388.
https://doi.org/10.3390/
genes13122388
Academic Editor: Manmeet Rawat
Received: 17 November 2022
Accepted: 9 December 2022
Published: 16 December 2022
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genes
G C A T
T A C G
G C A T
Review
Genetic and Epigenetic Etiology of Inflammatory Bowel
Disease: An Update
Sara Jarmakiewicz-Czaja 1, Magdalena Zieli ´nska 1, Aneta Sokal 1and Rafał Filip 2, 3, *
1Institute of Health Sciences, Medical College of Rzeszow University, 35-959 Rzeszow, Poland
2Institute of Medicine, Medical College of Rzeszow University, 35-959 Rzeszow, Poland
3Department of Gastroenterology with IBD Unit, Clinical Hospital No. 2, 35-301 Rzeszow, Poland
*Correspondence: r.s.filip@wp.pl
Abstract:
Inflammatory bowel disease (IBD) is a chronic disease with periods of exacerbation and
remission of the disease. The etiology of IBD is not fully understood. Many studies point to the
presence of genetic, immunological, environmental, and microbiological factors and the interactions
between them in the occurrence of IBD. The review looks at genetic factors in the context of both IBD
predisposition and pharmacogenetics.
Keywords:
Crohn’s disease; genetic factors; inflammation bowel disease; pharmacogenetics;
ulcerative colitis
1. Introduction
Inflammatory Bowel Disease (IBD) is diagnosed in patients with a genetic predis-
position who have been shown to have abnormalities of the immune system, usually in
correlation with specific environmental factors [
1
]. They are characterized by periods of
active phase of the disease and remission. The course and severity of the disease can vary in
patients depending on the location and extent of the inflammation [
2
]. The most common
IBD are ulcerative colitis (UC) and Crohn’s disease (CD). CD and UC can occur in both
men and women of all ages. Western lifestyles are causing an increase in the incidence of
IBD year after year. Researchers predict that its prevalence will increase significantly in
the next few years [
3
]. IBD was initially diagnosed in western Europe and North America.
The authors of numerous publications point to the development of industrialization in
these regions of the world as a reason. After 1950, due to a large increase in population and
the development of medical care, industry, and the economy, there was also an increase in
the incidence of IBD. Subsequently, stabilization of the incidence of IBD was observed in
western countries between 1990 and 2015 [
4
]. Mak et al. in their review present that there
has been a sharp increase in the incidence of IBD in the East over the past decade. They
also noted that environmental factors and genetic susceptibility differ between eastern and
western populations [
5
]. However, in both western and eastern countries, the cost of IBD in
health care systems continues to increase, indicating the need to anticipate future burdens.
Due to the aging population and the presence of comorbidities, the period of exacerbation
in CD or UC may be longer and more intense [
3
,
6
]. The incidence of UC is higher year after
year compared to CD. The most common diagnosis of UC is made in the third and fourth
decades of life, while CD is diagnosed primarily in people in the second and third decades
of life. Up to 16% of IBD cases are diagnosed after age 65, while approximately 4% are
diagnosed before age 5. They are most often diagnosed in the Caucasian race. Ashkenazi
Jews of Central and Eastern European descent are a particularly vulnerable group, with a
four-time higher incidence of CD than others in the Caucasian population. The incidence
of IBD varies depending on the geographical location and industrial development of the
country. They occur primarily in Europe, especially in Scandinavia and the UK, North
America, China, South Korea, Japan, India, and Australia [7].
Genes 2022,13, 2388. https://doi.org/10.3390/genes13122388 https://www.mdpi.com/journal/genes

Genes 2022,13, 2388 2 of 23
The etiology of IBD is not fully understood. Several studies point to the presence
of genetic, immunological, environmental and microbiological factors and the interplay
between them in the occurrence of IBD [8].
2. Etiology—Genetics Factors
The first genetic factor that, in 2001, was associated with the occurrence of CD was a
mutation in the nucleotide oligomerization domain containing the protein 2 gene (NOD2). The
NOD2 gene encodes a protein that functions as a receptor that recognizes components of
the building wall of pathogenic bacteria. The pattern recognition receptor (PRR) is found in
intestinal epithelial cells and monocytes, where it stimulates their autophagy [
9
]. The main
variants of NOD2 mutations associated with CD are the following: R702W and G908R [
10
].
Relatives with a positive family history for these conditions may show susceptibility to the
disease, but this depends primarily on the phenotype of the disease. Other alterations of
genes responsible for autophagy, e.g., ATG16L1—autophagy-related 16-like 1, LRRK2—repeat
kinase rich in leucine, 2, and IRGM—immune-related GTPase M, which can predispose to
IBD, are also presented in the literature [
11
–
13
]. IL-10 receptor mutations (IL10RA and
IL10RB) are also examples that can lead to colitis [
14
,
15
]. Additionally, some 240 gene loci
associated with the predisposition and occurrence of IBD have been found. A direct, shared
association with CD and UC has been demonstrated at 30 loci [
16
]. In addition, some of the
loci may be predictive of IBD. In the case of CD, the detected loci include: FOXO3, IGFBP1,
and XACT [17].
2.1. Genetic Factors and the Microbiome in Inflammatory Bowel Disease
In recent years, the topic of the influence of genetic factors and the microbiome on IBD
has received a lot of attention from researchers [
18
]. One of the most important challenges
in IBD research is to determine how the relationship between genetic factors, immune
factors, and the intestinal microbiota, influenced by certain environmental factors, leads to
chronic intestinal inflammation. However, intestinal inflammation may be a major factor
that strongly influences the composition of the microbiota and therefore it is not obvious to
determine the influence of genetics on the intestinal microbiome in people diagnosed with
IBD. To date, it is not entirely clear whether dysbiosis (an imbalance or altered composition
and function of the microbiota, leading to disrupted host-microbiota interactions) is a cause
or a consequence of inflammatory bowel disease [
19
]. In patients with IBD, there is a
decrease in both the diversity of the microbiota species. According to the study, compared
to healthy individuals, IBD patients tend to have a greater abundance of members of the
Bacteroidetes group and Proteobacteria, such as Enterobacteriaceae (including Escherichia coli)
and a smaller number of Firmicutes (e.g., Lactobacillus) [
20
,
21
]. A decrease in the number of
Roseburia bacteria (Firmicutes cluster) has been reported in CD patients [
22
,
23
]. Patients with
IBD patients show a decrease in the number of species that produce butyrate, a short-chain
fatty acid that positively modulates intestinal balance and reduces inflammation [
24
]. It has
been documented that the prevalence of specific bacteria, such as Actinobacteria, Campylobac-
ter species and Enterobacteria, may be important in the development of IBD [
25
]. Many of the
genetic mutations associated with IBD are related to immune function, and in particular
with interactions between the immune system and the microbiome. The microbiota affects
the activation of certain genes associated with hypomethylated active regulatory regions,
thus causing the expression of genes associated with IBD [
26
]. The susceptibility genes for
IBD involved in pathogen recognition and elimination likely influence dysbiosis. These
mainly include NOD2 (nucleotide binding oligomerization domain containing 2), ATG16L1
(autophagy-related 16-like 1), CARD9 (caspase recruitment domain family member 9) and CLEC7A
(C-Type Lectin Domain Containing 7A) [27–30].
2.1.1. NOD2 (Nucleotide Binding Oligomerization Domain Containing 2)
The strongest genetic risk locus in IBD is the NOD2 gene mutation [
31
,
32
]. The protein
encoded by the NOD2 gene is expressed in intestinal epithelial cells (including Paneth cells)

Genes 2022,13, 2388 3 of 23
and lymphocytes of the lamina propria (including T cells), and most strongly in monocytes
and macrophages. It acts as a defense factor against bacteria and contributes to the immune
response against commensal microorganisms [
33
]. It reacts specifically to a peptidoglycan
component found in the cell wall of Gram-positive bacteria and Gram-negative bacteria,
muramyl dipeptide (MDP), and acts as a potent regulator of cell differentiation, prolifera-
tion, and apoptosis through the mitogen-activated protein kinase (MAPK) pathway [
34
]. As
a result, mutations in the NOD2 gene alter Paneth cells’ ability to recognize and eliminate
invading pathogens that cause the development of inflammatory bowel lesions [
30
,
34
].
Additionally, NOD2 is required for the initiation of bacterial autophagy, which proceeds
with the recruitment of the autophagy molecule ATG16L1 to the membrane-bound bacterial
uptake site. NOD2 mutations have also been associated with an increase in the number
of E.coli (Proteobacteria type) and a decrease in the number of Faecalibacterium prausnitzii
(Firmicutes type) [35]. The NOD2 gene mutation and its impact on the microbiota in IBD is
shown in Table 1.
Table 1. The NOD2 gene mutation and its impact on the microbiota in IBD.
Genes Studied Conclusions of the Study
Animal studies NOD2 gene
•
In mouse models of colitis, the NOD2 gene mutation is associated with dysbiosis,
which does not cause changes in mucosal or immune tissue [36].
•Mice with NOD2 gene mutation show inefficient recognition and clearance of
bacterial pathogens. They have been observed to have statistically significant
increases in Porphyromonadaceae (Bacteroidetes), Enterobacteriaceae, Sutterellaceae
(Proteobacteria) and Coriobacteriaceae (Actinobacteria) [37].
Research
involving humans NOD2 gene
•In 474 patients with IBD, there was an association between the dose of NOD2
risk alleles, consisting of rs104895431, rs104895467, rs2066844, rs2066845,
rs5743277, rs5743293, and the increased relative abundance of Enterobacteriaceae.
The association may be independent of the disease and may play a role in the
pathogenesis only in individuals with other risk factors [38].
•
Carriers of the C allele at rs2066845 were significantly associated with an increase
in relative abundance in the fecal bacterial family Erysipelotrichaceae. NOD2
polymorphisms contribute to the composition of the fecal microbiome in
asymptomatic individuals. It is unknown whether this modulation of the
microbiome affects the future development of CD [39].
•An association has been confirmed between the ileal phenotype of CD-affected
individuals with a reduced relative abundance of the Ruminococcaceae family and
an increased relative abundance of the Actinobacteria group and the
Firmicutes/Bacillus class [40].
•
In a cohort of 1,514 healthy individuals, the NOD2 locus was associated with the
enterobactin biosynthesis pathway, which is highly correlated with the
abundance of E. coli. The authors suggested that enterobactin produced by E. coli
inhibits myeloperoxidase (MPO), a bactericidal host enzyme, thus providing a
survival advantage that allows E. coli to bypass the innate host immune response
in inflammatory bowel disease [41].
•An increase in anaerobic bacteria from the Enterobacteriaceae family has been
shown in the microbiota of CD patients compared to controls without IBD [42].
•The ATG16L1 (Autophagy-related 16-like 1 protein) and NOD2 genes probably
played an essential role in the beneficial immunomodulatory properties of
Bacteroides fragilis, which protects mice from experimental colitis [43].
•Candida albicans was shown to be the most abundant species in CD-positive
patients, as well as in those with CD-associated NOD2 mutations. More studies
have been required to determine whether Candida is an intestinal commensal or a
pathogen in patients with CD [44].
NOD2 plays a key role in gut microbiota homeostasis by detecting both commensal
and pathogenic microorganisms [
45
]. In a review by Turpin et al. researchers highlighted
the role of NOD2 in the pathogenesis of IBD by affecting the intestinal microbiota, although
the exact mechanism of this phenomenon has not yet been determined [46].

Genes 2022,13, 2388 4 of 23
2.1.2. ATG16L1 (Autophagy-Related 16-like 1)
Most of the evidence for an association between this genetic variant and the etiology of
IBD comes from functional studies using the variant ATG16L1 T300A. The ATG16L1 T300A
polymorphism is a genetic factor that increases the risk of Crohn’s disease pathogenesis [
47
].
ATG16L1 contributes to the regulation of the autophagy pathway, which includes lysosome
degradation and intracellular bacterial clearance [48].
ATG16L1 and NOD2 interact in the autophagy-dependent antimicrobial pathway,
suggesting that defects in both pathways may affect the abundance of Bacteroides [
49
].
Evidence pointing to a role for autophagy in the etiology of IBD comes from genome-wide
association studies, which have identified single nucleotide polymorphisms (SNPs) in
genes related to autophagy as susceptibility factors for CD. Autophagy is an evolutionarily
conserved cellular process in eukaryotes in which cytoplasmic materials are degraded
inside the lysosome [
50
]. This allows the cell to recycle its damaged components and
use degraded intracellular materials and proteins in energy production and de novo
synthesis [
51
]. The interaction between genes and their products is essential for the proper
elimination of invading pathogens [
52
]. Loss of ATG16L1 function alters autophagy in
intestinal epithelial cells (Paneth cells) and influences their possibility to secrete various
antimicrobial peptides. This promotes bacterial proliferation and invasion through the
intestinal epithelium. The ATG16L1 gene mutation and its impact on the microbiota in IBD
is shown in Table 2.
Table 2. The ATG16L1 gene mutation and its impact on the microbiota in IBD.
Genes Studied Conclusions of the Study
Animal studies ATG16L1 gene
•There were changes in the composition of the fecal microbiota of knock-in mice
expressing the variant ATG16L1 (T300A) compared to wild-type (WT) mice. An
increase in the number of Bacteroides (Bacteroides ovatus) was demonstrated.
During dextran sulfate sodium (DSS)-induced colitis, knock-in mice show an
altered fecal microbial composition associated with a decrease in Firmicutes and
an increase in Bacteroidetes, Proteobacteria, and Cyanobacteria compared to WT
mice. Changes occurred before the onset of the disease, suggesting that ATG16L1
T300A contributes to dysbiosis before the onset of IBD symptoms [28].
•Mice with ATG16L1 (T300A) mutations show reduced antimicrobial autophagy
and abnormal lysozyme distribution in Paneth cells [53].
•ATG16L1 mice show morphological abnormalities in Paneth and cup cells, but
do not develop intestinal autophagy or inflammatory bowel disease [54].
•ATG16L1 T300A/T300A mice showed a significant increase in the abundance of
Tyzzerella, Mucispirillum, Ruminococcaceae and Cyanobacteria in both feces and
intestinal mucosa, while Akkermansia, a mucin-associated bacterium, was
significantly reduced in ATG16L1 T300A/T300A mice. Dysbiosis in ATG16L1
T300A mice may be an important factor that contributes to increased
susceptibility to IBD [55].
Research
involving humans ATG16L1 gene
•The inflamed ileum of patients homozygous for the ATG16L1 allele
(ATG16L1-T300A) contained an increased number of Fusobacteriaceae, while the
inflamed ileal tissue of patients homozygous for the protective allele of ATG16L1
(ATG16L1-300) showed a decreased number of Bacteroidaceae and
Enterobacteriaceae and an increase in Lachnospiraceae. [56].
The findings suggest that CD-associated ATG16L1 polymorphisms (ATG16L1-T300A,
ATG16L1-300) can alter the composition of the microbiota through changes in antimicrobial
peptide secretion, but in a study of 313 patients with IBD, IBD-GRS (based on 200 SNPs
associated with IBD risk) showed no association with the composition of the microbiota.
These findings suggest that host genetics may influence the composition of the microbiome,
but inflammation can mask or alter this relationship [
57
]. Current data confirm that the
spolymorphism predisposes to CD, also identifying an additive effect of the G allele in
patients with CD, but no association is shown between the ECM1 polymorphisms (G290S,

Genes 2022,13, 2388 5 of 23
T130M) and susceptibility to UC [
58
]. The results point to a strong genetic background
that plays a key role in the development of CD. ATG16L1 T300A contributes to intestinal
dysbiosis and dysregulated immune responses before the onset of disease symptoms, and
autophagy is crucial to maintaining intestinal homeostasis, adequate intestinal immune
responses, and antimicrobial protection [
59
]. The findings show that defective autophagy
alone does not cause intestinal dysbiosis, but can do so in combination with an infectious
agent.
2.1.3. CARD9 (Caspase Recruitment Domain 9)
CARD9 also plays a role in the response to bacteria by interacting with NOD2. It is
selectively expressed in myeloid immune cells, including dendritic cells, macrophages,
neutrophils, and consists of an N-terminal activating domain and recruitment caspase
(CARD), a coiled coil domain, and a C-terminal tail without specific domain structure, and
is an important regulator of immunity against bacteria, fungi, and viruses [
60
]. In 2018,
the variant rs10781499 of CARD9 was confirmed to be a genetic high-risk factor for IBD,
altering the composition of the intestinal microbiota in patients with IBD. CARD9 deficiency
is associated with intestinal fungal dysbiosis, revealing CARD9 signaling as a critical link
between intestinal mucosal immunity and intestinal fungi [
61
]. Some variants of CARD9
show an increased risk (rs10870077, rs10781499, and rs4077515), while others (rs141992399,
rs200735402) show a protective effect against IBD [
62
]. This could be attributed to the
fact that the CARD9 variants have different mechanisms of pathogenesis and therefore
different susceptibilities to disease. In a study of the Chinese Han population, the CARD9
predisposing variants rs10870077 and rs10781499 do not increase susceptibility to IBD.
These divergences can be partly explained by the different prevalence, phenotypes, and
epidemiology among patients of the Chinese Han population and western countries [
63
].
The CARD9 gene mutation and its impact on the microbiota in IBD is presented in Table 3.
Table 3. The CARD9 gene mutation and its impact on the microbiota in IBD.
Genes Studied Conclusions of the Study
Aminal studies CARD9 gene
•Disturbed microbial tryptophan metabolism in CARD9 was associated with
susceptibility to colitis. Administration of Lactobacillus strains that metabolize
tryptophan to AHR ligands was sufficient to reduce colitis in CARD9 -/- mice.
The gut microbiota of CARD9-/- mice has a pro-inflammatory effect because it
enhances colitis when transferred to germ-free wild-type mice [61].
•CARD9 effectively controlled staphylococcal virulence to promote pathogen
elimination through gut microbiota-independent and -dependent mechanisms.
Mice with induced colitis had lower levels of Clostridiaceae and higher levels of
Firmicutes in the basal composition of fecal bacteria. The fecal fungal composition
of CARD9-/- mice was altered and dominated by representatives of the
Ascomycota, Basidiomycota, and Zygomycota types. Genetic susceptibility to
intestinal pathogens can be counteracted by dietary intervention, which restores
humoral immunity and a competitive microbiota [64].
Studies in mice have shown that defects in innate immunity genes, such as CARD9,
affected the composition of the microbiota. It is not clear how CARD9 can restore intestinal
epithelial homeostasis and restore beneficial bacterial colonization after inflammation.
Noting the close relationship between protective genetic variants and therapeutic advances,
this may be a good strategy for the rational design of IBD therapy. [19].
2.1.4. CLEC7A (C-Type Lectin Domain Containing 7A)
This gene encodes a member of the C-type lectin/C-type lectin-like domain (CTL/CTLD)
superfamily. The encoded glycoprotein is a small type II membrane receptor with an undu-
lating extracellular C-type lectin-like domain and a cytoplasmic domain with a tyrosine-based
immunoreceptor activation motif. It acts as a pattern recognition receptor that recognizes

Genes 2022,13, 2388 6 of 23
various glucans with
β
-1,3 and
β
-1,6 bonds from fungi and plants and therefore plays a
role in the innate immune response [
65
]. A recent study showed that bacterial-fungal inter-
actions are crucial in the development of intestinal inflammation [
66
]. Fungal colonization
of the gut is influenced by the bacterial population of Enterobacteriaceae, which collaborates
with yeast to promote their colonization and active role in intestinal inflammation. These
findings also suggest potential therapeutic applications, such as enhancing the protective
effects of a probiotic yeast strain, such as Saccharomyces boulardii CNCM I-745, or combating
Candida albicans infection. For example, specific targeting of Enterobacteriaceae along with
antifungal drugs may be a promising strategy in patients with Candida albicans overgrowth.
Among the receptors that detect fungal ligands, C-type lectin receptors (Dectin-1, Dectin-2,
Dectin-3, and Mincle) are the most studied, as they were initially associated with the immune
response to fungal infections [67].
A recent review highlighted that most of the properties of Blautia bacteria are associated
with potential probiotic functions, and the causal relationship between the abundance of
Blautia and inflammatory bowel disease is not fully understood [
68
]. In people with CD,
Blautia counts were significantly reduced in the microbiota of the cecal mucosa compared
to healthy subjects [69].
2.2. Inheritance of the Microbiota
For many years, twin studies have provided a basis for considering the importance
of linking host genes and microbiota inheritance as interdependent hereditary forces that
could explain a person’s susceptibility to IBD and even help determine the actual cause
of the disease. A study by Turpin et al. involving 271 related healthy individuals from
123 pedigrees found that almost a third of the bacterial taxa in the stool were heritable [
46
].
Recent publications have identified that the taxon with the highest heritability was Chris-
tensenellaceae (a family within Firmicutes), while Bacteroidetes are generally not heritable [
61
].
In relation to the case of the Bifidobacterium-lactase gene locus (LCT), the host’s genetics are
likely to shape the microbiome through dietary preferences, which are themselves herita-
ble [
70
,
71
]. The finding that there are familial impacts on microbiota constitution implies
that specific genetic variants may explain individual variation in microbiota profiles, but
this deserves further research. Dysbiosis of the gut microbiota is a characteristic feature of
IBD, and both the risk of IBD and the composition of the microbiota are related to genetic
and immunological determinants.
2.3. Genetic Factors and the Immune System in IBD
The gut is the cluster of the largest number of immune cells in the body, and the
gut microbiota directly influences immune function [
65
]. Various immune mechanisms,
such as mucus secretion, immunoglobulin A (IgA) and antimicrobial peptides, shape the
intestinal microbiota and prevent direct contact with the epithelium [
72
]. Subsequent
adverse microbial conditions caused by environmental factors can further disrupt immune
homeostasis in the intestine, ultimately leading to IBD. The pathways of several key genetic
risk factors for IBD (particularly NOD2 and autophagy) disrupt Paneth cell function,
leading to colitis [
51
,
52
]. The pathways highlighted by these genes associated with IBD
mainly include: microbial detection, activation, and immune suppression. On the basis of
current reports, some of the genes are discussed in the following [73].
2.3.1. NOD2
NOD2 encodes a pattern recognition receptor that is crucial in the immune
response
[39,41,42].
When the ligand binds, it induces activation of NF-
κ
Band MAPK,
and thus the transcription of pro-inflammatory molecules such as IL6, IL8, IL1
β
, TNF-
α
[
73
].
The result is the activation of innate immune cells and the differentiation of acquired im-
mune cells [
39
]. As mentioned above, NOD2 is expressed in Paneth cells, suggesting that
its polymorphisms may result in defective antimicrobial defense (e.g., reduced release of
α-defensin) [74].

Genes 2022,13, 2388 7 of 23
2.3.2. ATG16L1 T300A
Autophagy plays a key role in the regulation of the interaction between the intestinal
microbiota and innate and acquired immunity, and in host defense against intestinal
pathogens [
75
]. In a study by Lavoie et al., it was shown that the CD ATG16L1 T300A
risk allele contributes to dysbiosis in mice, specifically due to increased Bacteroides and
is associated with increased Th1 and Th17 cells in the lamina propria of the colon and
ileum without the development of intestinal inflammation [
28
]. In a study by Zhang
et al. ATG16L1-deficient mice showed exacerbated DSS-induced colitis with an increased
ratio of pro-inflammatory to anti-inflammatory macrophages, increased production of
pro-inflammatory cytokines, and increased numbers of intestinal bacteria coated with
IgA [
76
]. The ATG16L1 T300A mutation, by affecting Paneth cells and altering the secretion
of antimicrobial peptides, promotes the proliferation of bacteria and their penetration
through the intestinal epithelium.
Other autophagy-associated genetic variants, such as LRRK2 and IRGM, have been
associated with an increased risk of IBD [
11
]. They encode repeat kinase 2 proteins rich in
leucine and guanosine triphosphate M associated with immunity [
77
–
79
]. Patients with
the LRRK2 mutation and CD showed increased intestinal dendritic cell activation and
thus increased expression and release of pro-inflammatory molecules such as IL2 and
TNF-
α
,while inhibition of LRRK2 resulted in a reduction of IL2 and TNF-
α
in patients with
CD [
70
]. PTPN2 (Protein tyrosine phosphatase non-receptor type 2) represents an additional
gene/protein associated with autophagy initiated by Paneth and lymphoid cells. This
results in inappropriate autophagosome formation and impaired bacterial elimination after
mutation [
80
]. High levels of INF-
γ
, IL17 and IL22 have been detected in the serum and
intestinal mucosa of patients with PTPN2 variants [
81
]. Interestingly, in a recent study by
Hoffmann et al., the risk allele of PTPN2 rs7234029 was clearly associated with a lack of
response to anti-interleukin-12/23 treatment (89.9% vs. 67.6%, p= 0.005) [
82
]. In a study by
Liu et al. analysis of intestinal bacteria from ATG16L1 T300A/T300A mice showed that they
had an altered microbiota in both the terminal ileum and the colon compared to wild-type
cultured mice. Furthermore, increased production of inflammatory cytokines by immune
cells in mice deficient in ATG16L1 in response to bacteria may activate an adaptive immune
response to the intestinal microbiota. Akkermansia, a mucin-associated bacterium, was
significantly reduced in ATG16L1 T300A/T300A mice, and cup cells had reduced mucin
secretion resulting from defective autophagy [63].
2.3.3. CARD9
Patients with CARD9 mutations have primary immunodeficiency disorder (PID), re-
sulting in susceptibility to fungal infections [
83
]. Several single nucleotide polymorphisms
(SNPs) in the human CARD9 gene are associated with inflammatory diseases, particularly
IBD (rs10781499, rs10870077, and rs4077515). CARD9 controls the virulence of pathogens
in a microbiota-independent manner, promoting a specific humoral response [
69
]. A pre-
viously described study by Lamas et al. showed that CARD9-/- mice generally exhibit
reduced production of inflammatory cytokines, which contributes to the inability to control
fungal growth. IL-6, TNF-
α
and IL-1
β
are cytokines that depend on the function of CARD9
and protect against fungal infections [
64
]. Furthermore, CARD9 mutation in IBD results
in a decrease in the production of pro-inflammatory cytokines (IL-6, TNFαand IFNγ) and
Th17 and innate lymphoid cell-ILC-related cytokines (IL-17A, IL-17F, IL-22) [
84
–
86
]. The
crucial role of CARD9 in intestinal immune homeostasis is also highlighted by the impact
of CARD9 signaling on the development of colorectal cancer.
2.3.4. IL23R (Interleukin 23 Receptor)
The interleukin-23 receptor is a type I cytokine receptor and is encoded in humans by
the IL23R gene. IL23R is expressed in many cell types, including myeloid cells [
87
]. It is
particularly important in maintaining T-cell-dependent immunity and its high levels have
been demonstrated in both CD and UC patients. IL23 is particularly important for the

Genes 2022,13, 2388 8 of 23
maintenance and development of the Th17 lineage through a positive feedback loop that
regulates IL17, ROR
γ
t, TNF, IL1, and IL6. This phenomenon is involved in the expansion of
pathogenic pro-inflammatory Th17 cells in CD. Polymorphisms in the gene encoding IL23R
have been analyzed and linked to the pathogenesis of IBD, indicating an important role for
the IL23/IL17 axis in mucosal inflammation [
88
]. Furthermore, IL23 interacts with dendritic
cells and macrophages leading to the continued production of various pro-inflammatory
molecules, including IL6, IL12, Il17, INF-
γ
, TNF-
α
and IL23 itself [
89
]. The variant IL23R
rs11209026 (Arg381Gln) has been described as a variant encoding IL23R that protects
against IBD, leading to a significantly reduced risk of CD [
90
]. The presence of alleles
IL-23R rs1004819 and rs11209032 indicates an increased risk of UC in Caucasians [91].
2.3.5. Interleukin 10 (IL-10)
Interleukin 10 interacts with type II cytokine receptors and is a cytokine with anti-
inflammatory effects. It has been shown to modulate both innate and acquired immu-
nity [
92
]. Mutations in IL-10 and its IL10R receptor have been identified as susceptibility
variants to IBD [
93
]. IL10 inhibits the production of pro-inflammatory cytokines such as
interferon-
γ
,IL-2, IL-3, and TNF-
α
.The loss of IL-10 promotes the development of IBD
due to an excessive immune response to the microbiota [
94
]. A factor associated with
IL-10 is the signal transducer and activator of the transcription 3 (STAT3) polymorphism
(in loci rs744166). This is a factor responsible for the regulation of gene transcription that
regulates angiogenesis and cell proliferation. In active CD, an increase in STAT3 activation
is observed in intestinal epithelial cells [
95
,
96
]. IL-10 polymorphisms may be associated
with the early onset of colitis [
97
]. Changes in the IL-10 sequence have been shown to
increase susceptibility to IBD [98,99].
2.3.6. TNFSF15/TL1A (Tumor Necrosis Factor Superfamily Member 15)
TNFSF15 (encoding a cytokine also known as Tumor necrosis factor (TNF)-like cytokine
1A (TL1A)) is associated with CD and UC in populations of different ethnicities [
100
]. The
protein encoded by this gene is a cytokine that belongs to the tumor necrosis factor (TNF)
ligand family and it is expressed in endothelial cells. Expression of this protein is inducible
by TNF and IL-1
α
.The expression of TL1A expression is related to inflammation levels
in IBD. A meta-analysis by Zhang et al. found significant associations between six TN-
FSF15 polymorphisms and CD risk (rs3810936, rs6478108, rs4979462, rs6478109, rs7848647,
rs7869487) with the exception of the rs4263839 polymorphism. Polymorphisms rs3810936,
rs6478108, and rs6478109 were significantly associated with the risk of UC. Ethnic differ-
ences had no effect on risk [
101
]. There is now evidence that interactions between TL1A
and its functional receptor DR3 (death domain receptor 3) affect intestinal mucosal immunity
under both homeostatic conditions and various inflammatory conditions [
102
]. In a review
by Valatas et al. the authors highlighted that the interpretation of the role of the TNFSF15
mutation is influenced by ethnicity, as a stronger association with Asians was reported [
103
].
The study by Liu et al., which included patients with IBD and healthy individuals in Europe
and Asia, found that although allele frequencies in European and Asian populations are
similar, TNFSF15 variants have a stronger association with IBD susceptibility in Asian
individuals [
104
]. Other researchers have suggested that certain TNFSF15 alleles may have
predictive value for the severity of IBD. In the Chinese population, the polymorphism
rs10114470 allele was associated with an increased probability of constrictive, penetrating,
or perianal complications [
105
]. DR3 signaling enhances CD4+ lymphocyte proliferation
by increasing both IL-2 production and IL-2RA and IL-2RB expression [
106
]. TL1A pref-
erentially increases mouse memory CD4+ T cell proliferation, but can also induce mild
proliferation and strong expression of IL-2 and IFN-
γ
by naive T cells. TL1A costimulation
of CD4+ T lymphocytes results in the production of multiple cytokines, including IL-2,
IL-4, IL-13, interferon-
γ
(IFN
γ
)and IL-17 [
107
–
109
]. TL1A enhances many immune path-
ways that, if maintained, may be involved in the development of fibrosis. Interleukin 17A
promotes fibrosis in experimental models of pulmonary and cutaneous fibrosis and has

Genes 2022,13, 2388 9 of 23
been found to be overexpressed in intestinal stenosis in patients with CD [
107
]. IL-13 is
associated with experimental mouse intestinal fibrosis, acting mainly through TGF
β
,and is
also increased in constriction in patients with CD. elevated expression of TL1A and DR3
was found in the SAMP1/YitFc mouse model of ileitis, which is phenotypically associated
with the development of overt intestinal strictures [
108
]. In human fibrotic conditions,
including IBD, the immune and profibrotic events responsible for TL1A are not sufficiently
studied. The potential impact of TL1A on these pathways was highlighted in a report on
TL1A expression by human intestinal myofibroblasts isolated from patients with IBD. TL1A
expression by intestinal myofibroblasts was upregulated by pro-inflammatory cytokines
(IFN-
γ
, TNF-
α
, IL-1
α
)or intestinal tissue culture supernatants from IBD patients [
109
]. A
summary of the described genes versus immune system in IBD is presented in Table 4.
Table 4. Summary of genes described versus immune system in IBD.
Gene Group Name of the Gene Function
Genes associated with
molecular pattern
recognition of pathogens
NOD2/CARD15,
CARD9
Activation of pro-inflammatory and
anti-inflammatory cytokines and regulation
of inflammation and cell apoptosis.
Genes associated with
autophagy
ATG16L1, IRGM,
LRRK2
Key role in regulating the interaction
between the gut microbiota and innate and
acquired immunity, and in host defense
against intestinal pathogens.
Genes associated with
lymphocyte differentiation
IL23R
Activation and development of the Th17
lineage and its effects on dendritic cells and
macrophages leading to the production of
various pro-inflammatory molecules.
Genes encoding
interleukins IL-10
An anti-inflammatory cytokine that inhibits
the production of
pro-inflammatory cytokines.
Genes encoding the
protein TNFSF15
The TNFSF15 gene product (TL1A) is a
TNF-like factor that is expressed in
endothelial cells, macrophages and
lymphocytes of the intestinal lamina propria.
Immune dysregulation, microbial dysbiosis, and environmental factors are considered
key factors in IBD, but the family history of the disease also plays a key role.
2.4. Practical Implementation of Genetics in IBD
One of the strongest risk factors for the development of IBD is a positive family history,
which may have some influence on the phenotype of IBD [
110
,
111
]. According to Santos
et al., it occurs in approximately 8-12% of patients with IBD [
112
]. Other studies indicate
that this level is averaged between 4.5-14.5%, and according to Chao et al. it affects up to
20% of patients with IBD [
113
–
116
]. The greatest finding in this regard was a 34-year cohort
study in the Danish population, in which Moller et al. showed that the highest incidence
rate of IBD occurred in first-degree relatives (FDR) (almost 8 times higher for CD and 4 times
for UC), second- and third-degree relatives, and the highest risk was observed early in life
(especially <20 years of age) [
105
]. Current researchers confirm that IBD with a positive
family history is associated with a younger age of diagnosis and a more unfavorable disease
phenotype [
117
]. This is supported by research findings and indicates that the prevalence of
a positive family history of IBD in the pediatric population is increasing [
118
,
119
]. Children
diagnosed between 2016 and 2020 had a higher prevalence of positive family history
compared to those diagnosed between 2010 and 2015 (31.8% vs. 20.7%, respectively, p
= 0.024) [
120
]. However, some articles show different data, suggesting that there is no
association between the onset of IBD and multigenerational consanguinity [
120
]. Families
with multiple affected individuals are more likely to have a compatible type of disease

Genes 2022,13, 2388 10 of 23
(CD or UC), but 25% of cases find patients with two different types of disease in the
same family [
121
]. Some studies have shown that a positive family history of CD is an
independent risk factor for intestinal resection and the use of tumor necrosis factor (TNF)
therapy, but some reports are contradictory and most studies have not determined the
concordance of the type of IBD and the strength of the family history [122,123].
2.4.1. Different Degrees of Relatedness in IBD
Studies on the risk of familial IBD indicate an increased risk of CD and UC in first-
degree relatives. According to Kevans et al., a higher genetic risk of IBD is observed in CD
in first-degree relatives and the genetic profile of affected CDs is enriched with IBD risk
alleles (rs2188962 in the IBD5 locus region and rs3764147 in the LACC1 region) compared to
controls [
124
]. In a study by Hoffmann et al. 16.6% of the patients indicated having at least
one first degree relative who also suffered from IBD [
82
]. According to Gabbani, about
5%-23% of patients have at least one first degree relative with IBD [
125
]. In a prospective
study by Capone et al., the prevalence of a positive family history increased from 13.7%
at diagnosis to 26.6% after 20 years in first-degree relatives and from 38.5% to 52.2% in all
relatives. At 20 years of follow-up, an additional 10% of the probands had a sibling, 6.1%
had a parent, 1.9% had a grandparent and 4.5% had a cousin diagnosed with IBD [
126
].
Current results also indicate that offspring have an earlier onset and more severe form of
the disease compared to parents. In a study conducted in central China, the median age of
diagnosis was lower in patients with a positive family history (29.0 vs. 36.0 for CD; 35.5 vs.
41.0 for UC) [
127
]. Ballester et al. obtained similar results, also showing that the median age
at diagnosis was lower in the group with a positive family history. Ballester et al. obtained
similar results, also showing that the median age at diagnosis was lower in the group with
a positive family history (32 vs. 29, p= 0.07), and 14.2% of the patients had relatives with
IBD [
128
]. In the observation by Halfvarson et al., those with IBD compared to controls were
more likely to have a mother, father, full siblings (and a child with IBD [
129
]. The strength
of the association increased with the number of first-degree affected relatives and was
modified by the IBD subtype and the age of diagnosis. In a study by Borren et al., a family
history of IBD was found in 32% of the patients studied (n= 2094), 17% had an affected first-
degree relative, and 21% had a second-degree relative [
130
]. However, there was an earlier
age of diagnosis only if the affected family member had UC [= but not CD. In the univariate
analysis, CD patients with a positive family history were more likely to have complicated
disease [56%, especially the association was observed in siblings. In particular, studies of
twins and families for IBD have shown that a child has a 26-fold higher risk of developing
CD when another child already has it, and the risk is 9 times higher for UC [
131
]. A study
by Park et al. also confirms a higher concordance of the type and phenotype of IBD in
first-degree relatives than in second- or third-degree relatives [
132
]. Furthermore, the risk of
IBD in the offspring increases significantly if both parents have IBD, with an estimated risk,
depending on observation, of 33-52% [
133
]. This relationship was challenged by Mouzan
et al. in a study of 138 children, which did not show an association between parental
consanguinity and IBD in the children studied [
134
]. A study comparing the prevalence
and family history of IBD between China and the United States showed that the three most
common types of relatives affected by IBD were cousin, sibling, and parent in the United
States compared to child and sibling in China [
135
]. Interestingly, dysbiotic changes have
been observed in healthy first-degree relatives of IBD patients with an associated increase
in fecal calprotectin (a biomarker of intestinal inflammation) [
136
,
137
]. The location (loci)
of CD susceptibility genes within chromosomes 1, 3, 4, 5, 6, 7, 10, 12, 14, 16, 19 and X is also
known [
138
–
144
]. The regions on chromosomes 16, 12, 6, 14, 5, 19 have been confirmed and
named IBD1 through IBD7, respectively [
145
]. Of these seven loci, only IBD1 (chromosome
16q12) has been replicated in all studies, while IBD2 (chromosome 12), IBD3 (chromosome
6) and IBD4 (chromosome 14) have been replicated in some studies [146].
Some genes are involved in the development of both CD and UC (3p21.31, NKX2-3,
CCNY). In addition, other genes, ie HERC2, ECM1, STAT3, and PTPN2, have been linked

Genes 2022,13, 2388 11 of 23
only to UC but not to CD. Furthermore, to date, more than 20 exclusive UC loci have been
recognized, including ARPC2, IL10 and ECM1, among others [147–150].
2.4.2. Inflammatory Bowel Disease in Twins
Twin cohorts are often used to study the heritability of diseases. In IBD, twins are the
group with the highest risk of developing the disease; in addition, twin studies also allow
control of genetic variation, microbiome, and epigenome. Studies of twins have provided
the best evidence for a genetic predisposition to IBD, which is stronger in CD than in UC.
The main premise of twin studies is that pairs of twins share a similar environment and
consistent genetic variation, with monozygotic twins (MZ) sharing 100% of segregating
genes and dizygotic twins (DZ) sharing 50% [
151
]. Studies have shown that concordance
rates are significantly higher in monozygotic twins than in dizygotic twins for both CD
and UC [
105
]. Similarly, in a study by Annese et al., the concordance in the diagnosis
of UC (15.3 vs. 3%) and CD is higher in monozygotic twins than in dizygotic twins [
17
].
According to Bell et al. MZ twins share common genotypes and epigenetic profiles at
conception [
121
]. Furthermore, it should be considered that some epigenetic differences
emerge during the lifetime of MZ twins, but interindividual differences with respect to
the epigenome and intestinal microbiota remain smaller between twin pairs than between
unrelated individuals [
152
]. An evaluation of cohorts of twins from various countries, for
example Norway, suggests that environmental factors are more important than previously
thought and that the lifetime concordance rates of pairs of twins with MZ never reach
close to 100% [
153
]. A current analysis of the UK IBD Twins Registry showed significantly
higher concordance for CD between pairs of MZ twins compared to pairs of DZ twins.
In addition, the data also showed a trend towards a higher concordance of MZ pairs in
UC, although statistical significance was not reached [
154
]. This is consistent with other
cohorts of twins and indicates the heritability of CD. A recent report showed that the gut
microbiome of healthy twins from pairs of discordant twins with IBD showed signatures
similar to IBD, indicating that discordant monozygotic twins with IBD share not only the
same genetic background, but also the same gut microbiome [
155
]. Monozygotic twins
with UC incompatibility have also been shown to differ in the bacterial composition of
their gut microbiota, and affected twins show less diversity than their healthy twins [
156
].
Interestingly, a study of monozygotic twins of different ages found that the immune systems
of MZ twins became increasingly divergent at later ages, suggesting that the immunological
differences are mainly due to environmental and non-hereditary factors [
157
]. New genes
have also been identified that could potentially play a role in the pathogenesis of IBD
among twins. CYP2C18 expression has been observed to be strongly up-regulated in IBD
affected twins [
158
]. Studies on the familial occurrence of IBD provide valuable information
not only for researchers but also for healthy relatives who are naturally concerned about
the risk of the disease. In addition to genetic factors, environmental factors, intestinal
microbiota composition and role of the immune system; epigenetics is also involved in the
pathophysiology of IBD.
2.5. Epigenetics
Epigenetics deals with the study of mechanisms that affect hereditary changes in
phenotype, regardless of the DNA sequence [
54
]. It probably plays a role in the pathogenesis
of IBD, as certain environmental factors can influence the risk of developing IBD through
epigenetic modifications, such as DNA methylation, post-translational modifications of
histones, and the expression of noncoding RNAs [
159
]. Epigenetic mechanisms have been
shown to play an important role in several fundamental biological processes, including
cell differentiation, transcription of cell type-specific genes and cell function, and immune
memory [160].

Genes 2022,13, 2388 12 of 23
2.5.1. DNA Methylation
DNA methylation is the most common and best studied epigenetic direction of
IBD [
161
–
163
]. Moret-Tatay et al. in 2019 identified an epigenetic methylation signa-
ture (methylation status of the DEFA5 and TNF genes as a characteristic biomarker) to
characterize CD patients and support the likely influence of the environment and immune
system on CD pathogenesis [
164
]. Considering that some environmental factors may medi-
ate epigenetic regulation, many researchers have described the diet as one of the risk factors
for IBD. An example described by Rapozo et al. is single-carbon metabolism dependent on
dietary components (e.g., methionine, betaine, and folic acid), which are involved in DNA
methylation pathways and methyl group supply [
165
]. In addition, Silva et al. showed
that butyrate deficiency may be partly responsible for excessive condensation of chromatin
structure and histone deacetylase-mediated gene expression [
166
]. Interestingly, melatonin
and a probiotic (Bifidobacterium longum), may regulate the DNA methylation status of
intestinal epithelial cells [
167
,
168
]. Pan et al. demonstrated the influence of the microbiota
on the maturation of DNA methylation features and changes in the transcriptome. They
found that it can regulate the intestinal transcriptome during postnatal development and,
through its corresponding DNA methylation state, targets a portion of genes that respond
to the microbiota [
169
]. Ansari et al. showed that the microbiota affects the activation of
some genes associated with hypomethylated active regulatory regions, thus inducing the
expression of genes associated with colitis and IBD [
170
]. Hypomethylation of ribosomal
protein kinase S6 A2 (RPS6KA2) has also been identified as a diagnostic aid in predicting
the complex disease behavior (constrictive/penetrating disease) of CD and extensive UC
disease [
171
]. RPS6KA2 is responsible for modulating cell growth, motility, and prolifer-
ation and regulating the PI3K/Akt/mTor pathway and autophagy. Autophagy has been
shown to be one of the most important pathogenesis of CD.
An analysis by Kraiczy et al. demonstrated the role of DNA methylation in the reg-
ulation of human intestinal epithelial development and function. They confirmed the
developmental origin of IBD through epigenetic mechanisms by overlapping genomic loci
that undergo significant changes in DNA methylation during gastrointestinal develop-
ment with loci observed in children diagnosed with IBD [
172
]. Howell et al. performed
a complete genome analysis that revealed differences in intestinal segment and disease-
specific differences, DNA methylation, and transcriptional changes in human epithelial
cells obtained from mucosal biopsies from pediatric patients with IBD, compared to healthy
controls [
161
]. A study involving 18 CD patients compared to 25 healthy controls identi-
fied 4287 differentially methylated positions in DNA derived from peripheral blood cells,
indicating that CD patients exhibit, as the authors put it, “a specific methylation land-
scape” [
173
]. A study by McDermott et al. that evaluated genome-wide DNA methylation
changes associated with CD and UC and IBD activity showed that in the case of CD, the
most identified pathways include immune responses, regulation of T cell activation, and
cellular responses to bacterial-derived molecules, suggesting that epigenetic modification
is involved in the dysregulation of bacterial and immune responses in IBD [
174
]. A recent
study by Venkateswaran et al. among pediatric patients, mostly of European origin, focused
on identifying quantitative trait loci (mQTLs) or SNPs that bind to DNAm at specific CpG
sites. Blood mQTLs have been shown to be reproducible, supporting their generalizability
across age groups, ancestry, disease status and DNA sample source, and provide a valuable
resource for future research on blood mQTLs [175].
Furthermore, IBD increases the risk of colorectal cancer (CRC), which has a genetic
basis, but epigenetics may also be a factor in the disease [
176
]. Rajamäki et al. showed
that there was global hypermethylation in IBD-associated CRC (IBD-CRC) compared to
sporadic CRC clustered separately. There was no association with younger age at diagnosis
or differential expression of methylation-regulating enzymes, suggesting that these methy-
lation changes are due to inflammation [
177
]. A recent meta-analysis of research studies
indicated that methodological homogenization of IBD epigenetic studies is necessary to
allow consolidation and independent validation, and an indicated direction for future

Genes 2022,13, 2388 13 of 23
research was the identification of epigenetic biomarkers of peripheral blood leukocyte
DNA methylation in IBD [178].
2.5.2. Histone Modifications
Another epigenetic mechanism of transcriptional regulation involves post-translational
modifications of histone proteins (also known as histone modifications). Histone mod-
ification plays an important role in the occurrence and development of IBD. Among
post-translational histone modifications, acetylation and methylation are the most studied
post-translational modifications [
179
,
180
]. Histone modification in IBD may be an indicator
of microbiota-host interactions. The decrease in Roseburia abundance in the gastrointestinal
tract of patients with UC is associated with a reduced methylation of the KHDC3L gene.
These findings suggest that epigenetics and the gut microbiota may work together to reg-
ulate the occurrence of IBD [
148
]. Because p62 is involved in the inflammatory response
and is elevated in patients with IBD, and histone modification plays an important role in
regulating p62 expression, a study by Chen et al. elucidated the epigenetic mechanism by
which SETD8 regulates p62 expression and suppresses the inflammatory response in colitis.
The authors suggest that targeting SETD8 may be a promising therapy for IBD [181].
2.5.3. Expression of Noncoding RNAs
In addition to the described mechanisms, epigenetic regulation can also involve non-
coding ncRNAs, which, depending on their length, can be divided into lncRNAs, mncRNAs,
sncRNAs, and microRNAs (miRNAs). MicroRNAs are a group of noncoding RNAs that
mediate RNA silencing and gene expression. ncRNAs are differentially expressed between
controls and IBD patients, and there is also a difference in expression between CD and UC
patients [
182
]. In IBD, miRNAs are involved in the regulation of the intestinal mucosal
barrier, T cell differentiation, the Th17 signaling pathway, and autophagy, so recent studies
have focused on microRNAs [
183
–
186
]. MiRNA has been found to be a key regulator
of intestinal immunity and is involved in innate immunity and adaptive immunity. In
response to inflammation, miRNAs can affect the maturation and differentiation of immune
cells. For example, bone marrow-derived miRNA-223 can reduce IL-1
β
release by inhibiting
NLRP3, thus alleviating colitis in mice [
187
]. Exosomes containing miRNA-155 are released
into the gastrointestinal tract, host macrophages are induced to polarize towards M1, and
colitis increases [
188
]. Short-chain fatty acids-SCFAs can also promote miRNA expression
in B cells and regulate B cell differentiation [
189
,
190
]. In addition, the host can also regulate
the structure and growth of the intestinal flora through miRNAs. Liu et al. showed that
miR-30d in feces can attack Akkermansia muciniphila and increase the abundance of modified
bacteria by up-regulating lactase expression [
63
]. Furthermore, some miRNAs, such as
miR-199a-5p and miR-1226, can play an important role in the interaction between the host
and the microbiota, providing new ideas to maintain intestinal homeostasis.
According to the study, miRNA-146a can alleviate colitis by targeting the TRAF6 and
NF-
κ
B signaling pathways and can inhibit the activation of pro-inflammatory macrophages
(M1), as well as the production and release of pro-inflammatory factors through the TLR4
pathway [
191
,
192
]. Furthermore, the results show that miR-223 expression is positively
correlated with the activity of UC disease. Fecal miR-223 can distinguish well between
patients with IBD in active and remission phases, with a sensitivity and specificity of 80 and
93%, respectively [
193
]. A prospective study by Kalla et al. reports that miR-3615 and
miR-4792 in blood T cells contribute to the prognosis of UC [
194
]. However, most current
studies focus only on detecting the changing trend in miRNA expression, and further
quantitative analyzes are still needed. In the current literature, a developing research
avenue is lncRNA, which plays an important role in the pathogenesis of IBD [
195
–
198
].
New reports indicate that interferon
γ
-antisense 1 (IFNG-AS1), which is elevated in the
intestinal mucosa of patients with IBD, is a mediator of the inflammatory signaling cascade
in the pathophysiology of IBD [160,199].

Genes 2022,13, 2388 14 of 23
The epigenetic mechanisms described contribute to the development, progression,
and maintenance of IBD. They are typically triggered by a number of environmental factors.
Some authors list three critical periods in which the environment can promote the onset of
IBD; these are: the prenatal period (in response to the mother’s lifestyle), the early postnatal
period (during colonization of the intestinal microbiota), and just before the onset of the
disease [
200
]. Epigenetics is an important and needed research direction in the pathogenesis
of IBD, and the identification of epigenetic signatures in IBD may help develop new clinical
biomarkers of the disease.
2.6. Pharmacogenetics in Inflammatory Bowel Disease
Researchers are increasingly identifying genetic factors as an extremely important
component of the appropriate susceptibility of the body to selected treatments for IBD.
Through the development of pharmacogenetics, specific types of treatment have begun to
be studied with specific types of drugs in patients. One such drug is Infliximab, which was
studied by Arijs et al. and they linked the expression of five mucosal genes in UC to the lack
of therapeutic response after Infliximab [
201
]. McGovern et al. present in their article that it
is extremely important to know the pathways of therapeutic intervention to establish effec-
tive therapy in IBD [
202
]. The response to anti-TNF-
α
therapy depends on both TNF-
α
and
TNFR(TNF Receptor) polymorphisms (A allele in -308 TNF-
α
and G allele in TNFRSF1A),
as well as equal types of immune and cytokine pathway polymorphisms [
203
]. Van den
Bosch et al. indicate that metabolic reactions between intestinal microbes, as well as lipid
and amino acid metabolites, can also affect the efficacy of anti-TNF therapy [
204
]. However,
Zhang et al. in their study noted that the efficacy of glucocorticosteroid (GC) treatment may
depend on DNA methylation (DNAm), confirming that the systemic response may depend
on epigenetic mechanisms [
205
]. Furthermore, Lucafo et al. indicate that long noncoding
RNA (lncRNA) GAS5 has been shown to reduce sensitivity to GC treatment [
206
]. In
addition, high expression of glucocorticoid receptor
β
steroid resistance in patients with
UC [
207
]. Azathiopurine (AZA), 6-mercaptopurine (6-MP), which are among the thiop-
urine compounds, have been widely studied. Park et al. in their article present, among
other things, that the polymorphism of the thiopurine S-methyltransferase (TPMT) allele
is associated with a poorer therapeutic response of AZA and 6-MP [
208
]. It is associated
with high levels of 6-TGN (6-thioguanine nucleotide), which can lead to the development
of myelotoxicity [
209
]. In addition to the TPMT polymorphism (TPMT *1/*3C), NUDT15
p.Arg139Cys (nucleoside diphosphate-linked moiety X-type motif 15, p.Arg139Cys vari-
ant) may be associated with the appearance of leukopenia [
210
]. Ye et al. in their review
article indicate that up to 14% of Europeans who undergo thiopurine treatment with the
TPMT polymorphism have myelosuppressive episodes [
211
]. Therefore, it is important
to measure the metabolites and enzymes associated with thiopurines to reduce the risk
of complications [
212
]. In another study, the authors focused on anti-integrin therapy
used in UC patients. They showed that the expression of the integrin
α
E gene (ITGAE)
and granzyme A (GZMA mRNA) may be associated with the response to etrolizumab
therapy [
213
]. Personalized medicine, which is based on pharmacogenetics and therapeutic
drug monitoring (TDM), should be an integral factor in the treatment of patients with
IBD [214].
3. Conclusions
There is a year-on-year increase in the incidence of IBD, especially in eastern countries.
Researchers are increasingly looking at genetic factors linked to the gut microbiota that
may predispose to UC or CD. In addition to NOD2, strong correlations have been detected
between ATG16L1 T300A, CARD9, CLEC7A, and IBD. Genetic factors and altered intestinal
microbiota are also associated with an intensification of the immune system in patients
with IBD, during the exacerbation of the disease. Furthermore, recent scientific reports also
point to important epigenetic mechanisms that are involved in selected basic biological

Genes 2022,13, 2388 15 of 23
processes and probably play a significant role in the pathogenesis of IBD, but more research
is needed in this area.
The gene and its polymorphisms associated with inflammatory bowel disease are
described in Supplementary Table S1.
Supplementary Materials:
The following supporting information can be downloaded at: https:
//www.mdpi.com/article/10.3390/genes13122388/s1, Table S1: Gene and its polymorphysms con-
nected with inflammatory bowel disease.
Author Contributions:
Conceptualization, R.F. and S.J.-C.; methodology, R.F. and S.J.-C.; software,
S.J.-C.; validation, R.F., S.J.-C. and A.S.; formal analysis, R.F.; investigation, R.F.; resources, S.J.-C.,
M.Z., A.S. and R.F.; data curation, S.J.-C. and R.F.; writing—original draft preparation, S.J.-C., M.Z.
and A.S.; writing—review and editing, S.J.-C., A.S., M.Z. and R.F.; visualization, S.J.-C.; supervision,
R.F.; project administration, S.J.-C.; funding acquisition, R.F. All authors have read and agreed to the
published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
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