Dysbiosis in Inflammatory Bowel Disease: Pathogenic Role and Potential Therapeutic Targets

Abstract

Microbe–host communication is essential to maintain vital functions of a healthy host, and its disruption has been associated with several diseases, including Crohn’s disease and ulcerative colitis, the two major forms of inflammatory bowel disease (IBD). Although individual members of the intestinal microbiota have been associated with experimental IBD, identifying microorganisms that affect disease susceptibility and phenotypes in humans remains a considerable challenge. Currently, the lack of a definition between what is healthy and what is a dysbiotic gut microbiome limits research. Nevertheless, although clear proof-of-concept of causality is still lacking, there is an increasingly evident need to understand the microbial basis of IBD at the microbial strain, genomic, epigenomic, and functional levels and in specific clinical contexts. Recent information on the role of diet and novel environmental risk factors affecting the gut microbiome has direct implications for the immune response that impacts the development of IBD. The complexity of IBD pathogenesis, involving multiple distinct elements, suggests the need for an integrative approach, likely utilizing computational modeling of molecular datasets to identify more specific therapeutic targets.

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Citation: Santana, P.T.; Rosas, S.L.B.;
Ribeiro, B.E.; Marinho, Y.; de Souza,
H.S.P. Dysbiosis in Inflammatory
Bowel Disease: Pathogenic Role and
Potential Therapeutic Targets. Int. J.
Mol. Sci. 2022,23, 3464. https://
doi.org/10.3390/ijms23073464
Academic Editor: Alip Borthakur
Received: 28 February 2022
Accepted: 21 March 2022
Published: 23 March 2022
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International Journal of
Molecular Sciences
Review
Dysbiosis in Inflammatory Bowel Disease: Pathogenic Role and
Potential Therapeutic Targets
Patricia Teixeira Santana 1, Siane Lopes Bittencourt Rosas 1, Beatriz Elias Ribeiro 1, Ygor Marinho 1
and Heitor S. P. de Souza 1 ,2 ,*
1Department of Clinical Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, RJ, Brazil;
pattsant@gmail.com (P.T.S.); sianeros@gmail.com (S.L.B.R.); bakerribeiro@gmail.com (B.E.R.);
ygormarinho@rocketmail.com (Y.M.)
2
D’Or Institute for Research and Education (IDOR), Rua Diniz Cordeiro 30, Botafogo, Rio de Janeiro 22281-100,
RJ, Brazil
*Correspondence: heitor.souza@gmail.com; Tel.: +55-21-39382669
Abstract:
Microbe–host communication is essential to maintain vital functions of a healthy host, and
its disruption has been associated with several diseases, including Crohn’s disease and ulcerative
colitis, the two major forms of inflammatory bowel disease (IBD). Although individual members of the
intestinal microbiota have been associated with experimental IBD, identifying microorganisms that
affect disease susceptibility and phenotypes in humans remains a considerable challenge. Currently,
the lack of a definition between what is healthy and what is a dysbiotic gut microbiome limits
research. Nevertheless, although clear proof-of-concept of causality is still lacking, there is an
increasingly evident need to understand the microbial basis of IBD at the microbial strain, genomic,
epigenomic, and functional levels and in specific clinical contexts. Recent information on the role of
diet and novel environmental risk factors affecting the gut microbiome has direct implications for
the immune response that impacts the development of IBD. The complexity of IBD pathogenesis,
involving multiple distinct elements, suggests the need for an integrative approach, likely utilizing
computational modeling of molecular datasets to identify more specific therapeutic targets.
Keywords:
inflammatory bowel disease; gut dysbiosis; inflammation; immunomodulation; epigenetics
1. Introduction
In the last two decades, the gut microbiota has become a focus of major interest in the
study of inflammatory bowel disease (IBD) pathogenesis. Technological advancements
have allowed the characterization of several gut microbiome abnormalities in patients with
Crohn’s disease (CD) and ulcerative colitis (UC), the two major forms of IBD. Abnormal
immune reactivity against commensal microorganisms [
1
,
2
] and defects in innate and
adaptive immunity have long been described in studies on IBD [
3
–
5
]. Nonetheless, the
most consistent association between IBD and bacteria has been derived from animal models.
For example, germ-free mice do not develop colitis, and inflammatory changes can be
induced after colonization with commensal bacteria [
6
]. In a study using interleukin
(IL)-10-deficient mice, which are genetically susceptible to colitis development, antibiotic
administration early in life increased the risk of colitis [7].
Regarding genetic predisposition, several studies have identified altered regulators of
the complex network underlying IBD in patients, many of which control the immune re-
sponse to microbes. Nucleotide-binding oligomerization domain 2 (NOD2) polymorphisms,
which encode an intracellular pattern recognition receptor and regulate the production
of defensins by Paneth cells, have been associated with the risk of CD [
8
]. Several other
gene variants related to bacterial clearance or protection against epithelial invasion have
also been associated with IBD [
9
]. Currently, healthy immune homeostasis is linked to a
state of tolerance towards resident microbiota, and disequilibrium of normal homeostatic
Int. J. Mol. Sci. 2022,23, 3464. https://doi.org/10.3390/ijms23073464 https://www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2022,23, 3464 2 of 25
conditions has been proposed as a necessary event for the initiation and/or maintenance of
inflammation in IBD [10].
Although there is not yet a clear definition of what a healthy gut microbiome is, dysbio-
sis has generally been defined as an altered balance between the microbiota and its host [
11
].
Hence, commensal microbiota play a critical role in the early education of the immune
system and microorganisms, and their products modulate immune responses through
the induction of immune cells, signaling pathways, and inflammatory mediators [
9
]. In
contrast, exposure to environmental triggers, such as dietary components, gastrointestinal
infections, medications, psychological stress, and smoking, in genetically susceptible in-
dividuals leads to dysbiosis-associated mucosal immune dysfunction, which delineates
IBD. Prolonged dysbiotic conditions, characterized by increased aggressive bacterial strains
and decreased regulatory species, result in dysfunction of the mucosal immune response
(Figure 1). Together with defective intestinal barrier function, gut dysbiosis is likely to
sustain mucosal inflammation and potentially lead to IBD [
12
]. In this review, we aimed to
discuss and summarize the basic mechanisms and potential associations between dysbiosis
and IBD development, as well as exposome influences, methodological approaches to the
microbiome, epigenetic changes, and recent developments in therapeutics.
Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 2 of 25
invasion have also been associated with IBD [9]. Currently, healthy immune homeostasis
is linked to a state of tolerance towards resident microbiota, and disequilibrium of normal
homeostatic conditions has been proposed as a necessary event for the initiation and/or
maintenance of inflammation in IBD [10].
Although there is not yet a clear definition of what a healthy gut microbiome is,
dysbiosis has generally been defined as an altered balance between the microbiota and its
host [11]. Hence, commensal microbiota play a critical role in the early education of the
immune system and microorganisms, and their products modulate immune responses
through the induction of immune cells, signaling pathways, and inflammatory mediators
[9]. In contrast, exposure to environmental triggers, such as dietary components,
gastrointestinal infections, medications, psychological stress, and smoking, in genetically
susceptible individuals leads to dysbiosis-associated mucosal immune dysfunction,
which delineates IBD. Prolonged dysbiotic conditions, characterized by increased
aggressive bacterial strains and decreased regulatory species, result in dysfunction of the
mucosal immune response (Figure 1). Together with defective intestinal barrier function,
gut dysbiosis is likely to sustain mucosal inflammation and potentially lead to IBD [12].
In this review, we aimed to discuss and summarize the basic mechanisms and potential
associations between dysbiosis and IBD development, as well as exposome influences,
methodological approaches to the microbiome, epigenetic changes, and recent
developments in therapeutics.
Figure 1. The role of gut dysbiosis in the pathogenesis of inflammatory bowel disease. Gut
microbiota reflect an interaction of host genetics with dynamic exposure to innumerable stimuli
from the exposome. Crosstalk amongst these factors results in long-standing consequences to the
gut microbiota and epigenetic modifications in a multidirectional fashion, potentially affecting
susceptibility to diseases. The prevalence of either regulatory (eubiosis) or inflammatory (dysbiosis)
species within the gut microbial community determines the respective predominant immune
response. Treg, regulatory T-cell; Breg, regulatory B-cell; ILC, innate lymphoid cell; IgA,
immunoglobulin A; MØ, macrophage; TSLP, thymic stromal lymphopoietin.
2. Intestinal Microbial Dysbiosis
The gut microbiota is an important physical, chemical, and immunological interface
between the environment and host; thus, any dysregulation or breakdown of this barrier
can contribute to disease states. For example, altered physical epithelial barrier function,
Figure 1.
The role of gut dysbiosis in the pathogenesis of inflammatory bowel disease. Gut microbiota
reflect an interaction of host genetics with dynamic exposure to innumerable stimuli from the expo-
some. Crosstalk amongst these factors results in long-standing consequences to the gut microbiota
and epigenetic modifications in a multidirectional fashion, potentially affecting susceptibility to
diseases. The prevalence of either regulatory (eubiosis) or inflammatory (dysbiosis) species within the
gut microbial community determines the respective predominant immune response. Treg, regulatory
T-cell; Breg, regulatory B-cell; ILC, innate lymphoid cell; IgA, immunoglobulin A; MØ, macrophage;
TSLP, thymic stromal lymphopoietin.
2. Intestinal Microbial Dysbiosis
The gut microbiota is an important physical, chemical, and immunological interface
between the environment and host; thus, any dysregulation or breakdown of this barrier
can contribute to disease states. For example, altered physical epithelial barrier function, a
thinner mucus layer, and altered responses to endoplasmic reticulum stress (via mutations

Int. J. Mol. Sci. 2022,23, 3464 3 of 25
in MUC19,ITLN1,FUT2, and XBP1) have all been identified as risk factors for IBD [
13
–
15
].
Currently, the pathogenesis of human IBD is believed to involve inappropriate activation of
the immune system when genetically susceptible individuals are exposed to gut antigens,
such as microbiome components [
16
]. Although alterations in the gut microbiome have
been proposed to be critical in IBD pathogenesis, it is not yet clear how this process occurs
and whether dysbiosis is a central cause or a common consequence of the disease [17].
In healthy individuals, 99% of gut bacterial phyla are Firmicutes, Bacteroidetes, Pro-
teobacteria, and Actinobacteria. Firmicutes and Bacteroidetes account for approximately
90% of the total microbiome composition. These phyla are critically important in main-
taining gut homeostasis and produce short-chain fatty acids (SCFAs), especially butyrate
and propionate, from the fermentation of dietary components such as indigestible fibers.
SCFAs are important energy sources for colonic mucosa cells but have also been shown to
play key roles in regulating immune homeostasis [
18
]. Dysbiosis is defined as an alteration
in gut microbiota composition and diversity and a shift in the balance between commensal
and potentially pathogenic microorganisms [
19
]. Several pieces of evidence support the
role of the microbiome and dysbiosis in IBD development. For example, experimental mice
subjected to germ-free conditions develop attenuated colitis [
20
]. In studies using mouse
models, the transfer of bacterial strains associated with IBD induces intestinal inflammation
in genetically susceptible mice [
21
]. Similarly, fecal transplantation from human IBD donors
to germ-free mice stimulates proinflammatory responses, with increased Th17 cell infil-
tration and proinflammatory mediators compared with transplants from healthy human
donors [
22
]. Britton et al. colonized groups of adult wild-type or Rag1-deficient mice in
germ-free conditions with human microbiota and assessed the mucosal immune response.
Microbiota from healthy human donors induced, on average, higher frequencies of ROR
γ
t
+ Foxp3 + Treg cells in the intestinal lamina propria and prevented disease exacerbation.
In contrast, microbiota from IBD donors resulted in enhanced ROR
γ
t + Th17 effector cell
frequencies and enhanced disease severity in colitis-susceptible mice [23].
Determining the groups of microbes that are related to the development of intestinal
inflammation has been a focus of extensive research. Patients with IBD tend to present
several changes, not only in composition, but also in the diversity of their microbiome pop-
ulations when compared to healthy individuals (Table 1). Evidence shows that alterations
in microbiome components can also be involved in different IBD phenotypes [
24
]. The IBD
microbiota has been characterized by an increase in the abundance of Bacteroidetes and
Proteobacteria and a decrease in Firmicutes compared to control individuals. Specifically,
levels of Faecalibacterium prausnitzii, a highly metabolically active commensal bacterium,
are reduced in individuals with IBD [
25
]. Patients with IBD have reduced microbiome
diversity (mostly a decrease in the relative abundance of Firmicutes) and an increase in
the presence of Proteobacteria, such as Enterobacteriaceae and Bilophila, and certain mem-
bers of Bacteroidetes [
26
]. Dysbiosis can potentially lead to a reduction in key functions
necessary for maintaining intestinal barrier integrity and gut homeostasis. Therefore, alter-
ations in the immune response and proinflammatory activity could be due to a dysbiotic
microenvironment.

Int. J. Mol. Sci. 2022,23, 3464 4 of 25
Table 1. Association between the gut microbiome and inflammatory bowel disease.
Microbiome
Components
Presence
in IBD Possible Mechanisms Evidence References
Firmicutes
Faecalibacterium
prausnitzii
Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 4 of 25
role in gut physiology and has
beneficial effects, including
protection against pathogen inva-
sion, modulation of the immune
system, and promotion of anti-in-
flammatory activity
CD. Its deficiency was shown in
colonic CD. Low F. prausnitzii
levels in patients with IBD under-
going surgery is associated with a
higher risk of post-operative recur-
rence
Eubacterium spp.
Involved in the production of
SCFAs, especially butyrate. It is
important in inflammation mod-
ulation and the promotion of epi-
thelial barrier integrity
Found deficient in samples from
patients with CD and UC [24,28]
Ruminococcus albus Possibly involved in SCFA me-
tabolism and its protective and
anti-inflammatory roles
Found decreased in samples from
patients with CD and UC [24,29]
Ruminococcus gna-
vus
Involved in bile and amino acid
biosynthesis pathways, including
amino acid, energy, carbohy-
drate, and nucleotide metabolism
Lack of supporting evidence of
possible mechanisms involved
Found decreased in the stool of pa-
tients with treatment-naïve new-
onset CD
Found increased in samples from
patients with CD compared to con-
trols
[24,30]
Clostridioides dif-
ficile
A and B toxins produced by this
bacterium may activate caspase-1
and secrete mature IL-1b and IL-
18 (proinflammatory cytokines)
that cause damage to the epithe-
lial barrier and intestinal cells
High prevalence of infection by C.
difficile has been demonstrated
among patients with IBD
[31,32]
Listeria monocyto-
genes
Possibly associated with invasive
infection of epithelial cells
Listeria monocytogenes infection
rates seem to be elevated in pa-
tients with IBD
[31,33]
Verrucomicrobia
Akkermansia mu-
ciniphila
Possibly involved with the
production of SCFAs, which can
activate the GPR43 and thereby
increase the number of Foxp3+
regulatory T cells in the colon
Decreased in stools of both CD and
UC patients.
Human strain ATCC BAA-835T
and murine strain 139 exerted anti-
inflammatory effects on
DSS-induced chronic colitis in
mice
[34–36]
Actinobacteria
Eggerthella lenta
Lack of well-explored possible
mechanisms
Found increased in samples from
patients with CD compared to con-
trols
[24]
Bifidobacterium bifi-
dum
Mucin metabolism performed by
B. bifidum could activate en-
hanced production of mucin,
thereby increasing the mucus
layer depth and strengthening
the epithelial barrier function
Found decreased in samples from
patients with IBD. Some studies
suggest that probiotics containing
this bacterium could have positive
responses in the treatment of IBD
[37,38]
Mycobacterium
avium
Associated with increased pro-
duction of proinflammatory cyto-
kines. Mutations in
NOD2/CARD15 receptors may
cause intracellular survival of the
The abundance of this bacteria, es-
pecially the subspecies paratubercu-
losis
,
is higher in patients with IBD
than in controls
[39,40]
It is a highly active metabolic
commensal bacterium involved in the
production of butyrate. This metabolite
plays a major role in gut physiology and
has beneficial effects, including
protection against pathogen invasion,
modulation of the immune system, and
promotion of anti-inflammatory activity
Presence of F. prausnitzii may serve as a
biomarker of intestinal health in adults.
Low levels of this bacteria could be
predictive for CD. Its deficiency was
shown in colonic CD. Low F. prausnitzii
levels in patients with IBD undergoing
surgery is associated with a higher risk
of post-operative recurrence
[25,27]
Eubacterium spp.
Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 4 of 25
role in gut physiology and has
beneficial effects, including
protection against pathogen inva-
sion, modulation of the immune
system, and promotion of anti-in-
flammatory activity
CD. Its deficiency was shown in
colonic CD. Low F. prausnitzii
levels in patients with IBD under-
going surgery is associated with a
higher risk of post-operative recur-
rence
Eubacterium spp.
Involved in the production of
SCFAs, especially butyrate. It is
important in inflammation mod-
ulation and the promotion of epi-
thelial barrier integrity
Found deficient in samples from
patients with CD and UC [24,28]
Ruminococcus albus Possibly involved in SCFA me-
tabolism and its protective and
anti-inflammatory roles
Found decreased in samples from
patients with CD and UC [24,29]
Ruminococcus gna-
vus
Involved in bile and amino acid
biosynthesis pathways, including
amino acid, energy, carbohy-
drate, and nucleotide metabolism
Lack of supporting evidence of
possible mechanisms involved
Found decreased in the stool of pa-
tients with treatment-naïve new-
onset CD
Found increased in samples from
patients with CD compared to con-
trols
[24,30]
Clostridioides dif-
ficile
A and B toxins produced by this
bacterium may activate caspase-1
and secrete mature IL-1b and IL-
18 (proinflammatory cytokines)
that cause damage to the epithe-
lial barrier and intestinal cells
High prevalence of infection by C.
difficile has been demonstrated
among patients with IBD
[31,32]
Listeria monocyto-
genes
Possibly associated with invasive
infection of epithelial cells
Listeria monocytogenes infection
rates seem to be elevated in pa-
tients with IBD
[31,33]
Verrucomicrobia
Akkermansia mu-
ciniphila
Possibly involved with the
production of SCFAs, which can
activate the GPR43 and thereby
increase the number of Foxp3+
regulatory T cells in the colon
Decreased in stools of both CD and
UC patients.
Human strain ATCC BAA-835T
and murine strain 139 exerted anti-
inflammatory effects on
DSS-induced chronic colitis in
mice
[34–36]
Actinobacteria
Eggerthella lenta
Lack of well-explored possible
mechanisms
Found increased in samples from
patients with CD compared to con-
trols
[24]
Bifidobacterium bifi-
dum
Mucin metabolism performed by
B. bifidum could activate en-
hanced production of mucin,
thereby increasing the mucus
layer depth and strengthening
the epithelial barrier function
Found decreased in samples from
patients with IBD. Some studies
suggest that probiotics containing
this bacterium could have positive
responses in the treatment of IBD
[37,38]
Mycobacterium
avium
Associated with increased pro-
duction of proinflammatory cyto-
kines. Mutations in
NOD2/CARD15 receptors may
cause intracellular survival of the
The abundance of this bacteria, es-
pecially the subspecies paratubercu-
losis
,
is higher in patients with IBD
than in controls
[39,40]
Involved in the production of SCFAs,
especially butyrate. It is important in
inflammation modulation and the
promotion of epithelial barrier integrity
Found deficient in samples from
patients with CD and UC [24,28]
Ruminococcus
albus
Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 4 of 25
role in gut physiology and has
beneficial effects, including
protection against pathogen inva-
sion, modulation of the immune
system, and promotion of anti-in-
flammatory activity
CD. Its deficiency was shown in
colonic CD. Low F. prausnitzii
levels in patients with IBD under-
going surgery is associated with a
higher risk of post-operative recur-
rence
Eubacterium spp.
Involved in the production of
SCFAs, especially butyrate. It is
important in inflammation mod-
ulation and the promotion of epi-
thelial barrier integrity
Found deficient in samples from
patients with CD and UC [24,28]
Ruminococcus albus Possibly involved in SCFA me-
tabolism and its protective and
anti-inflammatory roles
Found decreased in samples from
patients with CD and UC [24,29]
Ruminococcus gna-
vus
Involved in bile and amino acid
biosynthesis pathways, including
amino acid, energy, carbohy-
drate, and nucleotide metabolism
Lack of supporting evidence of
possible mechanisms involved
Found decreased in the stool of pa-
tients with treatment-naïve new-
onset CD
Found increased in samples from
patients with CD compared to con-
trols
[24,30]
Clostridioides dif-
ficile
A and B toxins produced by this
bacterium may activate caspase-1
and secrete mature IL-1b and IL-
18 (proinflammatory cytokines)
that cause damage to the epithe-
lial barrier and intestinal cells
High prevalence of infection by C.
difficile has been demonstrated
among patients with IBD
[31,32]
Listeria monocyto-
genes
Possibly associated with invasive
infection of epithelial cells
Listeria monocytogenes infection
rates seem to be elevated in pa-
tients with IBD
[31,33]
Verrucomicrobia
Akkermansia mu-
ciniphila
Possibly involved with the
production of SCFAs, which can
activate the GPR43 and thereby
increase the number of Foxp3+
regulatory T cells in the colon
Decreased in stools of both CD and
UC patients.
Human strain ATCC BAA-835T
and murine strain 139 exerted anti-
inflammatory effects on
DSS-induced chronic colitis in
mice
[34–36]
Actinobacteria
Eggerthella lenta
Lack of well-explored possible
mechanisms
Found increased in samples from
patients with CD compared to con-
trols
[24]
Bifidobacterium bifi-
dum
Mucin metabolism performed by
B. bifidum could activate en-
hanced production of mucin,
thereby increasing the mucus
layer depth and strengthening
the epithelial barrier function
Found decreased in samples from
patients with IBD. Some studies
suggest that probiotics containing
this bacterium could have positive
responses in the treatment of IBD
[37,38]
Mycobacterium
avium
Associated with increased pro-
duction of proinflammatory cyto-
kines. Mutations in
NOD2/CARD15 receptors may
cause intracellular survival of the
The abundance of this bacteria, es-
pecially the subspecies paratubercu-
losis
,
is higher in patients with IBD
than in controls
[39,40]
Possibly involved in SCFA metabolism
and its protective and anti-inflammatory
roles
Found decreased in samples from
patients with CD and UC [24,29]
Ruminococcus
gnavus
Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 4 of 25
role in gut physiology and has
beneficial effects, including
protection against pathogen inva-
sion, modulation of the immune
system, and promotion of anti-in-
flammatory activity
CD. Its deficiency was shown in
colonic CD. Low F. prausnitzii
levels in patients with IBD under-
going surgery is associated with a
higher risk of post-operative recur-
rence
Eubacterium spp.
Involved in the production of
SCFAs, especially butyrate. It is
important in inflammation mod-
ulation and the promotion of epi-
thelial barrier integrity
Found deficient in samples from
patients with CD and UC [24,28]
Ruminococcus albus
Possibly involved in SCFA me-
tabolism and its protective and
anti-inflammatory roles
Found decreased in samples from
patients with CD and UC [24,29]
Ruminococcus gna-
vus
Involved in bile and amino acid
biosynthesis pathways, including
amino acid, energy, carbohy-
drate, and nucleotide metabolism
Lack of supporting evidence of
possible mechanisms involved
Found decreased in the stool of pa-
tients with treatment-naïve new-
onset CD
Found increased in samples from
patients with CD compared to con-
trols
[24,30]
Clostridioides dif-
ficile
A and B toxins produced by this
bacterium may activate caspase-1
and secrete mature IL-1b and IL-
18 (proinflammatory cytokines)
that cause damage to the epithe-
lial barrier and intestinal cells
High prevalence of infection by C.
difficile has been demonstrated
among patients with IBD
[31,32]
Listeria monocyto-
genes
Possibly associated with invasive
infection of epithelial cells
Listeria monocytogenes infection
rates seem to be elevated in pa-
tients with IBD
[31,33]
Verrucomicrobia
Akkermansia mu-
ciniphila
Possibly involved with the
production of SCFAs, which can
activate the GPR43 and thereby
increase the number of Foxp3+
regulatory T cells in the colon
Decreased in stools of both CD and
UC patients.
Human strain ATCC BAA-835T
and murine strain 139 exerted anti-
inflammatory effects on
DSS-induced chronic colitis in
mice
[34–36]
Actinobacteria
Eggerthella lenta Lack of well-explored possible
mechanisms
Found increased in samples from
patients with CD compared to con-
trols
[24]
Bifidobacterium bifi-
dum
Mucin metabolism performed by
B. bifidum could activate en-
hanced production of mucin,
thereby increasing the mucus
layer depth and strengthening
the epithelial barrier function
Found decreased in samples from
patients with IBD. Some studies
suggest that probiotics containing
this bacterium could have positive
responses in the treatment of IBD
[37,38]
Mycobacterium
avium
Associated with increased pro-
duction of proinflammatory cyto-
kines. Mutations in
NOD2/CARD15 receptors may
cause intracellular survival of the
The abundance of this bacteria, es-
pecially the subspecies paratubercu-
losis
,
is higher in patients with IBD
than in controls
[39,40]
Involved in bile and amino acid
biosynthesis pathways, including amino
acid, energy, carbohydrate, and
nucleotide metabolism
Lack of supporting evidence of possible
mechanisms involved
Found decreased in the stool of patients
with treatment-naïve new-onset CD
Found increased in samples from
patients with CD compared to controls
[24,30]
Clostridioides
difficile
Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 4 of 25
role in gut physiology and has
beneficial effects, including
protection against pathogen inva-
sion, modulation of the immune
system, and promotion of anti-in-
flammatory activity
CD. Its deficiency was shown in
colonic CD. Low F. prausnitzii
levels in patients with IBD under-
going surgery is associated with a
higher risk of post-operative recur-
rence
Eubacterium spp.
Involved in the production of
SCFAs, especially butyrate. It is
important in inflammation mod-
ulation and the promotion of epi-
thelial barrier integrity
Found deficient in samples from
patients with CD and UC [24,28]
Ruminococcus albus Possibly involved in SCFA me-
tabolism and its protective and
anti-inflammatory roles
Found decreased in samples from
patients with CD and UC [24,29]
Ruminococcus gna-
vus
Involved in bile and amino acid
biosynthesis pathways, including
amino acid, energy, carbohy-
drate, and nucleotide metabolism
Lack of supporting evidence of
possible mechanisms involved
Found decreased in the stool of pa-
tients with treatment-naïve new-
onset CD
Found increased in samples from
patients with CD compared to con-
trols
[24,30]
Clostridioides dif-
ficile
A and B toxins produced by this
bacterium may activate caspase-1
and secrete mature IL-1b and IL-
18 (proinflammatory cytokines)
that cause damage to the epithe-
lial barrier and intestinal cells
High prevalence of infection by C.
difficile has been demonstrated
among patients with IBD
[31,32]
Listeria monocyto-
genes
Possibly associated with invasive
infection of epithelial cells
Listeria monocytogenes infection
rates seem to be elevated in pa-
tients with IBD
[31,33]
Verrucomicrobia
Akkermansia mu-
ciniphila
Possibly involved with the
production of SCFAs, which can
activate the GPR43 and thereby
increase the number of Foxp3+
regulatory T cells in the colon
Decreased in stools of both CD and
UC patients.
Human strain ATCC BAA-835T
and murine strain 139 exerted anti-
inflammatory effects on
DSS-induced chronic colitis in
mice
[34–36]
Actinobacteria
Eggerthella lenta
Lack of well-explored possible
mechanisms
Found increased in samples from
patients with CD compared to con-
trols
[24]
Bifidobacterium bifi-
dum
Mucin metabolism performed by
B. bifidum could activate en-
hanced production of mucin,
thereby increasing the mucus
layer depth and strengthening
the epithelial barrier function
Found decreased in samples from
patients with IBD. Some studies
suggest that probiotics containing
this bacterium could have positive
responses in the treatment of IBD
[37,38]
Mycobacterium
avium
Associated with increased pro-
duction of proinflammatory cyto-
kines. Mutations in
NOD2/CARD15 receptors may
cause intracellular survival of the
The abundance of this bacteria, es-
pecially the subspecies paratubercu-
losis
,
is higher in patients with IBD
than in controls
[39,40]
A and B toxins produced by this
bacterium may activate caspase-1 and
secrete mature IL-1b and IL-18
(proinflammatory cytokines) that cause
damage to the epithelial barrier and
intestinal cells
High prevalence of infection by C.
difficile has been demonstrated among
patients with IBD
[31,32]
Listeria
monocytogenes
Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 4 of 25
role in gut physiology and has
beneficial effects, including
protection against pathogen inva-
sion, modulation of the immune
system, and promotion of anti-in-
flammatory activity
CD. Its deficiency was shown in
colonic CD. Low F. prausnitzii
levels in patients with IBD under-
going surgery is associated with a
higher risk of post-operative recur-
rence
Eubacterium spp.
Involved in the production of
SCFAs, especially butyrate. It is
important in inflammation mod-
ulation and the promotion of epi-
thelial barrier integrity
Found deficient in samples from
patients with CD and UC [24,28]
Ruminococcus albus Possibly involved in SCFA me-
tabolism and its protective and
anti-inflammatory roles
Found decreased in samples from
patients with CD and UC [24,29]
Ruminococcus gna-
vus
Involved in bile and amino acid
biosynthesis pathways, including
amino acid, energy, carbohy-
drate, and nucleotide metabolism
Lack of supporting evidence of
possible mechanisms involved
Found decreased in the stool of pa-
tients with treatment-naïve new-
onset CD
Found increased in samples from
patients with CD compared to con-
trols
[24,30]
Clostridioides dif-
ficile
A and B toxins produced by this
bacterium may activate caspase-1
and secrete mature IL-1b and IL-
18 (proinflammatory cytokines)
that cause damage to the epithe-
lial barrier and intestinal cells
High prevalence of infection by C.
difficile has been demonstrated
among patients with IBD
[31,32]
Listeria monocyto-
genes
Possibly associated with invasive
infection of epithelial cells
Listeria monocytogenes infection
rates seem to be elevated in pa-
tients with IBD
[31,33]
Verrucomicrobia
Akkermansia mu-
ciniphila
Possibly involved with the
production of SCFAs, which can
activate the GPR43 and thereby
increase the number of Foxp3+
regulatory T cells in the colon
Decreased in stools of both CD and
UC patients.
Human strain ATCC BAA-835T
and murine strain 139 exerted anti-
inflammatory effects on
DSS-induced chronic colitis in
mice
[34–36]
Actinobacteria
Eggerthella lenta
Lack of well-explored possible
mechanisms
Found increased in samples from
patients with CD compared to con-
trols
[24]
Bifidobacterium bifi-
dum
Mucin metabolism performed by
B. bifidum could activate en-
hanced production of mucin,
thereby increasing the mucus
layer depth and strengthening
the epithelial barrier function
Found decreased in samples from
patients with IBD. Some studies
suggest that probiotics containing
this bacterium could have positive
responses in the treatment of IBD
[37,38]
Mycobacterium
avium
Associated with increased pro-
duction of proinflammatory cyto-
kines. Mutations in
NOD2/CARD15 receptors may
cause intracellular survival of the
The abundance of this bacteria, es-
pecially the subspecies paratubercu-
losis
,
is higher in patients with IBD
than in controls
[39,40]
Possibly associated with invasive
infection of epithelial cells
Listeria monocytogenes infection rates
seem to be elevated in patients with IBD
[31,33]
Verrucomicrobia
Akkermansia
muciniphila
Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 4 of 25
role in gut physiology and has
beneficial effects, including
protection against pathogen inva-
sion, modulation of the immune
system, and promotion of anti-in-
flammatory activity
CD. Its deficiency was shown in
colonic CD. Low F. prausnitzii
levels in patients with IBD under-
going surgery is associated with a
higher risk of post-operative recur-
rence
Eubacterium spp.
Involved in the production of
SCFAs, especially butyrate. It is
important in inflammation mod-
ulation and the promotion of epi-
thelial barrier integrity
Found deficient in samples from
patients with CD and UC [24,28]
Ruminococcus albus Possibly involved in SCFA me-
tabolism and its protective and
anti-inflammatory roles
Found decreased in samples from
patients with CD and UC [24,29]
Ruminococcus gna-
vus
Involved in bile and amino acid
biosynthesis pathways, including
amino acid, energy, carbohy-
drate, and nucleotide metabolism
Lack of supporting evidence of
possible mechanisms involved
Found decreased in the stool of pa-
tients with treatment-naïve new-
onset CD
Found increased in samples from
patients with CD compared to con-
trols
[24,30]
Clostridioides dif-
ficile
A and B toxins produced by this
bacterium may activate caspase-1
and secrete mature IL-1b and IL-
18 (proinflammatory cytokines)
that cause damage to the epithe-
lial barrier and intestinal cells
High prevalence of infection by C.
difficile has been demonstrated
among patients with IBD
[31,32]
Listeria monocyto-
genes
Possibly associated with invasive
infection of epithelial cells
Listeria monocytogenes infection
rates seem to be elevated in pa-
tients with IBD
[31,33]
Verrucomicrobia
Akkermansia mu-
ciniphila
Possibly involved with the
production of SCFAs, which can
activate the GPR43 and thereby
increase the number of Foxp3+
regulatory T cells in the colon
Decreased in stools of both CD and
UC patients.
Human strain ATCC BAA-835T
and murine strain 139 exerted anti-
inflammatory effects on
DSS-induced chronic colitis in
mice
[34–36]
Actinobacteria
Eggerthella lenta
Lack of well-explored possible
mechanisms
Found increased in samples from
patients with CD compared to con-
trols
[24]
Bifidobacterium bifi-
dum
Mucin metabolism performed by
B. bifidum could activate en-
hanced production of mucin,
thereby increasing the mucus
layer depth and strengthening
the epithelial barrier function
Found decreased in samples from
patients with IBD. Some studies
suggest that probiotics containing
this bacterium could have positive
responses in the treatment of IBD
[37,38]
Mycobacterium
avium
Associated with increased pro-
duction of proinflammatory cyto-
kines. Mutations in
NOD2/CARD15 receptors may
cause intracellular survival of the
The abundance of this bacteria, es-
pecially the subspecies paratubercu-
losis
,
is higher in patients with IBD
than in controls
[39,40]
Possibly involved with the production
of SCFAs, which can activate the GPR43
and thereby increase the number of
Foxp3+ regulatory T cells in the colon
Decreased in stools of both CD and UC
patients.
Human strain ATCC BAA-835T and
murine strain 139 exerted
anti-inflammatory effects on
DSS-induced chronic colitis in mice
[34–36]
Actinobacteria
Eggerthella lenta
Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 4 of 25
role in gut physiology and has
beneficial effects, including
protection against pathogen inva-
sion, modulation of the immune
system, and promotion of anti-in-
flammatory activity
CD. Its deficiency was shown in
colonic CD. Low F. prausnitzii
levels in patients with IBD under-
going surgery is associated with a
higher risk of post-operative recur-
rence
Eubacterium spp.
Involved in the production of
SCFAs, especially butyrate. It is
important in inflammation mod-
ulation and the promotion of epi-
thelial barrier integrity
Found deficient in samples from
patients with CD and UC [24,28]
Ruminococcus albus Possibly involved in SCFA me-
tabolism and its protective and
anti-inflammatory roles
Found decreased in samples from
patients with CD and UC [24,29]
Ruminococcus gna-
vus
Involved in bile and amino acid
biosynthesis pathways, including
amino acid, energy, carbohy-
drate, and nucleotide metabolism
Lack of supporting evidence of
possible mechanisms involved
Found decreased in the stool of pa-
tients with treatment-naïve new-
onset CD
Found increased in samples from
patients with CD compared to con-
trols
[24,30]
Clostridioides dif-
ficile
A and B toxins produced by this
bacterium may activate caspase-1
and secrete mature IL-1b and IL-
18 (proinflammatory cytokines)
that cause damage to the epithe-
lial barrier and intestinal cells
High prevalence of infection by C.
difficile has been demonstrated
among patients with IBD
[31,32]
Listeria monocyto-
genes
Possibly associated with invasive
infection of epithelial cells
Listeria monocytogenes infection
rates seem to be elevated in pa-
tients with IBD
[31,33]
Verrucomicrobia
Akkermansia mu-
ciniphila
Possibly involved with the
production of SCFAs, which can
activate the GPR43 and thereby
increase the number of Foxp3+
regulatory T cells in the colon
Decreased in stools of both CD and
UC patients.
Human strain ATCC BAA-835T
and murine strain 139 exerted anti-
inflammatory effects on
DSS-induced chronic colitis in
mice
[34–36]
Actinobacteria
Eggerthella lenta
Lack of well-explored possible
mechanisms
Found increased in samples from
patients with CD compared to con-
trols
[24]
Bifidobacterium bifi-
dum
Mucin metabolism performed by
B. bifidum could activate en-
hanced production of mucin,
thereby increasing the mucus
layer depth and strengthening
the epithelial barrier function
Found decreased in samples from
patients with IBD. Some studies
suggest that probiotics containing
this bacterium could have positive
responses in the treatment of IBD
[37,38]
Mycobacterium
avium
Associated with increased pro-
duction of proinflammatory cyto-
kines. Mutations in
NOD2/CARD15 receptors may
cause intracellular survival of the
The abundance of this bacteria, es-
pecially the subspecies paratubercu-
losis
,
is higher in patients with IBD
than in controls
[39,40]
Lack of well-explored possible
mechanisms
Found increased in samples from
patients with CD compared to controls [24]
Bifidobacterium
bifidum
Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 4 of 25
role in gut physiology and has
beneficial effects, including
protection against pathogen inva-
sion, modulation of the immune
system, and promotion of anti-in-
flammatory activity
CD. Its deficiency was shown in
colonic CD. Low F. prausnitzii
levels in patients with IBD under-
going surgery is associated with a
higher risk of post-operative recur-
rence
Eubacterium spp.
Involved in the production of
SCFAs, especially butyrate. It is
important in inflammation mod-
ulation and the promotion of epi-
thelial barrier integrity
Found deficient in samples from
patients with CD and UC [24,28]
Ruminococcus albus Possibly involved in SCFA me-
tabolism and its protective and
anti-inflammatory roles
Found decreased in samples from
patients with CD and UC [24,29]
Ruminococcus gna-
vus
Involved in bile and amino acid
biosynthesis pathways, including
amino acid, energy, carbohy-
drate, and nucleotide metabolism
Lack of supporting evidence of
possible mechanisms involved
Found decreased in the stool of pa-
tients with treatment-naïve new-
onset CD
Found increased in samples from
patients with CD compared to con-
trols
[24,30]
Clostridioides dif-
ficile
A and B toxins produced by this
bacterium may activate caspase-1
and secrete mature IL-1b and IL-
18 (proinflammatory cytokines)
that cause damage to the epithe-
lial barrier and intestinal cells
High prevalence of infection by C.
difficile has been demonstrated
among patients with IBD
[31,32]
Listeria monocyto-
genes
Possibly associated with invasive
infection of epithelial cells
Listeria monocytogenes infection
rates seem to be elevated in pa-
tients with IBD
[31,33]
Verrucomicrobia
Akkermansia mu-
ciniphila
Possibly involved with the
production of SCFAs, which can
activate the GPR43 and thereby
increase the number of Foxp3+
regulatory T cells in the colon
Decreased in stools of both CD and
UC patients.
Human strain ATCC BAA-835T
and murine strain 139 exerted anti-
inflammatory effects on
DSS-induced chronic colitis in
mice
[34–36]
Actinobacteria
Eggerthella lenta
Lack of well-explored possible
mechanisms
Found increased in samples from
patients with CD compared to con-
trols
[24]
Bifidobacterium bifi-
dum
Mucin metabolism performed by
B. bifidum could activate en-
hanced production of mucin,
thereby increasing the mucus
layer depth and strengthening
the epithelial barrier function
Found decreased in samples from
patients with IBD. Some studies
suggest that probiotics containing
this bacterium could have positive
responses in the treatment of IBD
[37,38]
Mycobacterium
avium
Associated with increased pro-
duction of proinflammatory cyto-
kines. Mutations in
NOD2/CARD15 receptors may
cause intracellular survival of the
The abundance of this bacteria, es-
pecially the subspecies paratubercu-
losis
,
is higher in patients with IBD
than in controls
[39,40]
Mucin metabolism performed by B.
bifidum could activate enhanced
production of mucin, thereby increasing
the mucus layer depth and
strengthening the epithelial barrier
function
Found decreased in samples from
patients with IBD. Some studies suggest
that probiotics containing this bacterium
could have positive responses in the
treatment of IBD
[37,38]
Mycobacterium
avium
Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 4 of 25
role in gut physiology and has
beneficial effects, including
protection against pathogen inva-
sion, modulation of the immune
system, and promotion of anti-in-
flammatory activity
CD. Its deficiency was shown in
colonic CD. Low F. prausnitzii
levels in patients with IBD under-
going surgery is associated with a
higher risk of post-operative recur-
rence
Eubacterium spp.
Involved in the production of
SCFAs, especially butyrate. It is
important in inflammation mod-
ulation and the promotion of epi-
thelial barrier integrity
Found deficient in samples from
patients with CD and UC [24,28]
Ruminococcus albus Possibly involved in SCFA me-
tabolism and its protective and
anti-inflammatory roles
Found decreased in samples from
patients with CD and UC [24,29]
Ruminococcus gna-
vus
Involved in bile and amino acid
biosynthesis pathways, including
amino acid, energy, carbohy-
drate, and nucleotide metabolism
Lack of supporting evidence of
possible mechanisms involved
Found decreased in the stool of pa-
tients with treatment-naïve new-
onset CD
Found increased in samples from
patients with CD compared to con-
trols
[24,30]
Clostridioides dif-
ficile
A and B toxins produced by this
bacterium may activate caspase-1
and secrete mature IL-1b and IL-
18 (proinflammatory cytokines)
that cause damage to the epithe-
lial barrier and intestinal cells
High prevalence of infection by C.
difficile has been demonstrated
among patients with IBD
[31,32]
Listeria monocyto-
genes
Possibly associated with invasive
infection of epithelial cells
Listeria monocytogenes infection
rates seem to be elevated in pa-
tients with IBD
[31,33]
Verrucomicrobia
Akkermansia mu-
ciniphila
Possibly involved with the
production of SCFAs, which can
activate the GPR43 and thereby
increase the number of Foxp3+
regulatory T cells in the colon
Decreased in stools of both CD and
UC patients.
Human strain ATCC BAA-835T
and murine strain 139 exerted anti-
inflammatory effects on
DSS-induced chronic colitis in
mice
[34–36]
Actinobacteria
Eggerthella lenta
Lack of well-explored possible
mechanisms
Found increased in samples from
patients with CD compared to con-
trols
[24]
Bifidobacterium bifi-
dum
Mucin metabolism performed by
B. bifidum could activate en-
hanced production of mucin,
thereby increasing the mucus
layer depth and strengthening
the epithelial barrier function
Found decreased in samples from
patients with IBD. Some studies
suggest that probiotics containing
this bacterium could have positive
responses in the treatment of IBD
[37,38]
Mycobacterium
avium
Associated with increased pro-
duction of proinflammatory cyto-
kines. Mutations in
NOD2/CARD15 receptors may
cause intracellular survival of the
The abundance of this bacteria, es-
pecially the subspecies paratubercu-
losis
,
is higher in patients with IBD
than in controls
[39,40]
Associated with increased production of
proinflammatory cytokines. Mutations
in NOD2/CARD15 receptors may cause
intracellular survival of the bacteria and
ultimately cause infection
The abundance of this bacteria,
especially the subspecies
paratuberculosis, is higher in patients
with IBD than in controls
[39,40]
Proteobacteria

Int. J. Mol. Sci. 2022,23, 3464 5 of 25
Table 1. Cont.
Microbiome
Components
Presence
in IBD Possible Mechanisms Evidence References
Escherichia coli
Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 4 of 25
role in gut physiology and has
beneficial effects, including
protection against pathogen inva-
sion, modulation of the immune
system, and promotion of anti-in-
flammatory activity
CD. Its deficiency was shown in
colonic CD. Low F. prausnitzii
levels in patients with IBD under-
going surgery is associated with a
higher risk of post-operative recur-
rence
Eubacterium spp.
Involved in the production of
SCFAs, especially butyrate. It is
important in inflammation mod-
ulation and the promotion of epi-
thelial barrier integrity
Found deficient in samples from
patients with CD and UC [24,28]
Ruminococcus albus Possibly involved in SCFA me-
tabolism and its protective and
anti-inflammatory roles
Found decreased in samples from
patients with CD and UC [24,29]
Ruminococcus gna-
vus
Involved in bile and amino acid
biosynthesis pathways, including
amino acid, energy, carbohy-
drate, and nucleotide metabolism
Lack of supporting evidence of
possible mechanisms involved
Found decreased in the stool of pa-
tients with treatment-naïve new-
onset CD
Found increased in samples from
patients with CD compared to con-
trols
[24,30]
Clostridioides dif-
ficile
A and B toxins produced by this
bacterium may activate caspase-1
and secrete mature IL-1b and IL-
18 (proinflammatory cytokines)
that cause damage to the epithe-
lial barrier and intestinal cells
High prevalence of infection by C.
difficile has been demonstrated
among patients with IBD
[31,32]
Listeria monocyto-
genes
Possibly associated with invasive
infection of epithelial cells
Listeria monocytogenes infection
rates seem to be elevated in pa-
tients with IBD
[31,33]
Verrucomicrobia
Akkermansia mu-
ciniphila
Possibly involved with the
production of SCFAs, which can
activate the GPR43 and thereby
increase the number of Foxp3+
regulatory T cells in the colon
Decreased in stools of both CD and
UC patients.
Human strain ATCC BAA-835T
and murine strain 139 exerted anti-
inflammatory effects on
DSS-induced chronic colitis in
mice
[34–36]
Actinobacteria
Eggerthella lenta
Lack of well-explored possible
mechanisms
Found increased in samples from
patients with CD compared to con-
trols
[24]
Bifidobacterium bifi-
dum
Mucin metabolism performed by
B. bifidum could activate en-
hanced production of mucin,
thereby increasing the mucus
layer depth and strengthening
the epithelial barrier function
Found decreased in samples from
patients with IBD. Some studies
suggest that probiotics containing
this bacterium could have positive
responses in the treatment of IBD
[37,38]
Mycobacterium
avium
Associated with increased pro-
duction of proinflammatory cyto-
kines. Mutations in
NOD2/CARD15 receptors may
cause intracellular survival of the
The abundance of this bacteria, es-
pecially the subspecies paratubercu-
losis
,
is higher in patients with IBD
than in controls
[39,40]
Epithelium-associated invasive E. coli
has frequently been isolated from ileal
and colonic mucosa from patients with
CD and can infect and damage
intestinal epithelial cell monolayers, and
synthesize α-hemolysin
Found increased numbers of E. coli
strains with virulence properties
isolated from samples of patients with
IBD. Several studies indicate that there
is a link between the prevalence of E.
coli and IBD relapses
[41,42]
Haemophilus
parainfluenzae
Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 4 of 25
role in gut physiology and has
beneficial effects, including
protection against pathogen inva-
sion, modulation of the immune
system, and promotion of anti-in-
flammatory activity
CD. Its deficiency was shown in
colonic CD. Low F. prausnitzii
levels in patients with IBD under-
going surgery is associated with a
higher risk of post-operative recur-
rence
Eubacterium spp.
Involved in the production of
SCFAs, especially butyrate. It is
important in inflammation mod-
ulation and the promotion of epi-
thelial barrier integrity
Found deficient in samples from
patients with CD and UC [24,28]
Ruminococcus albus Possibly involved in SCFA me-
tabolism and its protective and
anti-inflammatory roles
Found decreased in samples from
patients with CD and UC [24,29]
Ruminococcus gna-
vus
Involved in bile and amino acid
biosynthesis pathways, including
amino acid, energy, carbohy-
drate, and nucleotide metabolism
Lack of supporting evidence of
possible mechanisms involved
Found decreased in the stool of pa-
tients with treatment-naïve new-
onset CD
Found increased in samples from
patients with CD compared to con-
trols
[24,30]
Clostridioides dif-
ficile
A and B toxins produced by this
bacterium may activate caspase-1
and secrete mature IL-1b and IL-
18 (proinflammatory cytokines)
that cause damage to the epithe-
lial barrier and intestinal cells
High prevalence of infection by C.
difficile has been demonstrated
among patients with IBD
[31,32]
Listeria monocyto-
genes
Possibly associated with invasive
infection of epithelial cells
Listeria monocytogenes infection
rates seem to be elevated in pa-
tients with IBD
[31,33]
Verrucomicrobia
Akkermansia mu-
ciniphila
Possibly involved with the
production of SCFAs, which can
activate the GPR43 and thereby
increase the number of Foxp3+
regulatory T cells in the colon
Decreased in stools of both CD and
UC patients.
Human strain ATCC BAA-835T
and murine strain 139 exerted anti-
inflammatory effects on
DSS-induced chronic colitis in
mice
[34–36]
Actinobacteria
Eggerthella lenta
Lack of well-explored possible
mechanisms
Found increased in samples from
patients with CD compared to con-
trols
[24]
Bifidobacterium bifi-
dum
Mucin metabolism performed by
B. bifidum could activate en-
hanced production of mucin,
thereby increasing the mucus
layer depth and strengthening
the epithelial barrier function
Found decreased in samples from
patients with IBD. Some studies
suggest that probiotics containing
this bacterium could have positive
responses in the treatment of IBD
[37,38]
Mycobacterium
avium
Associated with increased pro-
duction of proinflammatory cyto-
kines. Mutations in
NOD2/CARD15 receptors may
cause intracellular survival of the
The abundance of this bacteria, es-
pecially the subspecies paratubercu-
losis
,
is higher in patients with IBD
than in controls
[39,40]
Involved in glycerol-phospholipid
and lipopolysaccharide metabolism,
thereby promoting inflammation
Found increased in stool samples from
patients with treatment-naïve new-onset
CD
[30]
Campylobacter
spp.
Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 4 of 25
role in gut physiology and has
beneficial effects, including
protection against pathogen inva-
sion, modulation of the immune
system, and promotion of anti-in-
flammatory activity
CD. Its deficiency was shown in
colonic CD. Low F. prausnitzii
levels in patients with IBD under-
going surgery is associated with a
higher risk of post-operative recur-
rence
Eubacterium spp.
Involved in the production of
SCFAs, especially butyrate. It is
important in inflammation mod-
ulation and the promotion of epi-
thelial barrier integrity
Found deficient in samples from
patients with CD and UC [24,28]
Ruminococcus albus Possibly involved in SCFA me-
tabolism and its protective and
anti-inflammatory roles
Found decreased in samples from
patients with CD and UC [24,29]
Ruminococcus gna-
vus
Involved in bile and amino acid
biosynthesis pathways, including
amino acid, energy, carbohy-
drate, and nucleotide metabolism
Lack of supporting evidence of
possible mechanisms involved
Found decreased in the stool of pa-
tients with treatment-naïve new-
onset CD
Found increased in samples from
patients with CD compared to con-
trols
[24,30]
Clostridioides dif-
ficile
A and B toxins produced by this
bacterium may activate caspase-1
and secrete mature IL-1b and IL-
18 (proinflammatory cytokines)
that cause damage to the epithe-
lial barrier and intestinal cells
High prevalence of infection by C.
difficile has been demonstrated
among patients with IBD
[31,32]
Listeria monocyto-
genes
Possibly associated with invasive
infection of epithelial cells
Listeria monocytogenes infection
rates seem to be elevated in pa-
tients with IBD
[31,33]
Verrucomicrobia
Akkermansia mu-
ciniphila
Possibly involved with the
production of SCFAs, which can
activate the GPR43 and thereby
increase the number of Foxp3+
regulatory T cells in the colon
Decreased in stools of both CD and
UC patients.
Human strain ATCC BAA-835T
and murine strain 139 exerted anti-
inflammatory effects on
DSS-induced chronic colitis in
mice
[34–36]
Actinobacteria
Eggerthella lenta
Lack of well-explored possible
mechanisms
Found increased in samples from
patients with CD compared to con-
trols
[24]
Bifidobacterium bifi-
dum
Mucin metabolism performed by
B. bifidum could activate en-
hanced production of mucin,
thereby increasing the mucus
layer depth and strengthening
the epithelial barrier function
Found decreased in samples from
patients with IBD. Some studies
suggest that probiotics containing
this bacterium could have positive
responses in the treatment of IBD
[37,38]
Mycobacterium
avium
Associated with increased pro-
duction of proinflammatory cyto-
kines. Mutations in
NOD2/CARD15 receptors may
cause intracellular survival of the
The abundance of this bacteria, es-
pecially the subspecies paratubercu-
losis
,
is higher in patients with IBD
than in controls
[39,40]
Invasive strains of this bacteria in
patients with IBD
can survive in intracellular and
anaerobic conditions
Increased in patients with IBD
compared to controls [43]
Eikenella
corrodens
Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 4 of 25
role in gut physiology and has
beneficial effects, including
protection against pathogen inva-
sion, modulation of the immune
system, and promotion of anti-in-
flammatory activity
CD. Its deficiency was shown in
colonic CD. Low F. prausnitzii
levels in patients with IBD under-
going surgery is associated with a
higher risk of post-operative recur-
rence
Eubacterium spp.
Involved in the production of
SCFAs, especially butyrate. It is
important in inflammation mod-
ulation and the promotion of epi-
thelial barrier integrity
Found deficient in samples from
patients with CD and UC [24,28]
Ruminococcus albus Possibly involved in SCFA me-
tabolism and its protective and
anti-inflammatory roles
Found decreased in samples from
patients with CD and UC [24,29]
Ruminococcus gna-
vus
Involved in bile and amino acid
biosynthesis pathways, including
amino acid, energy, carbohy-
drate, and nucleotide metabolism
Lack of supporting evidence of
possible mechanisms involved
Found decreased in the stool of pa-
tients with treatment-naïve new-
onset CD
Found increased in samples from
patients with CD compared to con-
trols
[24,30]
Clostridioides dif-
ficile
A and B toxins produced by this
bacterium may activate caspase-1
and secrete mature IL-1b and IL-
18 (proinflammatory cytokines)
that cause damage to the epithe-
lial barrier and intestinal cells
High prevalence of infection by C.
difficile has been demonstrated
among patients with IBD
[31,32]
Listeria monocyto-
genes
Possibly associated with invasive
infection of epithelial cells
Listeria monocytogenes infection
rates seem to be elevated in pa-
tients with IBD
[31,33]
Verrucomicrobia
Akkermansia mu-
ciniphila
Possibly involved with the
production of SCFAs, which can
activate the GPR43 and thereby
increase the number of Foxp3+
regulatory T cells in the colon
Decreased in stools of both CD and
UC patients.
Human strain ATCC BAA-835T
and murine strain 139 exerted anti-
inflammatory effects on
DSS-induced chronic colitis in
mice
[34–36]
Actinobacteria
Eggerthella lenta
Lack of well-explored possible
mechanisms
Found increased in samples from
patients with CD compared to con-
trols
[24]
Bifidobacterium bifi-
dum
Mucin metabolism performed by
B. bifidum could activate en-
hanced production of mucin,
thereby increasing the mucus
layer depth and strengthening
the epithelial barrier function
Found decreased in samples from
patients with IBD. Some studies
suggest that probiotics containing
this bacterium could have positive
responses in the treatment of IBD
[37,38]
Mycobacterium
avium
Associated with increased pro-
duction of proinflammatory cyto-
kines. Mutations in
NOD2/CARD15 receptors may
cause intracellular survival of the
The abundance of this bacteria, es-
pecially the subspecies paratubercu-
losis
,
is higher in patients with IBD
than in controls
[39,40]
Possibly involved in lipid and
polysaccharide metabolism, resulting in
proinflammatory responses
Increased in patients with IBD
compared to controls [30]
Fusobacteria
Fusobacterium
nucleatum
Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 4 of 25
role in gut physiology and has
beneficial effects, including
protection against pathogen inva-
sion, modulation of the immune
system, and promotion of anti-in-
flammatory activity
CD. Its deficiency was shown in
colonic CD. Low F. prausnitzii
levels in patients with IBD under-
going surgery is associated with a
higher risk of post-operative recur-
rence
Eubacterium spp.
Involved in the production of
SCFAs, especially butyrate. It is
important in inflammation mod-
ulation and the promotion of epi-
thelial barrier integrity
Found deficient in samples from
patients with CD and UC [24,28]
Ruminococcus albus Possibly involved in SCFA me-
tabolism and its protective and
anti-inflammatory roles
Found decreased in samples from
patients with CD and UC [24,29]
Ruminococcus gna-
vus
Involved in bile and amino acid
biosynthesis pathways, including
amino acid, energy, carbohy-
drate, and nucleotide metabolism
Lack of supporting evidence of
possible mechanisms involved
Found decreased in the stool of pa-
tients with treatment-naïve new-
onset CD
Found increased in samples from
patients with CD compared to con-
trols
[24,30]
Clostridioides dif-
ficile
A and B toxins produced by this
bacterium may activate caspase-1
and secrete mature IL-1b and IL-
18 (proinflammatory cytokines)
that cause damage to the epithe-
lial barrier and intestinal cells
High prevalence of infection by C.
difficile has been demonstrated
among patients with IBD
[31,32]
Listeria monocyto-
genes
Possibly associated with invasive
infection of epithelial cells
Listeria monocytogenes infection
rates seem to be elevated in pa-
tients with IBD
[31,33]
Verrucomicrobia
Akkermansia mu-
ciniphila
Possibly involved with the
production of SCFAs, which can
activate the GPR43 and thereby
increase the number of Foxp3+
regulatory T cells in the colon
Decreased in stools of both CD and
UC patients.
Human strain ATCC BAA-835T
and murine strain 139 exerted anti-
inflammatory effects on
DSS-induced chronic colitis in
mice
[34–36]
Actinobacteria
Eggerthella lenta
Lack of well-explored possible
mechanisms
Found increased in samples from
patients with CD compared to con-
trols
[24]
Bifidobacterium bifi-
dum
Mucin metabolism performed by
B. bifidum could activate en-
hanced production of mucin,
thereby increasing the mucus
layer depth and strengthening
the epithelial barrier function
Found decreased in samples from
patients with IBD. Some studies
suggest that probiotics containing
this bacterium could have positive
responses in the treatment of IBD
[37,38]
Mycobacterium
avium
Associated with increased pro-
duction of proinflammatory cyto-
kines. Mutations in
NOD2/CARD15 receptors may
cause intracellular survival of the
The abundance of this bacteria, es-
pecially the subspecies paratubercu-
losis
,
is higher in patients with IBD
than in controls
[39,40]
Possibly involved in proinflammatory
and tumorigenic responses
Increased in patients with IBD
compared to controls. It is also
associated with colorectal cancer
[43]
Bacteroidetes
Bacteroides spp.
Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 4 of 25
role in gut physiology and has
beneficial effects, including
protection against pathogen inva-
sion, modulation of the immune
system, and promotion of anti-in-
flammatory activity
CD. Its deficiency was shown in
colonic CD. Low F. prausnitzii
levels in patients with IBD under-
going surgery is associated with a
higher risk of post-operative recur-
rence
Eubacterium spp.
Involved in the production of
SCFAs, especially butyrate. It is
important in inflammation mod-
ulation and the promotion of epi-
thelial barrier integrity
Found deficient in samples from
patients with CD and UC [24,28]
Ruminococcus albus Possibly involved in SCFA me-
tabolism and its protective and
anti-inflammatory roles
Found decreased in samples from
patients with CD and UC [24,29]
Ruminococcus gna-
vus
Involved in bile and amino acid
biosynthesis pathways, including
amino acid, energy, carbohy-
drate, and nucleotide metabolism
Lack of supporting evidence of
possible mechanisms involved
Found decreased in the stool of pa-
tients with treatment-naïve new-
onset CD
Found increased in samples from
patients with CD compared to con-
trols
[24,30]
Clostridioides dif-
ficile
A and B toxins produced by this
bacterium may activate caspase-1
and secrete mature IL-1b and IL-
18 (proinflammatory cytokines)
that cause damage to the epithe-
lial barrier and intestinal cells
High prevalence of infection by C.
difficile has been demonstrated
among patients with IBD
[31,32]
Listeria monocyto-
genes
Possibly associated with invasive
infection of epithelial cells
Listeria monocytogenes infection
rates seem to be elevated in pa-
tients with IBD
[31,33]
Verrucomicrobia
Akkermansia mu-
ciniphila
Possibly involved with the
production of SCFAs, which can
activate the GPR43 and thereby
increase the number of Foxp3+
regulatory T cells in the colon
Decreased in stools of both CD and
UC patients.
Human strain ATCC BAA-835T
and murine strain 139 exerted anti-
inflammatory effects on
DSS-induced chronic colitis in
mice
[34–36]
Actinobacteria
Eggerthella lenta
Lack of well-explored possible
mechanisms
Found increased in samples from
patients with CD compared to con-
trols
[24]
Bifidobacterium bifi-
dum
Mucin metabolism performed by
B. bifidum could activate en-
hanced production of mucin,
thereby increasing the mucus
layer depth and strengthening
the epithelial barrier function
Found decreased in samples from
patients with IBD. Some studies
suggest that probiotics containing
this bacterium could have positive
responses in the treatment of IBD
[37,38]
Mycobacterium
avium
Associated with increased pro-
duction of proinflammatory cyto-
kines. Mutations in
NOD2/CARD15 receptors may
cause intracellular survival of the
The abundance of this bacteria, es-
pecially the subspecies paratubercu-
losis
,
is higher in patients with IBD
than in controls
[39,40]
Involved in mucin metabolism, possibly
playing a role in damaging the
protective mucus layer
Increased in CD samples. Prominent in
patients with prior surgical resection [24,44–46]
Abbreviations: CD, Crohn’s disease; G protein-coupled receptor 43 (GPR43); IBD, inflammatory bowel disease;
SCFAs, short-chain fatty acids; UC, ulcerative colitis; IL, interleukin; NOD2/CARD15, nucleotide-binding
oligomerization domain 2/caspase recruitment domain family, member 15.
Clooney et al. showed that among the microbial species found to be significantly
increased in CD compared to controls, there was an increased presence of Ruminococcus
gnavus and Fusobacterium nucleatum. Conversely, the presence of Ruminococcus albus,Eu-
bacterium rectale, and Faecalibacterium prausnitzii were decreased in CD. Eubacterium and
Roseburia were among the most important species in classifying either CD or UC com-
pared with controls [
24
,
47
]. Furthermore, some species are particularly associated with
certain subgroups of patients. For instance, Bacteroides vulgatus,Akkermansia muciniphila,
and Escherichia/Shigella were increased in patients with a history of prior surgical resec-
tion [
44
]. In the largest pediatric Crohn’s cohort to date, including >400 patients and
200 controls, microbiomes from new-onset CD cases in multiple gastrointestinal locations
were analyzed by Gevers et al. An axis defined by an increased abundance of bacteria
such as Enterobacteriaceae, Pasteurellacaea, and Fusobacteriaceae and decreased abundance of
Erysipelotrichales, Bacteroidales, and Clostridiales was strongly correlated with disease status.
Moreover, microbiome comparison between patients with CD with and without antibiotic
exposure indicated that antibiotic use amplified the microbial dysbiosis associated with
CD in a new-onset pediatric cohort. The microbial dysbiosis index, which is characterized
by the differential relative abundance of specific taxa, was associated with disease severity.
Additionally, the rectal mucosa-associated microbiome, but not the fecal microbiome, has
been shown to be a robust disease predictor [
30
]. Similarly, another study of a pediatric IBD
cohort showed significant correlation between microbiota composition and disease severity,
with resolution of dysbiosis in patients responding to anti-tumor necrosis factor (TNF) ther-
apy [
48
]. Although changes in the gut microbiota profile in new-onset and treatment-naive
pediatric patients with IBD were further corroborated in a recent systematic review, no

Int. J. Mol. Sci. 2022,23, 3464 6 of 25
clear conclusion can be drawn at the moment due to inconsistent results and heterogeneous
methodologies [49].
In one of the largest longitudinal analyses of the IBD microbiome, Halfvarson et al.
dissected the long-term dynamic behavior of the gut microbiome by comparing patients
with IBD with healthy controls. Phylogenetic analysis of fecal samples showed that gut
microbiomes of different IBD subtypes displayed different species distributions relative
to controls. They identified potential microbial indicators of IBD subtypes, including
genera such as Lachnospira,Clostridium,Oscillospira, and many unidentified Ruminococcaceae.
Furthermore, they found that the microbiomes of patients with IBD fluctuate more than
those of healthy individuals, based on deviation from a newly defined healthy plane. In
addition, patients with ileal CD deviated the most from the healthy plane, especially those
who underwent surgical resection. Interestingly, the microbiomes of some patients with
IBD periodically visited the healthy plane and then deviated away from it [
17
]. In a study
of 132 participants with IBD and controls, Lloyd-Price et al. assessed host and microbial
data from colon biopsies, blood, and stool, for one year each. Principal coordinate analysis
based on species-level Bray–Curtis dissimilarity showed that most variation was driven by
a trade-off between the phyla Bacteroidetes and Firmicutes. Samples from individuals with
IBD (particularly CD) had lower alpha diversity. Moreover, in patients with CD, taxonomic
perturbations during dysbiosis were observed, such as a depletion of obligate anaerobes,
including F. prausnitzii and Roseburia hominis, and an enrichment of facultative anaerobes
such as Escherichia coli. In the metabolome, SCFAs were generally reduced during IBD
dysbiosis. Overall, metabolite pools were less diverse in individuals with IBD, paralleling
the observations of microbial diversity [
50
]. The investigation of whether the response
to treatment with biologic agents could be associated with alterations in the composition
of the intestinal microbiota of patients with CD was performed in a prospective study.
The therapeutic intervention based on adalimumab was associated with the restoration
of a eubiotic environment after six months of treatment. Particularly, in the cohort of
patients with CD, those receiving adalimumab displayed a reduction in Proteobacteria and
an increase in Lachnospiraceae. These results characteristically predominated among those
patients who achieved therapeutic success, suggesting that dysbiosis could be directly
involved with the response to treatment [51].
The role of pathogenic components in IBD has also been studied. For example,
adherent-invasive E. coli (AIEC) is more prevalent in the mucosa of patients with IBD
than in healthy individuals. Overall, the prevalence of AIEC in the mucosa of adult patients
with CD ranges from 21–63%, and it is more associated with ileal CD than with colonic
disease [
41
]. Mycobacterium avium, especially the subspecies paratuberculosis, has also been
implicated in IBD pathogenesis. The abundance of these bacteria is higher in patients with
IBD than in controls, and they are associated with increased production of proinflamma-
tory cytokines [
31
]. Similarly, Listeria monocytogenes, which induces a Th1-type immune
response [52], has also been shown to be increased in patients with IBD [33].
Archaea members have also been identified as part of the human microbiome, es-
pecially methane-producing species, such as Methanobrevibacter smithii,Methanosphaera
stadtmanae, and Methanomassiliicoccus luminyensis in human stools, and Methanobrevibacter
oralis in the oral mucosa [
53
,
54
]. Dysbiosis appears to affect the relative abundance of ar-
chaea members and, particularly in patients with IBD, M. smithii had a reduced abundance,
whereas the immunogenic M. stadtmanae was remarkably increased compared to healthy
controls [55,56].
Viruses and fungi are widely present in the gut and may play important roles in
homeostasis. Changes in the enteric group of viruses in the gastrointestinal tract can
have consequences on the bacterial microbiome and its diversity, as viruses are drivers of
bacterial resistance. For instance, viruses can be responsible for the horizontal transfer of
genetic material among bacterial communities, which implies a change in the balance of
different ecosystems. An increase in the abundance of Caudovirales bacteriophages has been
observed in patients with CD [
57
,
58
]. In addition, results from another study demonstrated

Int. J. Mol. Sci. 2022,23, 3464 7 of 25
an increased abundance of phages infecting Clostridiales, Alteromonadales, and Clostridium
acetobutylicum, as well as viruses from the Retroviridae family, in patients with IBD [
59
,
60
].
Similarly, fungal components regulate and trigger immune responses. However, the
gut mycobiome is less stable than the bacterial microbiome; therefore, a mycobiome signa-
ture has not yet been described [
61
]. Candida is the most prominent component of the fungal
microbiota in humans. Its cell wall constituents, such as beta-glucans, chitin, and mannoses,
can activate components of the innate immune system, such as Toll-like receptors (TLRs)
2 and 4, dectin-1, CD5, CD36, and SCARF1, and complement system components. The
activation of these molecules leads to immune signaling and proinflammatory responses.
Some studies have proposed a correlation between the gut mycobiome and gut bacterial
components. Mason et al. showed that the colonization of C. albicans strain CHN1 in the
stomach and cecum of C57BL6 mice prompted an overgrowth of Lactobacillus spp. and
Enterococcus spp. during antibiotic treatment [
62
]. However, Bernardes et al. demonstrated
that bacteria may influence fungal colonization. They showed that the colonization of bac-
teria together with fungi increased the relative abundance of C. parapsilosis and Issatchenkia
orientalis, and a lack of co-colonization with bacteria or elimination of bacteria by antibiotics
led to an overgrowth of C. albicans [63].
3. Influence of the Exposome
The first organisms on earth were microbes, and they have evolved and adapted to live
in extreme environments all over the planet. All biological entities appearing later on Earth,
including mammals, have evolved in a microbially dominant world. Therefore, humans
have coevolved with microbes immersed within two complex ecological communities:
the external and internal microbial environments. In this dualistic world of microbes, the
exposome and gut microbiome impact each other as well as all other “–omes” in a reciprocal
manner [64,65].
3.1. Geosocial Factors
Environmental factors have been associated with complex health conditions, including
chronic immune-mediated inflammatory diseases (IMIDs), which have been increasing in
incidence during the last century. Features are shared among the different IMIDs, including
IBD, such as an inflammatory basis, multifactorial nature, and yet-unknown causes. In
addition, epidemiological data revealing the co-occurrence of IMIDs and geographic ex-
pansion reinforce a common pathophysiological background that has evolved over the past
several decades to reach a worldwide distribution [
66
]. The emergence of IMIDs and IBD
has been linked to societal transformations, most commonly socioeconomic development
or industrialization [
67
,
68
]. Such changes have been almost invariably accompanied by in-
creasing urbanization [
69
], which, in turn, has been associated with distinct gut microbiota
compositions different to those found in rural areas that are supposedly protective against
IBD development [70,71].
Socioeconomic development and social behavior are crucial elements fueling the
emergence of IBD [
72
]. Such changes have been associated with improvements in sanitation,
quality of water supply in distribution systems, and a resulting decrease in infectious
diseases, which constitute the basis of the hygiene hypothesis [
73
]. Nonetheless, these
changes bring about several other simultaneous environmental modifications that need to
be considered. It is important to highlight, for example, changes in homes, family structures,
workplaces, dietary habits, the widespread use and production of chemicals, and the use of
medications, including antibiotics. Growing urbanization has led to a continuous increase
in population density in cities that have become progressively more polluted, competitive,
and stressful, causing dramatic changes in peoples’ lifestyles. Moreover, the attraction
between manpower and industry, or other economic activities, resulted in more human
agglomeration, whether that be in households or factories; it also gathered people from
different backgrounds, be they genetic, geographic, or cultural. These observations are
in accordance with previous studies showing that individuals who migrate from low to

Int. J. Mol. Sci. 2022,23, 3464 8 of 25
high prevalence IBD areas, that is, from less developed to more developed areas, are more
susceptible to developing IBD, predominantly affecting the first- and second-generation
offspring of these immigrants [74–77]. In addition, among the potentially relevant stimuli
from the exposome, cohabitation has been shown to strongly affect immune responses [
78
].
Transmission of microbial strains, predominantly detected among first-degree relatives
sharing a household, has recently been demonstrated [
79
], helping to explain the link
between the exposome and the immune response. This also reinforces a microbial basis for
IMIDs.
While several human diseases have been associated with abnormalities in host-
associated microbial communities, and the human body is seen as an ecosystem [
80
],
defining a healthy microbiome continues to represent a complex challenge due to the
formidable variability shown in population-based studies [
81
,
82
]. This is also true for IBD,
as a large study confirmed a reduction in microbial diversity in patients with CD and UC
but did not explain the increased variability compared to controls [
24
]. Whether such a
variance is stochastic or due to environmental factors has not yet been established [
83
]. Nev-
ertheless, the microbiome reflects a complex combination of endogenous and exogenous
elements, particularly environmental and lifestyle factors. Previous studies have shown
that the gut microbiome of Western populations is characteristically less diverse [
84
–
86
].
As the intestine represents the largest surface of contact with the external environment, IBD
could be facilitated by a combination of both a cleaner external milieu (as in the hygiene
hypothesis) and an impoverished biome influencing the internal milieu to become less
diverse, resulting in inappropriate immune system education and responses.
The hypothesis that loss of biodiversity is an important environmental factor has been
supported by data showing that reduced contact of people with the natural environment
may negatively impact the commensal microbiota and its immunomodulatory proper-
ties [
87
,
88
]. In addition to its worldwide distribution and progressive increase as a result
of diverse human activities, loss of biodiversity has been regarded as a critical factor in
the rise of allergic diseases [
89
], among which asthma, in particular, has been intimately
associated with IBD [
90
]. Loss of biodiversity has recently been proposed as a novel factor
in the pathogenesis and prevention of IBD, based on the non-uniform disease distribution
in large developing countries, showing pronounced regional dissimilarities and disease
hotspots associated with specific geosocial and ecosystem factors [91].
3.2. Antibiotics
Exposure to antibiotics has been associated with increased risk for developing IBD,
especially CD [
92
,
93
]. Evidence from different studies has shown that patients diagnosed
with IBD during childhood were more likely to have been exposed to antibiotics early in
life [
94
]. In a pediatric prospective study, the strongest association between antibiotic use
and future development of IBD was in the first 3 months following the use of antibiotics
and among children who had more courses of antibiotics [
95
]. Contrarily, a recent study
found that exposure to antibiotics during pregnancy, but not in infancy, is associated with
an increased risk of early onset IBD [
96
]. Although current evidence does not confirm a
consistent causal link with IBD, early exposure to antibiotics has been suggested to affect
the development of tolerance to the gut microbiota, consequently raising inappropriate
immune reactivity that underlies chronic intestinal inflammation [
97
]. Additionally, recent
evidence from a study investigating the microbiome of humans, domestic animals, and their
environment, in relation to antibiotic use, suggested the exchange of antimicrobial-resistant
strains between reservoirs [
98
]. Together, these data appear to support the idea that the risk
of developing IBD associated with intestinal dysbiosis may occur at both the individual and
community levels. This also includes crosstalk with nonhuman components, reinforcing
the existence of dynamic interactions between the environment and host regarding the
exchange and sharing of microorganisms.

Int. J. Mol. Sci. 2022,23, 3464 9 of 25
3.3. Dietary Factors
Several studies have investigated diet, arguably the most ubiquitous environmental
factor, and its potential to shape the gut microbiota. For instance, evidence has shown that a
high-calorie diet, consisting of fat- and carbohydrate-based foods, determines a preferential
expansion of the genera Bacteroides and Prevotella and the Bacteroidetes phylum in adults,
with shifts occurring in a relatively rapid fashion [
99
]. In another study, strictly animal-
based food increased the relative abundance of bile-tolerant microorganisms, reducing the
presence of microorganisms capable of metabolizing dietary plant polysaccharides. These
results showed shifts between carbohydrate and protein fermentation, confirming that
the microbiota can rapidly adjust to changes in dietary patterns. Moreover, changes in
microbial composition were followed by changes in the molecular output of the microbiome
with dietary interventions. SCFAs, products of bacterial digestion of fibers with critical
homeostatic functions in the mucosa and anti-inflammatory properties, were shown to
increase with plant-based diets. This may explain why a reduction in SCFAs in a typical
Western-style diet (animal-based, high-calorie, high-fat, and low-dietary fiber) has been
associated with the risk of IBD [
100
]. In fact, a Western-style diet, rich in sugar and fat,
has been the predominant profile associated with a higher risk of developing IBD. While
individuals who consume higher proportions of red meat and fats have a higher risk of
IBD, others who predominantly consume fibers from vegetables and fruits have a lower
risk [
101
,
102
]. Regarding dietary fat content, particularly polyunsaturated fatty acids,
recent data indicate that a high omega-6 to omega-3 ratio, typical of Western-style diets, is
associated with proinflammatory effects [
103
]. Furthermore, polyunsaturated fatty acids
have been shown to exert not only effects on the immune response, directly acting on
immune cells, but also influence the composition of the gut microbiota, thereby affecting
host–microbiome interactions at different levels [
104
]. The consumption of processed
foods, usually low in omega-3 fatty acids and micronutrients such as zinc and vitamins
D and E, another common feature of Westernized diets, has also been associated with the
development of chronic inflammatory diseases [
105
–
108
]. Globally, major shifts in dietary
patterns towards progressively more Westernized diets, together with socioeconomic and
demographic changes, represent a global transition that may explain the widespread
increase in the rates of several metabolic and IMIDs [
109
], potentially involving changes in
the gut microbiome and its interaction with the host.
4. Genetic Susceptibility
A clear connection with genetic predisposition has long been demonstrated in IBD,
more so in CD than in UC [
110
]. There are over 200 genetic loci associated with IBD
susceptibility, most of which regulate host–microbe interactions and immune-related path-
ways [
110
,
111
]. Some of the more studied genes include those involved in IL-23 receptors
and Janus-activated kinase signaling, and those in innate mucosal defense, cytokine pro-
duction, lymphocyte activation, epithelial barrier integrity, and multiple proteins involved
in autophagy [
112
]. Genome-wide association studies have highlighted higher IBD genetic
risk in individuals with NOD2 receptors, autophagy-related protein 16-like 1 (ATG16L1),
immunity-related GTPase family, M (IRGM), IL-23 receptor gene, protein tyrosine phos-
phatase, non-receptor type 2 (PTPN2), X-box binding protein 1 (XBP1), and leucine-rich
repeat kinase 2 (LRRK2) variants [
111
,
113
]. Genetic risk variants are also associated with
changes in microbiota composition; for example, Roseburia spp., an acetate-to-butyrate
converter, was less abundant in patients with IBD with these high-risk mutations [114].
Mutations in autophagy-related genes alter anti-bacterial, fungal, and viral responses
and impair the clearance of various invading pathogens such as Mycobacterium tubercu-
losis, Group A Streptococcus, L. monocytogenes, and E. coli [
115
–
117
]. An ATG16L1 single
nucleotide polymorphism (SNP) confers susceptibility to CD and is a common genetic
variation present in 40–50% of the population, although most individuals with this SNP do
not develop IBD [
118
,
119
]. The role of autophagy variants in Salmonella clearance is not
well established. Messer et al. observed that ATG16L1 deficiency promoted cell resistance

Int. J. Mol. Sci. 2022,23, 3464 10 of 25
to Salmonella, while Conway et al. observed autophagy induction after Salmonella infection
with the participation of ATG16L1 in intestines [
120
,
121
]. These variants also affect antimi-
crobial peptide production by Paneth cells, cytokine production, antigen presentation, and
response to endoplasmic reticulum stress [
122
]. Atg16L1-deficient mice exhibited elevated
inflammasome activation and IL-1
β
production when stimulated with lipopolysaccharides
(LPS) and abnormalities in ileal Paneth cells, such as the escape of antimicrobial peptides
into the cytoplasm [
123
]. There is crosstalk between NOD2 and ATG16L1, as NOD2 activa-
tion triggers autophagy in dendritic cells with the participation of ATG16L1, and deficiency
in ATG16L1 heightens cytokine production via NOD [
124
,
125
]. Patients with CD with risk
variants of ATG16L1 or NOD2 present with abnormal Paneth cell morphology [
126
]. In
mouse models, decreased expression levels of Atg5,Atg7, or Atg4B generated abnormal
Paneth cell functions, and in CD-like ileitis, deficiency of Atg16L1 also altered Paneth cell
morphology [
127
]. In addition, norovirus infection in Atg16L1-deficient animals increased
their susceptibility to dextran sodium sulfate (DSS) in a TNF-dependent phenotype re-
sembling aspects of IBD [
58
]. Complete knockout of Atg3,Atg5,Atg7, or Atg16L1 is lethal
in mice, and impairment of either Atg7 or Atg16L1 results in severe CD-like transmural
ileitis [
128
]. Autophagic defects also worsen goblet cell function, production of mucus
membrane defenses, and absorptive functions of the microvilli [129].
NOD2 recognizes bacterial peptidoglycan (muramyl dipeptide) in the cell walls of
Gram-negative and Gram-positive bacteria and triggers the production of intestinal an-
timicrobial peptides to protect cells and immune responses in the gut [
130
]. NOD2 ac-
tivation leads to NF-
κ
B activation and production of IL-1b, TNF-
α
, IL-6, IL-8, and
α
-
defensins [
130
,
131
]. NOD2 interacts with autophagy-related proteins to help destroy
intracellular pathogens, and mutations in NOD2, also known as the caspase recruitment
domain family, member 15 gene (CARD15), disrupt Paneth cells’ ability to recognize and
eliminate invading pathogens [
132
,
133
]. In IBD, NOD2 mutations are associated with
decreased release of defensins [
134
]. NOD2-mediated autophagy is important for the
generation of major histocompatibility complex (MHC)-II-restricted CD4+ T cell responses
in dendritic cells, and patients with CD with high-risk NOD2 or ATG16L1 variants exhibit
impaired MHC II antigen presentation [124].
IL-23 signaling affects both the innate and adaptive immune systems in mice and is
required for colitis development in several models [
135
–
137
]. The dominant IL23R SNP
protects against IBD and generates a soluble receptor antagonist of IL-23 [
138
]. Variants in
the autophagy-associated IRGM gene interfere with Paneth cell morphology and function,
and are associated with abnormal secretory granule development, decreased antimicrobial
peptide production, and higher susceptibility to colitis in a DSS-induced model [
139
].
Mutations in PTPN2 lead to defective autophagosome formation and bacterial elimination
and promote T cell differentiation into Th1 and Th17 types [
140
–
142
]. Patients with IBD
with PTPN2 variants demonstrate increased levels of interferon (IFN)-
γ
, IL-17, and IL-22
in the serum and intestinal mucosa [143]. LRRK2 is involved in the activation of dendritic
cells (DCs) and production of IL-2 and TNF-αin CD [144].
5. Epigenetic Modifications
Recent data have provided the basis for the hypothesis that epigenetic modifications,
resulting from interactions between the host and exposome, determine the phenotypic
expression of IBD. For instance, the relatively high discordance rate among monozygotic
twins [
145
] and an increased risk of developing the disease among people migrating
from low- to high-incidence regions of IBD [
146
] constitute important epidemiological
information to support the pathogenic role of epigenetic changes. Consequently, epigenetic
factors have been suggested to mediate critical interactions between the exposome and
genome, offering new insights into the pathogenesis of several diseases, including IBD [
147
].
Epigenetic changes related to the gut microbiome include modifications to DNA or
histones, as well as the regulation of non-coding RNAs [
148
]. For example, recent studies
have shown that microorganisms can bind to lysine on histones and regulate host chromatin

Int. J. Mol. Sci. 2022,23, 3464 11 of 25
by modifying histone proteins [
149
]. In turn, post-translational modifications of histones
induced by microorganisms lead to changes in transcriptional gene activity [
150
,
151
].
Other studies investigating microRNAs (miRNAs) have suggested their participation in
the immune response to microorganisms, resulting in the regulation of inflammatory
mediators [
152
]. For example, miR-10a has been shown to suppress CD4+ T cell production
of IL-10, favoring the induction of more severe colitis in genetically predisposed Rag1−/−
mice [
153
]. In addition, miR-155 has been shown to promote Th17 differentiation and
upregulate Th17-related cytokines [
154
]. Moreover, the induction of miR-155 and miR-146
family members has been implicated in the regulation of inflammatory responses triggered
by microorganisms [155,156].
Dietary components also promote epigenetic modifications either directly or through
the action of the gut microbiome, as some metabolites may modulate gene expression,
chromatin remodeling, and DNA methylation. For example, polyphenols in green tea or
soybeans, such as epigallocatechin-3-gallate and genistein, have been shown to inhibit
DNA methyltransferase activity. Additionally, the gut microbiome generates a variety of
SCFAs, such as acetate, butyrate, and propionate, which are essential for epithelial cell
homeostasis but can also epigenetically regulate the immune response [
157
]. Bacteria from
Clostridium,Eubacterium, and Butyrivibrio genera can synthesize butyrate, which inhibits
histone deacetylases, from non-digestible fibers in the gut lumen [
158
]. In addition to
being a nutrient for epithelial cells, SCFAs can also induce intracellular signaling pathways
through the activation of G-protein-coupled receptors, regulating cell metabolism, inflam-
mation, and oxidative stress [
159
,
160
]. Furthermore, the gut microbiome also contributes to
the absorption and secretion of minerals, such as iodine, zinc, selenium, cobalt, and other
cofactors that participate in epigenetic processes. Additionally, other key metabolites of the
gut microbiota, including S-adenosylmethionine, acetyl-coenzyme A, nicotinamide adenine
dinucleotide,
α
-ketoglutarate, and adenosine triphosphate, serve as essential cofactors for
epigenetic enzymes that regulate DNA methylation and histone modifications [161,162].
6. Inappropriate Immune Response
The epithelium and its specialized cell types act as a barrier, separating the microbiota
in the lumen from the immune cells in the lamina propria. In this reciprocal relationship,
the microbiota also produces the metabolites necessary for epithelial cells, such as SCFAs
and bacteriocins [
163
]. Immune cells in the lamina propria constitute the mucosa-associated
lymphoid tissue that responds to microbiota stimuli, along with the epithelium. Some in-
nate immune cells such as DCs, macrophages, natural killer cells, and innate lymphoid cells
(ILCs) sample lumen antigens and induce a tolerogenic immune response. Under homeo-
static conditions, this immune surveillance does not initiate a proinflammatory response;
in contrast, it induces Treg cells. These immune cells capture antigens and migrate to lym-
phoid tissues to activate lymphocytes and link innate and adaptive responses
[163,164]
. The
interaction between the immune system and microbiota, especially segmented filamentous
bacteria, symbiotically aids the maturation of the immune system [164,165].
The dysregulated immune response observed in IBD is thought to result from crosstalk
among genetic susceptibility, environmental factors, and gut microbiota [
166
,
167
]. Dys-
biosis changes the composition of the gut microbiota, resulting in the loss of commensal
bacteria and growth of pathogenic microorganisms [
17
,
168
]. In IBD, dysbiosis is charac-
terized by a decrease in alpha diversity, with a decrease in abundance of Bacteroidetes
and Firmicutes and an increase in that of Gamma-proteobacteria, especially AIEC [
114
,
169
].
Moreover, dysbiosis in IBD leads to a shift towards a proinflammatory environment with
activated immune cells. In this context, cells increase the expression levels of pattern
recognition receptors (PRRs) and the production of proinflammatory mediators in response
to pathogens [
170
]. PRRs recognize microbe-, pathogen-, and/or danger-associated molec-
ular patterns (MAMPs, PAMPs, and DAMPs, respectively, e.g., ATP and high mobility
group box 1 protein (HMGB1)) released by cells during inflammation [
171
]. Examples of
MAMPs include LPS (a TLR-4 ligand) and flagellin (a TLR-5 ligand) from bacteria,
β
-1,3-

Int. J. Mol. Sci. 2022,23, 3464 12 of 25
glucans (a dectin-1, C-type lectin receptor (CLR) ligand) from fungi, and viral nucleic acid
molecules [
172
]. TLRs and CLRs are distributed on the surface of immune cells, epithelial
cells, and other cell types, whereas NOD-like receptors (NLRs) and RIG-I-like receptors are
present in the cytoplasm [173,174].
Tissue-resident macrophages comprise a large population of macrophages in the gut
and control either tolerance or defense against microorganisms. Therefore, macrophages
exhibit specialized gene expression related to their localization within the intestinal mu-
cosa [
175
,
176
]. ILCs represent a group of innate immune cells, mostly localized at mucosal
sites, with important participation in immune-mediated diseases such as IBD. In addition to
increasing in density in the inflamed mucosa, ILC-1-producing IFN-
γ
cells characteristically
accumulate in CD [
177
]. Because of their proximity to the gut microbiome, mucosal ILCs
are thought to participate in a dichotomous regulatory mechanism, in which ILCs interfere
with the microbial composition of the gut, and the gut resident microbes shape the plasticity
and physiological functions of ILCs [178].
Inflammasomes have recently been regarded as central and specifically attractive in
IBD immunopathogenesis because of their participation in complex crosstalk between
the host mucosal immune system and environment, particularly the microbiota. Inflam-
masomes are multiprotein platforms formed in the cytoplasm that cleave and activate
caspase-1, leading to the production of inflammatory cytokines, including IL-1b and IL-18.
Inflammasomes comprise intracellular sensors formed by NLR proteins NLRP1, NLRP3,
NLRC4, NLRP6, and NAIP5, or by the DNA-sensing complex AIM2, and can be activated by
extracellular and intracellular pathogens in the presence of DAMPs [
179
]. Inflammasomes
participate in responses against several bacteria such as L. monocytogenes,M. tuberculosis,
and Fusobacterium [
180
]. In patients with CD, increased NLRP3 and AIM2 activity has been
reported, and an SNP in NLRP3 is associated with CD susceptibility [
181
,
182
]. In contrast,
NLRP3 inflammasome activation and production of IL-1b and IL-18 appear to be protective
in experimental IBD [183].
Together, through these mechanisms, innate immune cells sense PAMPs and DAMPs,
induce an inflammatory response, and shape adaptive immunity, promoting lymphoid
tissue expansion and T- (Th1, Th2, Th9, Th17, and Treg cells) and B-cell responses [
184
].
Additional direct and indirect participation of gut microbiota through the metabolism
of dietary vitamins and SCFAs, such as butyrate, also influences the immune response,
promoting Treg differentiation and tolerance [
185
,
186
]. For example, appropriate Th17 and
Th1 responses are important for the clearance of Citrobacter rodentium and non-typhoidal
Salmonella enterica infections [
187
,
188
]. Although, under normal conditions, the gut con-
stitutes a microenvironment controlled by balanced T-cell responses, prolonged dysbiosis
favors an inappropriate persistent proinflammatory response [189].
7. Microbial-Based Therapies
Antibiotics have long been considered in the treatment of IBD because of the preva-
lence of microbial abnormalities and the presence of known pathogens. Although the
use of antibiotics has been clearly supported for the treatment of infectious complications
related to IBD, several pieces of evidence have failed to find consistent beneficial asso-
ciations between antibiotic treatment and IBD remission [
190
]. Selby et al. did not find
beneficial outcomes for CD with treatment with clarithromycin, rifabutin, and clofazimine
aimed at eradicating M. avium subspecies paratuberculosis in a two-year randomized clinical
trial [
191
]. Nevertheless, some data support the clinical application of antibiotics such
as ciprofloxacin, with or without metronidazole, for treating active fistulizing perianal
CD [21,192].
Other methods of bacterial manipulation have provided additional evidence sup-
porting the role of the microbiota in the pathogenesis of IBD. One method of microbiota
manipulation in IBD is the introduction of dietary probiotics to control the growth of
pathological components and/or switch the global composition towards a healthier one.
E. coli Nissle 1917, a nonpathogenic strain clinically used as a probiotic, has been shown to

Int. J. Mol. Sci. 2022,23, 3464 13 of 25
be effective in inducing the remission of patients with UC. In addition, E. coli Nissle 1917
has been associated with maintenance of remission in patients with UC for at least one
year [
193
,
194
]. Similarly, the probiotic VSL#3, a set of eight bacterial strains (Bifidobacterium
breve,B. longum,B. infantis, Lactobacillus acidophilus, L. plantarum, L. paracasei, L. bulgaricus,
and Streptococcus thermophilus) has significantly reduced scores of disease severity and in-
duced remission in patients with UC compared to a placebo [
37
,
195
,
196
]. Other probiotics,
such as Lactobacillus GG, have been shown to be effective when associated with IBD oral
therapy, such as mesalamine [
38
,
197
]. Nevertheless, so far, data regarding the effectiveness
of probiotics for treating patients with CD have failed to reach substantial association with
the induction of remission.
Although currently available probiotics potentially modulate dysbiosis in IBD, their
effects are transient and limited in most IBD subsets. In fact, most existing probiotics
encounter colonization resistance in the host intestine and are present only for a limited
period, even after long-term administration. Therefore, new alternatives have been investi-
gated, including the use of genetically modified organisms with recombinant bacteria as
vectors to deliver therapeutic molecules at target sites in the gut. For example, modified
strains of Lactobacillus casei BL23 [
198
] and Streptococcus thermophilus CRL 807 [
199
] were
engineered to produce superoxide dismutase, which has anti-inflammatory properties.
Lactococcus lactis-secreting IL-10 [
200
], elafin (a human protease inhibitor) [
201
], and IL-27
(an immunosuppressive cytokine) [
202
] reportedly have anti-inflammatory effects in colitis
models and may therefore represent potential candidates for future clinical trials.
Another method of microbiota manipulation of increasing interest for potential thera-
peutic applications in various diseases is fecal microbiota transplantation (FMT). Recently,
randomized clinical trials have assessed the benefits of the use of FMT in the treatment
of patients with IBD. Moayyedi et al., for example, found that patients with recently di-
agnosed UC could be induced to remission after treatment with FMT [
203
]. Data from
another study showed that for patients in remission, treatment with FMT was able to
maintain clinical remission in 87.1% of patients compared to 66.7% receiving a placebo.
These results indicate that the long-term beneficial effect of FMT in patients with UC in
clinical remission could help sustain endoscopic, histological, and clinical remission [204].
A recent meta-analysis showed that FMT was effective in promoting clinical remission (OR
= 3.47, 95% CI = 1.93–6.25) and clinical response (OR = 2.48, 95% CI = 1.18–5.21) to patients
with active UC when compared to placebo [
205
]. Studies on the effectiveness of therapeutic
microbiota manipulation in IBD are still in progress, and the results are expected to further
understanding and guide the potential application in clinical practice.
8. Complex Genetic and Molecular Network
As previously mentioned, by using modern sequencing methodologies, several studies
have compared and described the microbiota composition of healthy individuals versus
patients with IBD [
17
,
50
,
168
]. For example, recent data revealed a loss of microbial diver-
sity in patients with IBD, with a clear separation between CD and healthy patients, and
a more heterogeneous profile in patients with UC [
168
]. Antibiotic resistance gene levels
were increased in IBD, and their abundance was positively correlated with Escherichia
and Bacteroides bacteria [
206
]. Furthermore, higher than normal levels of hydrogen sul-
fide generated by gut microbiota have been strongly associated with IBD pathogenesis
and indicate increased prevalence of sulfate-reducing bacteria, such as Deltaproteobacte-
ria,Desulfotomaculum,Desulfosporosinus,Thermodesulfobacterium, and Thermodesulfovibrio
genera [207].
In CD, metagenomic and metaproteomic studies have characterized a decrease in
levels of butanoate and propanoate metabolism genes, butyrate, and other SCFAs, in
agreement with the decrease in abundance of SCFA-producing Firmicutes bacteria seen in
taxonomic profiling studies [
208
,
209
]. Several functional changes in the microbiome of IBD
have been identified, including an increase in the activities of pathobionts, alterations in the
synthesis of amino acids, neurotransmitters, and vitamins, regulation of mineral absorption,

Int. J. Mol. Sci. 2022,23, 3464 14 of 25
degradation of complex carbohydrates, and effects on pathways related to SCFAs, cysteine,
and L-arginine synthesis [
168
,
209
,
210
]. In a metagenomic study with a pediatric CD cohort
undergoing anti-TNF-
α
therapy, greater microbiota changes were correlated with higher
levels of fungal and human DNA and variations in microbial genes. Examples of these vari-
ations include a decrease in selenocompound metabolic pathway activity and an increase
in levels of microbial genes encoding glycerophospholipid metabolism, aminobenzoate
degradation, sulfur relay systems, and glutathione metabolism [
211
]. Together, these data
indicate that further metabolomic studies could help differentiate, diagnose, and better
characterize disease activity [212].
The measurement of RNA transcripts in tissues from patients with IBD may predict
the pathways that are activated and involved in the disease. Using deep RNA sequencing,
studies of the transcripts have identified molecular subtypes of CD [
213
–
215
]. A remarkable
report on this topic is the Pediatric RISK Stratification Study, which showed that these
molecular signatures may predict disease behavior [
216
]. However, as RNA does not neces-
sarily represent the proteins produced in cells, there are limitations to this approach. For
example, a study on the feasibility of metatranscriptomics for fecal samples observed that
transcriptional profiles differed more between individuals than metagenomic functional
profiles [
168
]. Metatranscriptomic data also revealed some species-specific biases in the
transcriptional activity of gut bacteria, especially with IBD-specific microbial populations,
such as F. prausnitzii [210].
Metabolomics research, including analysis of plasma, serum, urine, stool, and in-
testinal biopsies, has provided data allowing for differentiation between healthy controls
and patients with IBD [
217
]. In the stool of patients with IBD, a loss of metabolites has
been observed in concordance with the loss of microbial diversity [
168
,
218
]. There were
lower levels of secondary bile acids, sphingolipids, short- and medium-chain fatty acids,
and vitamins, whereas primary bile acids, amino acids, polyamines, arachidonate, and
acylcarnitines were present in higher levels compared to the controls [
219
]. In IBD, far-
nesoid X receptor (FXR) activation, triggered by bile salts, led to the downregulation of
proinflammatory cytokines, and in CD, intestinal biopsies showed lower expression levels
of FXR [
220
,
221
]. Another compound commonly associated with IBD is tryptophan, an es-
sential aromatic amino acid obtained from the diet and a precursor of numerous molecules,
such as serotonin, melatonin, nicotinamide, and vitamin B3, as well as other intermediates.
Common sources of tryptophan are dairy foods, poultry, fish, and oats, and tryptophan is
metabolized by both the host and gut microbiota. Microbiota metabolism leads to indole
metabolites that can activate aryl hydrocarbon receptors (AhR) and participate in the onset
of IBD [
222
,
223
]. Few bacteria produce AhR agonists, such as Peptostreptococcus russellii and
members of Lactobacillus, whereas indole-propionic acid (IPA) production has been best
characterized in Clostridum sporogenes [
224
]. Indole induces the release of glucagon-like
peptide-1 and its derivatives, indoleacetic acid, indole-3-acetaldehyde, indole-3-aldehyde,
indoleacrylic acid, and indole-3-propionic acid. IPA via AhR affects T-cell immunity and ex-
erts anti-inflammatory effects in the gut [
225
]. AhR expression levels are reduced in patients
with CD, whereas tryptophan deficiency promotes more severe colitis in mice [226,227].
Proteomic studies have also been conducted to explore innate and adaptive immune
mechanisms in IBD. For example, compared to those in the controls, in patients with UC,
46 proteins, excluding neutrophils and their extracellular trap proteins, were more abun-
dant in the colon tissue [
228
,
229
]. In intestinal biopsies of patients with CD, the proteomes
of human Th1 and Th1/Th17 clones were studied, and 334 proteins were found to be
differentially expressed. Cytotoxic proteins, such as granzyme B and perforin, were more
abundant in Th1 cells than in Th17 cells, but only in a subgroup of Th1 cell clones from
patients with CD [
230
]. Regarding regulatory T cells (CD4+ Foxp3+), a proteomics study
identified a novel protein, THEMIS, which is important for the suppressive function of
Treg cells [
231
]. In agreement with proteomic studies, the lipidome and immune responses
have also been investigated in IBD. For instance, the inflamed mucosa of patients with UC
showed increased levels of seven eicosanoids (prostaglandin (PG) E2, PGD2, thrombox-

Int. J. Mol. Sci. 2022,23, 3464 15 of 25
ane B2, 5-hydroxyeicosatetraenoic acid (HETE), 11-HETE, 12-HETE, and 15-HETE) [
232
].
Macrophages from patients with CD challenged with heat-inactivated E. coli presented
lower levels of newly synthesized phosphatidylinositol [
233
]. Lipidomic analysis of the
phosphatidylcholine lipidome profile of rectal mucus obtained from patients with UC
showed lower levels of phosphatidylcholine compared to patients with CD and controls.
Interestingly, supplementation with delayed-release phosphatidylcholine was clinically
effective [234].
Although knowledge of the mechanisms underlying IBD continues to expand, novel
data stemming from individual pathogenic constituents are usually not integrated, lead-
ing to only limited data being utilized for achieving relevant progress in the field [
64
].
Regarding the microbiome, complexity becomes even more evident as modern evolving
technologies provide an exponential increase in novel information with an overwhelming
accumulation of data. Hence, it is currently believed that a better understanding of the
pathogenesis of complex diseases such as IBD will depend on the comprehensive inte-
gration of knowledge from different “–omes,” including the microbiome, exposome, and
genome.
9. Conclusions
In the last two decades, it has become increasingly evident that the microbiome, im-
mune system, genome, and exposome are comprised of highly complex, dynamic, and
mutually interactive systems. Nevertheless, the traditional approach for evaluating the in-
dividual components that presumably participate in the pathogenesis of IBD, including the
microbiota, has not been sufficient to determine the interconnecting pathways underlying
the multiple biological systems involved in the disease development. Even using the best of
the currently available methods, including clinical, laboratory, endoscopic, histological, and
imaging parameters, we still only have a narrow understanding of the intricate mechanisms
responsible for chronic inflammation and the peculiar dynamics and specificities affecting
each patient with IBD. Consequently, current treatments continue to be mostly empirical
and have limited efficacy.
Regarding the microbial component, although causality remains to be clearly estab-
lished, evidence indicating an association with IBD pathogenesis is rapidly accumulating.
However, a better understanding of the probable microbial basis of IBD depends on more
complete, deep, and unbiased investigations at multiple and simultaneous levels, including
microbial strains and genomic and functional features, ideally allowing the construction of
full transcriptomic and metabolomic profiles. High-throughput technologies capable of
analyzing innumerable parameters of the microbiome in conjunction with other system
variables have been developed in recent years. Hopefully, more integrative analysis will
enable data assembly in a comprehensive fashion to build an IBD network and translate
information into useful biological insights with direct influence on specific therapeutic
targets, clinical decisions, and disease outcomes, which will preferably be individualized.
Author Contributions:
Conceptualization, H.S.P.d.S.; writing—original draft preparation, P.T.S.,
S.L.B.R., B.E.R., Y.M. and H.S.P.d.S.; writing—review and editing, P.T.S. and S.L.B.R.; visualization,
B.E.R. and Y.M.; supervision, H.S.P.d.S. All authors have read and agreed to the published version of
the manuscript.
Funding:
This work was supported by grants from Coordenação de Aperfeiçoamento de Pessoal de
Nível Superior—Brazil (CAPES)—Finance Code 001, National Council for Scientific and Technological
Development (CNPq) (306634/2019-8), and the Fundação Carlos Chagas Filho de Amparo a Pesquisa
do Estado do Rio de Janeiro (FAPERJ) (E26/202.781/2017 and E26/211.740/2015).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.

Int. J. Mol. Sci. 2022,23, 3464 16 of 25
Acknowledgments:
The authors wish to thank the Brazilian research foundations CAPES, CNPq,
and FAPERJ for their financial support.
Conflicts of Interest: The authors declare no conflict of interest.
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