Journal of Microbiology (2018) Vol. 56, No. 3, pp.
189–198
DOI 10.1007/s12275-018-8049-8
REVIEW
Current understanding of microbiota- and dietary-therapies for
treating inflammatory bowel disease
Taekil Eom1, Yong Sung Kim2,
3 4,5,6
Chang Hwan Choi , Michael J. Sadowsky ,
1,7*
and Tatsuya Unno
1
Subtropical/tropical Organism Gene Bank, Jeju National University,
Jeju 63243, Republic of Korea
2
Department of Gastroenterology, Wonkwang Digestive Disease Research
Institute, Wonkwang University Sanbon Hospital, Gunpo 15865,
Republic of Korea
3
Department of Internal Medicine, Chung-Ang University College of
Medicine, Seoul 06974, Republic of Korea
4
BioTechnology Institute, University of Minnesota, St. Paul, Minnesota
55108, USA
5
Department of Soil, Water, and Climate, University of Minnesota, St.
Paul, Minnesota 55108, USA
6
Department of Plant and Microbial Biology, University of Minnesota,
St. Paul, Minnesota 55108, USA
7
Faculty of Biotechnology, School of life sciences, SARI, Jeju National
University, Jeju 63243, Republic of Korea
(Received Jan 27, 2018 / Revised Feb 6, 2018 / Accepted Feb 11, 2018)
Inflammatory bowel disease (IBD) is a result of chronic in-
flammation caused, in some part, by dysbiosis of intestinal
microbiota, mainly commensal bacteria. Gut dysbiosis can
be caused by multiple factors, including abnormal immune
responses which might be related to genetic susceptibility,
infection, western dietary habits, and administration of anti-
biotics. Consequently, the disease itself is characterized as
having multiple causes, etiologies, and severities. Recent stu-
dies have identified > 200 IBD risk loci in the host. It has been
postulated that gut microbiota interact with these risk loci
resulting in dysbiosis, and this subsequently leads to the de-
velopment of IBD. Typical gut microbiota in IBD patients
are characterized with decrease in species richness and many
of the commensal, and beneficial, fecal bacteria such as Fir-
micutes and Bacteroidetes and an increase or bloom of Pro-
teobacteria. However, at this time, cause and effect relation-
ships have not been rigorously established. While treatments
of IBD usually includes medications such as corticosteroids,
5-aminosalicylates, antibiotics, immunomodulators, and anti-
TNF agents, restoration of gut dysbiosis seems to be a safer
and more sustainable approach. Bacteriotherapies (now called
microbiota therapies) and dietary interventions are effective
way to modulate gut microbiota. In this review, we summarize
*For correspondence. E-mail: tatsu@jejunu.ac.kr; Tel.: +82-64-754-3354;
Fax: +82-64-756-3351
Copyright G2018, The Microbiological Society of Korea
eISSN 1976-3794
pISSN 1225-8873
factors involved in IBD and studies attempted to treat IBD
with probiotics. We also discuss the potential use of micro-
biota therapies as one promising approach in treating IBD.
As therapies based on the modulation of gut microbiota be-
comes more common, future studies should include indivi-
dual gut microbiota differences to develop personalized ther-
apy for IBD.
Keywords: dysbiosis, gut microbiota, inflammatory bowel
disease, probiotics, prebiotics, short chain fatty acids
Introduction
Inflammatory bowel disease (IBD) is a chronic immune-me-
diated inflammatory bowel condition that consists of two
main diseases, ulcerative colitis (UC) and Crohn’s disease
(CD). IBD is a widespread disease in the western world. In
Europe, the highest annual incidence of UC and CD were
24.3 and 12.7 per 100,000 person-years, respectively (Molo-
decky et al., 2012). According to the US Centers for Disease
Control and Prevention (CDC), IBD reports have been in-
creasing in the US, and it has been estimated that 1.3% of
U.S. adults (~ 3 million people) reported an IBD diagnosis,
either as CD or UC. It has also seen rapid increase in Asian
countries such as Japan, South Korea and China where wes-
ternization has progressed (Yang et al., 2008; Ng et al.,
2013b). IBD can occur in all ages but is usually diagnosed
between 15 and 40 years of age (Johnston and Logan, 2008).
The manifestation of symptoms depends on the disease and
the body site involved. For example, UC normally affects
only the large intestine and usually presents with a superfi-
cial ulcer due to localized inflammatory reaction in the mu-
cosa and submucosa. Symptoms include bloody diarrhea,
mucus discharge, and abdominal pain. In patients with pro-
ctitis only, disease presentation usually involves bloody stools,
blood mucus, and tenesmus (urgency to void), but abdomi-
nal pain is rare. In contrast, CD occurs in the entire gastro-
intestinal tract (mouth to anus) and involves the whole in-
testinal layer. Presentations include deep ulceration, stenosis,
and in some patients the presence of internal and external
fistula. Symptoms include abdominal pain, low grade fever,
fatigue, weight loss, diarrhea, and sometimes bloody stools.
Patients with IBD also exhibited extra-intestinal symptoms
such as arthritis, ankylosing spondylitis, sacroiliitis, conjunc-
tivitis, anterior uveitis/iritis, and episcleritis, erythema nodo-
sum, pyoderma gangrenosum, and primary sclerosing chol-
190 Eom et al.
angitis (Isene et al., 2015).
The pathogenesis of IBD is not completely understood.
Figure 1 shows factors involved in IBD. Current hypotheses
are that the homeostasis between microbiota, intestinal ep-
ithelial cells and immune cells are disrupted by genetic fac-
tors and environmental factors such as antibiotics, smok-
ing, diets, and stress (Ananthakrishnan, 2015), resulting in
a chronic state of dysregulated inflammation. IBD appears
to be caused by an abnormal immune response to commensal
intestinal bacteria rather than to infectious pathogens (Packey
and Sartor, 2008). To date, many studies have focused on the
role of innate and adaptive immunity in the intestinal mu-
cosa in IBD patients. In aspect of innate immunity, epithelial
barrier dysfunction including the disruption of mucin and
tight junctions, defective expression of antimicrobial pep-
tides, and abnormal microbial antigen sensing have been
reported to be the cause of IBD. In addition, dysregulation
of autophagy with unfolded protein XBP1 and ORMDL3 is
also considered to be pathogenesis of IBD (Kaser et al., 2010).
The adaptive immune response is a T-cell mediated immune
system, which has long-lasting memory against specific tar-
gets, including intra- and extra-cellular pathogens and allergy-
causing antigens. The T cells include helper (Th) and regu-
latory T cells (Tregs), that are differentiated from naive T cells
(T0). In CD, IL-12 stimulates Th-1 cells to secrete IFN-γ,
which induces production of TNF-α by activating mucosal
macrophages. In contrast, UC is characterized by a Th2-im-
mune response and excessive secretion of IL-5 and IL-13.
However, this idea is not universally accepted and there is
a controversial studies about this concept (Di Sabatino et
al., 2012). While CD and UC used to be considered as Th1-
and Th2-mediated diseases, respectively, recent studies have
suggested that Th17 is also involved in IBD (Zenewicz et
al., 2009). TGF-β promotes differentiation of T0 into Tregs
by inducing FoxP3 expression, conversely, in the presence
of IL-6, the production of Tregs is inhibited and TGF-β
promotes the expression of the nuclear hormone receptors
RORγt, promoting T0 differentiation into Th17 cells who
produce a number of cytokine molecules and amplify the in-
flammatory process (Galvez, 2014). The FoxP3 is a forkhead
Fig. 1. Factors involved in IBD
occurrence.
transcription factor family member that is mainly expressed
+
in a subset of CD4 T-cells that suppress the immune system
(Kim, 2009).
Treatment of IBD involves the induction and maintenance
of a state of remission. Currently available treatments include
5-aminosalicylate agents (5-ASA), corticosteroids, antibiotics,
nonsteroidal anti-inflammatory drugs (NSAID), immuno-
modulators (azathioprine, 6-mercaptopurine, methotrexate,
cyclosporine, tacrolimus), and anti-TNF therapies. Surgical
treatment may be required if there is no response to medica-
tions or if there is perforation, obstruction, bleeding, or other
tissue pathologies. While the risk of surgery within 10 years
after diagnosed CD or UC used to be 46.6 and 15.6%, res-
pectively, this has been decreasing over the past decades
(Frolkis et al., 2013).
Factors involved in IBD
Abnormal immune response associated with IBD
High-throughput DNA sequence analysis among IBD pa-
tients identified 215 human genetic defects associated with
IBD in the genome-wide association study (GWAS) (Luo
et al., 2017). While most of these genetic defects are yet to be
functionally-characterized, there are several IBD risk genes
that have been intensively studied. For example, MUC2 plays
a major role in secretion of mucin from goblet cells, and
failure in providing mucosal layer allows for the direct con-
-/-
tact of gut bacteria with epithelial cells. MUC2 mice have
been reported to develop colitis and an increased risk of col-
orectal cancer (Van der Sluis et al., 2006). In addition, clau-
din, a family of transmembrane proteins, plays a key role in
controlling apical tight junction of epithelial cells. Signifi-
cantly higher expression of claudin 2 has been reported for
UC patients, whereas defects in tight junctions are not exclu-
sive to CD (Ahmad et al., 2014). Whether the dysfunctional
tight junctions are the cause of IBD or the consequence of
IBD is still under discussion, nevertheless, improving apical
tight junctions is a promising approach to treat the symp-
toms of IBD (Landy et al., 2016). Thus as stated above, a di-

rect linkage between cause and effect is currently unclear
or unknown.
In the gastrointestinal tract, the presence of invaders can be
sensed by pattern recognition receptors (PRRs), via a process
called recognizing pathogen associated molecular patterns
(PAMPs). The PRRs include Toll-like receptors (TLRs) and
NOD-like receptors (NLRs). Signals from these receptors re-
sult in activation of nuclear factor (NF)-κB and production
of pro-inflammatory mediators. The TLRs, which are located
on cell membranes, play an important function in sensing
bacterial cells through recognition of lipopolysaccharide (LPS)
and peptidoglycans, which subsequently enhance the secre-
tion of immunoglobulin A (IgA) in the intestine (Shang et
al., 2008). Secretory IgA protects intestinal surface against
harmful stimuli. In contrast, NLRs are located in cytoplasmic
compartments. The NOD2 gene, one NLR, is the first reported
IBD risk gene (Hugot et al., 2001; Ogura et al., 2001). Genetic
defects in NOD2 lead to the development of ileal CD, by in-
creasing activation of NF-κB. There are, however, contra-
dicting reports on the role the NOD2 gene in presentation
of CD (Yamamoto and Ma, 2009).
Adaptive immune responses are initiated following inva-
sion of specific bacteria or viruses. There are three patterns
in adaptive immune responses in defense of: i) intracellular
invasion by bacteria or viruses; ii) extracellular parasites such
as helminths and Schistosoma; and iii) extracellular invasion
by bacteria or viruses. Under the intracellular invasion, im-
mune cells (i.e., macrophages and dendric cells) first produce
IL-12 to cause T0 differentiation into Th1, then Th1 sub-
sequently increases the amount of IFN-γ that activates im-
mune cells. It should be noted however, that overexpression
of IFN-γ leads to the development of CD (Powrie et al.,
1994). In case of extracellular invasion of parasites, T0 is
differentiated into Th2 under IL-4 and TGF-β. Th2 acti-
vates eosinophil and mast cells by producing IL-5 and IL-6,
respectively. Th2 also produces immunoglobulin E to attack
these parasites. While Th2 is effective in stopping inflamma-
tion caused by those parasites, dysregulation of Th2 may
cause over expression of IL-13, which subsequently induces
UC (Strober and Fuss, 2011). Th17 cells are pro-inflamma-
tory T helper cells generated in response to the invasion of
extracellular bacteria and viruses. Dysfunctional Th17 causes
autoimmune disorders. The use of anti-IL-23 materials have
been also tested for drug development for inflammatory di-
seases, such as psoriasis (Gaffen et al., 2014). Further studies
are needed to determine whether dysregulation of Th17 is
preferably associated with CD or UC (Zenewicz et al., 2009).
The Tregs, on the other hand, are the suppressor of Th cells
by producing TGF-β and IL-10, which subsequently de-
creases secretion of harmful cytokines. A decrease in the
number of Tregs leads to the weakened anti-inflammatory
effects, causing IBD (Boden and Snapper, 2008).
Gut microbiota associated with IBD
In healthy humans, commensal bacteria maintain a symbiotic
relationship with the host by modulating a number of innate
and adaptive immune systems. Defects in genes involved in
the immune systems could cause failure in maintaining com-
mensal gut microbiota, leading to dysbiosis. Imhann et al.
(2018) reported that 582 healthy humans with IBD risk loci
Roles of probiotics in IBD 191
have lower abundance of the genus Roseburia which was
negatively correlated to the IBD risk scores, suggesting that
IBD risk loci affect gut microbiota regardless the disease
characteristics. Roseburia is a heritable butyrate producer
that resides within mucosal layer (Van den Abbeele et al.,
2013; Goodrich et al., 2014). Gevers et al. (2014) investigated
new-onset treatment-naive gut microbiota in CD patients
and reported that intestinal microbial shifts occur with mu-
cosal microbiota, rather than luminal microbiota, at the early
stages of IBD. These shifts generally include decreased spe-
cies diversity and the abundances of Bacteroides, Clostridia,
Bifidobacteriaceae, Faecalibacterium, and Ruminococcaceae
as well as an increase in abundance of Enterobacteriaceae,
adherent-invasive E. coli (EHEC), Fusobacteriaceae, Myco-
bacterium avium, and Clostridium difficile. The chronic in-
flammation or bowel resection in patients with IBD further
shifts gut microbiota away from “healthy” gut microbiota
(Halfvarson et al., 2017). These studies, however, report cor-
relative data and the effects of individual microbiota on CD
presentation needs to be tested addressing Koch’s postulate.
In gut, epithelial cells are covered with two mucus layers
made of mucin produced by goblet cells. While the inner mu-
cus layer is nearly bacteria free, the outer mucus layer on the
large intestine contains mainly mucus degraders and some
commensal bacteria that feed on secondary metabolites pro-
duced from mucin degradation (Li et al., 2015). Figure 2
shows interactions within mucosal microbiota. Bacteria trap-
ped in the outer mucus layers often include mucolytic bac-
teria, such as members of Akkermansia, Bacteroides, Bifido-
bacterium, and Ruminococcus. Mucolytic bacteria degrade
mucin oligosaccharides, which can be further utilized by non-
mucolytic bacteria, providing different microbial metabolites
than those produced by luminal microbiota (Ouwerkerk et
al., 2013). The intestinal glycobiome transforms mucin gly-
cans into short chain fatty acids (SCFAs), which can be fur-
ther utilized by colonocytes as energy sources. It should be
noted that the presence of these bacteria does not imply
complete degradation of the mucus layer, and many bacteria
only utilize partial mucus-derived sugars (Marcobal et al.,
2013). Mucus-derived sugars include N-acetyl-D-glucosamine
(NAG), N-acetylgalactosamine, galactose, fucose, and sialic
Fig. 2. Interactions of intestinal bacteria with intestinal mucus.
192 Eom et al.
acid (Sonnenburg et al., 2010). The NAG and sialic acid were
known to repress virulence in Salmonella and enterohe-
morrhagic E. coli (EHEC) (Sicard et al., 2017). Fucose, on
the other hand, is also provided by the host in the form of
fucosylated-proteins through expression of the fut2 gene to
maintain commensal fucose-utilizers in the outer mucus
layer (Pickard et al., 2014). These commensal fucose-utilizers
inhibit the growth of pro-inflammatory pathogenic bacteria,
such as Citrobacter rodentium and Salmonella, and defects
in the fut2 gene may lead to inflammation (Goto et al., 2014).
Likewise, administration of antibiotics inhibits commensal
bacteria that feed on mucin-derived monosaccharides, which
allows expansion of antibiotic resistant pro-inflammatory
pathogenic bacteria, such as Salmonella enterica serotype
Typhimurium and Clostridium difficile, that feed on liberated
mucin-derived monosaccharides released by the mucin de-
graders (Ng et al., 2013a). Therefore, maintaining an intes-
tinal-mucosal microbial homeostasis may prevent occur-
rence of IBD, even for those having IBD risk loci.
Probiotics to treat IBD
Effects of probiotics on intestinal health
Although there is no legal definition for probiotics, it is ge-
nerally accepted as “live microorganisms that confer a health
benefit on the host when administered in adequate amounts”
(Sanders, 2008). The mechanism of action of probiotics has
been dropped from the definition, and the mode of action
and its beneficial effects differ among probiotics at the strain
level (Whelan and Quigley, 2013). With respect to IBD, the
potentially beneficial effects caused by probiotics have been
thought to include: i) inhibition of invasion by pathogenic
bacteria; ii) improvement of epithelial barrier functions;
and iii) immunomodulation (Dos Reis et al., 2017). Some of
the probiotics reduce intestinal pH through production of
SCFAs, which have been shown to inhibit intestinal patho-
genic E. coli (Fukuda et al., 2011). Moreover, production of
SCFAs, especially butyrate, feeds colonocytes and enhances
epithelial tight junction integrity (Ewaschuk et al., 2008).
Some probiotics are known to interfere with adhesion of gas-
trointestinal pathogens by competitive exclusion and bacte-
riocin production (Kravtsov et al., 2008). In addition, some
species of lactic acid bacteria induce cytokine secretion from
monocytes and activate NF-κB (Jensen et al., 2015), the ma-
jor key mediator in inflammation (Liu et al., 2017). It has
been reported that the abundance of Bifidobacterium is neg-
atively associated with IBD (Tojo et al., 2014), thus taking
probiotics may help regaining gut homeostasis.
There are conflicting results concerning the impact of pro-
biotics on gut microbiota (Maldonado-Gomez et al., 2016).
In some studies, it has been reported that probiotics may not
have impacts on healthy adults’ intestinal microbiota (Kris-
tensen et al., 2016). Sanders (2016) suggested that probiotics
do not directly change microbiota, but rather maintain gut
homeostasis so that gut dysbiosis caused by perturbations
can be minimized or allow faster recovery. Collectively, the
use of probiotics may be a promising approach to treat and
prevent IBD, but much more work is needed.
Probiotics intervention to treat IBD
Several probiotics including Lactobacillus strains (rhamnosus
GG, acidophilus, reuteri ATCC 55730, johnsonii), Bifidobac-
terium strains (breve, bifidum, animalis), Saccharomyces bou-
lardii, Escherichia coli Nissle (ECN) 1917, and VSL#3 (a
probiotic mix of 4 lactobacilli, 3 bifidobacteria and a Strep-
tococcus) have been studied for their efficacy in the treatment
of IBD (Abraham and Quigley, 2017). In individual studies,
treatment with several probiotics was reported to be effective,
but the sample size was small and there were inconsistent
results. The meta-analysis showed that only VSL#3 was effec-
tive in inducing remission of active UC (Derwa et al., 2017).
The VSL#3 mixture was also reported, in several clinical tri-
als, to be effective in the prevention of pouchitis following
an ileal pouch–anal anastomosis (IPAA) (Gionchetti et al.,
2003; Mimura et al., 2004). The ECN strain1917 appeared
equivalent to 5-ASA in preventing relapse of IBD (Losurdo
et al., 2015). However, the effect of various probiotics on the
treatment of CD is not clear in terms of induction of remi-
ssion, prevention of recurrence following active disease, or
prevention of post-operative recurrence (Derwa et al., 2017;
McIlroy et al., 2018).
It is not clear why the results of clinical studies are disap-
pointing despite the role of intestinal microbiota in the path-
ophysiology of IBD and the proven effects of probiotics in
preclinical studies. The meta-analysis also provides limited,
but not conclusive, information since different strains and
doses of probiotics were used, with different duration of use,
and with patients showing different disease severity in each
clinical studies (Derwa et al., 2017). This limitation is similar
to that for IBS, a disease in which probiotics are more com-
monly used (Mazurak et al., 2015). In addition, it has been
reported that efficacy of probiotics is strain-specific (Whelan
and Quigley, 2013) and may vary depending on the personal
microbiota (Kolmeder et al., 2016). It was also suggested that
orally administrated probiotics may have difficulty in reach-
ing the colon (Dos Reis et al., 2017). To date, probiotics are
not approved as pharmaceuticals and are marketed as diet-
ary supplements, therefore, not regulated by authorities. As
such, no health improvement can be claimed.
In the case of VSL#3, which showed beneficial effects on
treating UC, the formulation was recently changed and the
product differs depending on the country in which it is sold
(Biagioli et al., 2017). One study showed that the original
and newfound VSL#3 exhibited different proportion of dead
microbes and in vitro anti-tumoral effects (Cinque et al.,
2016). Lastly, it is very rare, but the potential risk of probiotic-
induced bacteremia should be considered in immunosup-
pressed patients with severe active IBD (Vahabnezhad et al.,
2013). In the future, well designed clinical studies for first and
next-generation probiotics following strict trial guidelines
are needed (Shanahan, 2017).
Prebiotics to treat IBD
Effects of prebiotics on intestinal health
Since many of traditional probiotics such as Lactobacillus
do not colonize the gut for long term, the utilization of com-

mensal intestinal microorganisms to treat or prevent IBD
may provide a sustainable solution to the problem (Sanchez
et al., 2017). The growth of beneficial bacteria is regulated
by complex non-digestible carbohydrates. Prebiotics are de-
fined as non-digestible carbohydrates that selectively pro-
mote the activity and growth of one or more strains of ben-
eficial bacteria in the large intestine, thus improving the in-
testinal environment and benefiting the host (Gibson and
Roberfroid, 1995). Therefore, the functionality of prebiotics
in the human digestive tract varies significantly depending on
the viability and metabolic activity of beneficial bacteria in
the intestines. Prebiotics are not degraded by the carbohy-
drate hydrolyzing enzymes secreted from the digestive tract
and are not absorbed in the intestines for use as an energy
source. Prebiotics are selectively decomposed by probiotic
strains such as Lactobacillus and Bifidobacterium in the large
intestine. Typical prebiotics include inulin, fructo-oligosac-
charide (FOS), galacto-oligosaccharide (GOS), and lactulose,
that are widely available in nature or obtained through en-
zymatic synthesis (Mussatto and Mancilha, 2007). Previous
studies have reported various functionalities in prebiotics,
including enhancement of intestinal immunity, anti-diabetic
and anti-obesity activities, and improvement of constipation
(Roberfroid, 2000; Slavin, 2013). Furthermore, prebiotics are
utilized by probiotic bacteria and metabolized into SCFAs,
such as acetate, propionate, and butyrate. Butyrate can be
used by colonocytes as a source of energy, subsequently sti-
mulates mucin biosynthesis and enhances intestinal barrier
(Maslowski and Mackay, 2011; Rios-Covian et al., 2016). It
has been reported that various prebiotics and probiotics have
potentials in treating IBD (Zhu et al., 2011). IBD patients
showed decreased fecal SCFAs (Takaishi et al., 2008). The
beneficial effects of SCFAs include: i) inhibiting adhesion of
pathogenic microorganisms to intestinal cells (Kamada et al.,
2013); ii) supporting secretion of antimicrobial substances
from epithelial cells within the colon (Sunkara et al., 2012);
iii) selectively allowing the growth of probiotics over patho-
genic Escherichia coli and Bacteroidaceae (Sun and O’Riordan,
2013); iv) providing anti-inflammatory effects for epithelial
cells through inhibition of activation of NF-kB and PPARγ,
and limiting production of IL-1β, IL-6, and TNF-α (Fung
et al., 2012); and v) stimulating epidermal growth factor re-
ceptor (EGFR) to maintain intestinal homeostasis by increa-
sing mucin synthesis (Andrianifahanana et al., 2006). These
results suggest that prebiotics have potential as therapeutic
and preventive agents for IBD, though the exact roles of
prebiotics in IBD have yet to be revealed.
Prebiotics intervention to treat IBD
A number of studies on the protective effects of prebiotics in
IBD treatment have focused on inulin, FOS and GOS, since
they can be extracted from plants at low cost. Mushroom and
seaweeds contain potentially prebiotic products such as β-
glucan, laminarin, and fucoidan, which have been also sug-
gested as potential prebiotics in treating IBD (O’Sullivan et
al., 2010; Daou and Zhang, 2012).
Inulin is a polysaccharide obtained from chicory roots,
which consists of 2 to 60 fructose molecules, with the sugar
chain linked by a β-(2,1) bond. The polysaccharide obtained
by enzymatic hydrolysis of inulin is called oligofructose (OF),
Roles of probiotics in IBD 193
which consists of 2 to 8 fructose molecules. Typically, inulin
has been reported to improve constipation, prevent intestinal
diseases, reduce serum cholesterol, lower blood lipid levels,
and lower blood glucose levels (Flamm et al., 2001). Because
inulin and OF are not degraded by the carbohydrate hydro-
lyzing enzyme secreted from the small intestine, over 80% of
ingested inulin and OF reach the large intestine and are used
in the production of SCFAs by various bacteria (Cherbut,
2002). In the westernized diet model, administration of in-
ulin and OF plays a role in increasing number of lactic acid
bacteria, which consequently reduced intestinal pH (Licht
et al., 2006). Furthermore, administration of inulin and OF
increased the synthesis of butyrate which inhibited dam-
ages on the intestinal epithelial cells due to inflammatory re-
actions (Videla et al., 2001). Others reported that the use of
mesalazine, an IBD therapeutic agent with inulin contain-
ing OF, decreased dyspepsia scores and fecal calprotectin in
IBD patients more effectively than the use without prebiotics
(Casellas et al., 2007). Studies have reported that the inges-
tion of inulin and OF reduced the production of aberrant
crypt foci (ACF), a precursor to colorectal cancer, and also
reported that the effects of long-chain inulin was more evi-
dent than those with the shorter sugar chain (Verghese et
al., 2005).
GOS is a polymer similar to the oligosaccharide of breast
milk, in which the sugar molecule is linked by a β-glycosidic
bond, and has shown similar effects as breast milk on intes-
tinal microorganisms (Rivero-Urgell and Santamaria-Orleans,
2001). The length of GOS sugar chains is typically in the range
from 3 to 10. GOS reaches the large intestine without being
affected by saliva, gastric acid, or the digestive juices of the
small intestine. GOS is known to enrich Bifidobacterium and
Lactobacillus in the large intestine, prevent pathogenic bac-
terial infection, reduces pH, increase fecal SCFA contents,
relieve constipation, stimulate immune activity, reduce allergy
and atopy, and prevent colon cancer (Sangwan et al., 2011).
Despite the various effects of GOS in the intestines, its effects
on IBD prevention have been controversial. In a 2,4,6-tri-
nitrobenzenesulfonic acid (TNBS)-induced IBD model, in-
gestion of GOS showed an increase of Bifidobacterium in the
intestines but did not reduce inflammation (Holma et al.,
2002). Conversely, ingestion of GOS showed activation of NK
cells and reduced severity of colitis induced by Helicobacter
hepaticus infection in Smad-3 knock-out mice (Gopalakri-
shnan et al., 2012). Collectively these results suggest that fur-
ther studies are required to determine the effect of GOS on
the prevention and treatment of IBD. Several studies have
convincingly shown that milk glycans have a prebiotic effect
on the microbiome of the infant gut and may be useful to pre-
venting diseases such as necrotizing enterocolitis in preterm
infants (Pacheco et al., 2015).
β-Glucan is an abundant polysaccharide in nature whose
glucose molecules are linked via β-bonds. This polysaccharide,
along with cellulose, is an important component of plant fiber
and a major constituent of cell walls in seaweed and fungi.
While β-glucans are postulated to have immunostimulatory
effects (Daou and Zhang, 2012), recent studies have reported
that the physiological functions attributed to β-glucan are
not direct effects, but rather due to intestinal microorganisms
whose activities are enhanced by β-glucan (Cloetens et al.,
194 Eom et al.
2012). Numerous studies on the prevention of IBD through
the ingestion of β-glucan have been conducted using dextran
sulfate sodium (DSS)- and TNBS-induced bowel inflamma-
tion models. It has been reported that oral administration
of glucan derived from the mushroom Pleurotus pulmona-
rius alleviated symptoms of intestinal inflammation induced
by DSS and inhibited the formation of colon cancer caused
by colitis (Lavi et al., 2010). Moreover, it has been reported
that a β-glucan polymer extracted from Shitake mushrooms
(Lentinus edodes) inhibits MAPK and PPARγ phosphory-
lation, resulting in reduction of the inflammatory cytokines
and oxidative stress induced by DSS (Shi et al., 2016). The
efficacy of β-glucan for the prevention of colitis has further
been verified in clinical trials. One study reported that the
administration of β-glucan extracted from Agaricus to IBD
patients reduced the level of inflammatory cytokines in the
blood and decreased the level of calprotectin, a fecal marker
of IBD (Forland et al., 2011). Similarly, administration of the
β-glucan extracted from the chaga mushroom to IBD pa-
tients inhibited inflammatory response-induced damage to
lymphocytes in blood (Najafzadeh et al., 2007).
Lastly, several varieties of seaweed are also potential pre-
biotics (O’Sullivan et al., 2010) which have long been con-
sumed as food in Korea, China, Japan, and Southeast Asian
countries. In contrast, seaweeds are mainly used for pharma-
ceuticals, cosmetics, and food additives in western countries.
Seaweeds are classified into three groups; brown algae (Pha-
ophyceae, about 1,750 species), red alage (Rhodophyceae,
about 6,000 species), and green algae (Chlorophyceae, about
1,500 species) (Kılınç et al., 2013). Seaweeds are abundant
in protein and carbohydrates and also contain omega-3 fatty
acids, carotenoids, vitamins, and minerals (Wells et al., 2017).
Seaweeds are particularly abundant in non-digestible poly-
saccharides (approximately 75% of their dry weight), typi-
cally including alginates, laminarins, and fucoidans in brown
algae, agars, and carrageenans in red algae, and ulvan in
green algae (Senthilkumar et al., 2013). Seaweed-derived poly-
saccharides studied for the prevention and inhibition of IBD
include brown algae alginates, laminarins, and fucoidans.
It has been reported that ingestion of alginate was linked to
an alleviation of the inflammatory response in the colon and
prevention of injury to the goblet cells in animal models of
DSS- and TNBS-induced colitis with no association of the
adverse effects such as potential weight loss or spleen reduc-
tion, seen with prednisolone treatments (Yamamoto et al.,
2013). Fucoidan, a sulfated polysaccharide mainly composed
of fucose and abundant in brown algae, has been reported
to have various physiological functions, such as immuno-
modulation, anticancer activity, anti-obesity effects (Ale et
al., 2011), and, more recently, prebiotic effects (Okolie et al.,
2017). In the DSS-induced IBD model, ingestion of fucoi-
dan improved inflammation-related indicators such as in-
flammatory cytokine levels, weight loss, diarrhea, and hema-
tochezia, while further inhibiting the reduction of crypt and
goblet cells in the large intestine (Lean et al., 2015). In an-
other IBD model, ingestion of fucoidan extracted from mo-
zuku seaweed (Cladosiphon okamuranus) decreased inflam-
matory cytokines such as IFNγ and IL-6, and increased in-
flammation-inhibiting IL-10 and TGF-ß (Matsumoto et al.,
2004). Laminarin is a β-glucan derived from brown algae.
Laminarin extracted from Laminaria reduced the expre-
ssion of cytokines and receptors which are related to the
Th17 and also decreased the abundance of E. coli, showing
the possibility for the prevention of IBD (O’Shea et al., 2016).
The use of prebiotics is not free of health risks. While a num-
ber of studies have reported beneficial effects of prebiotics,
they should be used with cautions since they may cause ab-
dominal pain, indigestion, diarrhea, and bloating or flatu-
lence (Marteau and Flourie, 2001). Excessive ingestion of
prebiotics could induce diarrhea due to osmotic retention of
fluid in the intestine (Swennen et al., 2006). FOS ingestion
in patients with gastroesophageal reflux disease increased
gastroesophageal reflux, but how this occurs is not known
(Piche et al., 2003). Inulin and FOS have been reported to in-
crease Lactobacillus and Bifidobacterium in the intestines,
but also increased colonization of Salmonella and in cecal
contents and mucosa (Ten Bruggencate et al., 2004). There-
fore, further studies are required to determine the protective
mechanisms of prebiotics against inflammation.
Other methods to treat IBD
Fecal microbiota transplantation (FMT) is a method used
to transplant microbiota obtained from healthy donors to
patients most presenting with recurrent Clostridium difficile
infection (rCDI). This technology has remarkable cure rates
for rCDI, approaching 96% (Sadowsky et al., 2017). Unlike
medical drugs including antibiotics and immunosuppre-
ssants, FMT increases the number and diversity of fecal bac-
terial populations in recipients, and engraftment lasts for
long time periods (Weingarden et al., 2015). This suggests
that FMT may be a promising therapy for IBD. However,
FMT has shown rather disappointing success rate in treating
IBD, when compared to treating CDI (Pigneur and Sokol,
2016). Systematical review of previous cases done to treat UC
with FMT suggested that there was only slightly higher rate
of clinical remission and response compared to placebo (19%
and 21%, respectively) (Costello et al., 2017). The efficacy of
FMT may vary depending on the fecal microbiota of the do-
nor, method used to prepare the microbiota, dose and fre-
quency, the patient’s condition, and delivery routes. The re-
lationship between FMT and clinical resolution of IBD ap-
pears complex, perhaps due to differing etiologies of UC and
CD and severity of disease systems. In a recent study, Kho-
ruts and colleagues (Khoruts et al., 2016) reported that IBD
influenced success of FMT for treatment of CDI. More-
over, while FMT did clear CDI in nearly 74.5% of 272 pa-
tients, those without IBD were cured at a greater rate (92%)
and nearly 25% of patients with IBD had a significant flare
following FMT. More importantly however, there was an
increase in failure rate due to IBD. Interestingly, while some
patients showed noteworthy improvements in their IBD after
FMT, a few had modest improvements and even less con-
tinued to struggle with their underlying IBD despite clear-
ing of CDI. As FMT is a relatively new approach, further
study is needed to improve FMT-based treatment of patients
with IBD.

Fig. 3. Factors affecting gut microbiota.
Conclusion
As gut microbiota is strongly associated with IBD, under-
standing how a patient’s gut microbiota respond to treat-
ments has become important. Recent studies indicated the
importance of mucosal microbiota, where bacteria have clo-
ser interaction with host cells than those in the lumen. Since
modulating luminal bacteria indirectly affects mucosal mi-
crobiota, diet- and microbiota-therapies, are the important
factors in managing IBD (Fig. 3). Few studies have investi-
gated roles of mucosal microbiota compared to that of lumi-
nal microbiota. The use of DSS-treated mice for IBD study
makes it difficult to obtain purely separated mucosal micro-
biota from the ones in lumen, thus further animal model IBD
studies may require larger subjects such as rats. Comparison
of microbiome between IBD biopsy and fecal samples may
also help us understand roles of mucosal microbiota.
The efficacy of the treatments developed for IBD usually
vary due to interindividual differences in gut microbiota. For
example, results expected from dietary intervention may vary
depending on how it was digested and absorbed by hosts,
which is mostly determined by types of gut microbiota. There-
fore, personalized treatments are needed, especially for di-
sease associated with gut dysbiosis. While FMT may replace
a majority of gut microbiota lost to toxin- and antibiotic-
induced dysbiosis, it gradually becomes personalized likely
due to host genetic differences (Staley et al., 2016). To de-
velop sustainable IBD treatments, personalized treatments
should be chosen based on characteristics of a patient’s gut
microbiota and genetics as well as dietary habits and life style
information. Recent development of next generation sequen-
cing technology and bioinformatics, coupled with compu-
tational infrastructure, may lead to the development of per-
sonalized IBD treatment through big data analysis and a
better understanding of host-microbe interactions in the gut
environment.
Roles of probiotics in IBD 195
Acknowledgements
We are grateful to Sustainable Agriculture Research Institute
(SARI) at Jeju National University for providing the experi-
mental facilities. This research was supported, in part, by the
Basic Science Research Program through the National Re-
search Foundation of Korea (NRF) funded by the Ministry
of Education (2016R1A6A1A03012862) and by the Tradi-
tional Culture Convergence Research Program through the
NRF, and funded by the Ministry of Science, ICT & Future
Planning (2016M3C1B5907205) to (TU). We also thank the
Minnesota Agricultural Experiment Station for support (to
MJS).
References
Abraham, B.P. and Quigley, E.M.M. 2017. Probiotics in inflamma-
tory bowel disease. Gastroenterol. Clin. North Am. 46, 769–782.
Ahmad, R., Chaturvedi, R., Olivares-Villagomez, D., Habib, T., Asim,
M., Shivesh, P., Polk, D.B., Wilson, K.T., Washington, M.K., Van
Kaer, L., et al. 2014. Targeted colonic claudin-2 expression renders
resistance to epithelial injury, induces immune suppression, and
protects from colitis. Mucosal Immunol. 7, 1340–1353.
Ale, M.T., Mikkelsen, J.D., and Meyer, A.S. 2011. Important deter-
minants for fucoidan bioactivity: a critical review of structure-
function relations and extraction methods for fucose-containing
sulfated polysaccharides from brown seaweeds. Mar. Drugs 9,
2106–2130.
Ananthakrishnan, A.N. 2015. Environmental risk factors for in-
flammatory bowel diseases: a review. Dig. Dis. Sci. 60, 290–298.
Andrianifahanana, M., Moniaux, N., and Batra, S.K. 2006. Regulation
of mucin expression: mechanistic aspects and implications for
cancer and inflammatory diseases. Biochim. Biophys. Acta 1765,
189–222.
Biagioli, M., Cipriani, S., Carino, A., Distrutti, E., Marchianò, S., and
Fiorucci, S. 2017. Variability in industrial production affects pro-
biotics activity: identification of batches of probiotic VSL#3 that
increases intestinal permeability and worsens colitis in rodents.
Gastroenterology 152, S969.
Boden, E.K. and Snapper, S.B. 2008. Regulatory T cells in inflam-
matory bowel disease. Curr. Opin. Gastroenterol. 24, 733–741.
Casellas, F., Borruel, N., Torrejon, A., Varela, E., Antolin, M., Guar-
ner, F., and Malagelada, J.R. 2007. Oral oligofructose-enriched
inulin supplementation in acute ulcerative colitis is well tolerated
and associated with lowered faecal calprotectin. Aliment. Phar-
macol. Ther. 25, 1061–1067.
Cherbut, C. 2002. Inulin and oligofructose in the dietary fibre con-
cept. Br. J. Nutr. 87 Suppl 2, S159–S162.
Cinque, B., La Torre, C., Lombardi, F., Palumbo, P., Van der Rest, M.,
and Cifone, M.G. 2016. Production conditions affect the in vitro
anti-tumoral effects of a high concentration multi-strain probiotic
preparation. PLoS One 11, e0163216.
Cloetens, L., Ulmius, M., Johansson-Persson, A., Akesson, B., and On-
ning, G. 2012. Role of dietary beta-glucans in the prevention of
the metabolic syndrome. Nutr. Rev. 70, 444–458.
Costello, S.P., Soo, W., Bryant, R.V., Jairath, V., Hart, A.L., and And-
rews, J.M. 2017. Systematic review with meta-analysis: faecal mi-
crobiota transplantation for the induction of remission for active
ulcerative colitis. Aliment. Pharmacol. Ther. 46, 213–224.
Daou, C. and Zhang, H. 2012. Oat beta-glucan: Its role in health pro-
motion and prevention of diseases. Compr. Rev. Food Sci. F. 11,
355–365.
Derwa, Y., Gracie, D.J., Hamlin, P.J., and Ford, A.C. 2017. Systematic
review with meta-analysis: the efficacy of probiotics in inflamma-
196 Eom et al.
tory bowel disease. Aliment. Pharmacol. Ther. 46, 389–400.
Di Sabatino, A., Biancheri, P., Rovedatti, L., MacDonald, T.T., and
Corazza, G.R. 2012. New pathogenic paradigms in inflammatory
bowel disease. Inflamm. Bowel Dis. 18, 368–371.
Dos Reis, S.A., da Conceicao, L.L., Siqueira, N.P., Rosa, D.D., da Silva,
L.L., and Peluzio, M.D. 2017. Review of the mechanisms of pro-
biotic actions in the prevention of colorectal cancer. Nutr. Res.
37, 1–19.
Ewaschuk, J.B., Diaz, H., Meddings, L., Diederichs, B., Dmytrash,
A., Backer, J., Looijer-van Langen, M., and Madsen, K.L. 2008.
Secreted bioactive factors from Bifidobacterium infantis enhance
epithelial cell barrier function. Am. J. Physiol. Gastrointest. Liver
Physiol. 295, G1025–G1034.
Flamm, G., Glinsmann, W., Kritchevsky, D., Prosky, L., and Rober-
froid, M. 2001. Inulin and oligofructose as dietary fiber: a review
of the evidence. Crit. Rev. Food Sci. Nutr. 41, 353–362.
Forland, D.T., Johnson, E., Saetre, L., Lyberg, T., Lygren, I., and Het-
land, G. 2011. Effect of an extract based on the medicinal mush-
room Agaricus blazei murill on expression of cytokines and cal-
protectin in patients with ulcerative colitis and Crohn’s disease.
Scand. J. Immunol. 73, 66–75.
Frolkis, A.D., Dykeman, J., Negron, M.E., Debruyn, J., Jette, N.,
Fiest, K.M., Frolkis, T., Barkema, H.W., Rioux, K.P., Panaccione,
R., et al. 2013. Risk of surgery for inflammatory bowel diseases
has decreased over time: a systematic review and meta-analysis
of population-based studies. Gastroenterology 145, 996–1006.
Fukuda, S., Toh, H., Hase, K., Oshima, K., Nakanishi, Y., Yoshimura,
K., Tobe, T., Clarke, J.M., Topping, D.L., Suzuki, T., et al. 2011.
Bifidobacteria can protect from enteropathogenic infection through
production of acetate. Nature 469, 543–547.
Fung, K.Y., Cosgrove, L., Lockett, T., Head, R., and Topping, D.L.
2012. A review of the potential mechanisms for the lowering of
colorectal oncogenesis by butyrate. Br. J. Nutr. 108, 820–831.
Gaffen, S.L., Jain, R., Garg, A.V., and Cua, D.J. 2014. The IL-23-
IL-17 immune axis: from mechanisms to therapeutic testing.
Nat. Rev. Immunol. 14, 585–600.
Galvez, J. 2014. Role of Th17 cells in the pathogenesis of human
IBD. ISRN Inflamm. 2014, 928461.
Gevers, D., Kugathasan, S., Denson, L.A., Vazquez-Baeza, Y., Van
Treuren, W., Ren, B., Schwager, E., Knights, D., Song, S.J., Yassour,
M., et al. 2014. The treatment-naive microbiome in new-onset
Crohn’s disease. Cell Host Microbe 15, 382–392.
Gibson, G.R. and Roberfroid, M.B. 1995. Dietary modulation of the
human colonic microbiota: introducing the concept of prebiotics.
J. Nutr. 125, 1401–1412.
Gionchetti, P., Rizzello, F., Helwig, U., Venturi, A., Lammers, K.M.,
Brigidi, P., Vitali, B., Poggioli, G., Miglioli, M., and Campieri,
M. 2003. Prophylaxis of pouchitis onset with probiotic therapy:
a double-blind, placebo-controlled trial. Gastroenterology 124,
1202–1209.
Goodrich, J.K., Waters, J.L., Poole, A.C., Sutter, J.L., Koren, O.,
Blekhman, R., Beaumont, M., Van Treuren, W., Knight, R., Bell,
J.T., et al. 2014. Human genetics shape the gut microbiome. Cell
159, 789–799.
Gopalakrishnan, A., Clinthorne, J.F., Rondini, E.A., McCaskey, S.J.,
Gurzell, E.A., Langohr, I.M., Gardner, E.M., and Fenton, J.I. 2012.
Supplementation with galacto-oligosaccharides increases the per-
centage of NK cells and reduces colitis severity in Smad3-defi-
cient mice. J. Nutr. 142, 1336–1342.
Goto, Y., Obata, T., Kunisawa, J., Sato, S., Ivanov, I.I., Lamichhane,
A., Takeyama, N., Kamioka, M., Sakamoto, M., Matsuki, T., et al.
2014. Innate lymphoid cells regulate intestinal epithelial cell gly-
cosylation. Science 345, 1254009.
Halfvarson, J., Brislawn, C.J., Lamendella, R., Vazquez-Baeza, Y., Wal-
ters, W.A., Bramer, L.M., D’Amato, M., Bonfiglio, F., McDonald,
D., Gonzalez, A., et al. 2017. Dynamics of the human gut micro-
biome in inflammatory bowel disease. Nat. Microbiol. 2, 17004.
Holma, R., Juvonen, P., Asmawi, M.Z., Vapaatalo, H., and Korpela,
R. 2002. Galacto-oligosaccharides stimulate the growth of bifido-
bacteria but fail to attenuate inflammation in experimental colitis
in rats. Scand. J. Gastroenterol. 37, 1042–1047.
Hugot, J.P., Chamaillard, M., Zouali, H., Lesage, S., Cezard, J.P.,
Belaiche, J., Almer, S., Tysk, C., O’Morain, C.A., Gassull, M., et al.
2001. Association of NOD2 leucine-rich repeat variants with sus-
ceptibility to Crohn’s disease. Nature 411, 599–603.
Imhann, F., Vich Vila, A., Bonder, M.J., Fu, J., Gevers, D., Vissche-
dijk, M.C., Spekhorst, L.M., Alberts, R., Franke, L., van Dullemen,
H.M., et al. 2018. Interplay of host genetics and gut microbiota
underlying the onset and clinical presentation of inflammatory
bowel disease. Gut 67, 108–119.
Isene, R., Bernklev, T., Hoie, O., Munkholm, P., Tsianos, E., Stock-
brugger, R., Odes, S., Palm, O., Smastuen, M., Moum, B., et al.
2015. Extraintestinal manifestations in Crohn’s disease and ul-
cerative colitis: results from a prospective, population-based Euro-
pean inception cohort. Scand. J. Gastroenterol. 50, 300–305.
Jensen, H., Dromtorp, S.M., Axelsson, L., and Grimmer, S. 2015.
Immunomodulation of monocytes by probiotic and selected lac-
tic acid bacteria. Probiotics Antimicrob. Proteins 7, 14–23.
Johnston, R.D. and Logan, R.F. 2008. What is the peak age for on-
set of IBD? Inflamm. Bowel Dis. 14 Suppl 2, S4–S5.
Kamada, N., Chen, G.Y., Inohara, N., and Nunez, G. 2013. Control
of pathogens and pathobionts by the gut microbiota. Nat. Im-
munol. 14, 685–690.
Kaser, A., Martinez-Naves, E., and Blumberg, R.S. 2010. Endoplasmic
reticulum stress: implications for inflammatory bowel disease
pathogenesis. Curr. Opin. Gastroenterol. 26, 318–326.
Khoruts, A., Rank, K.M., Newman, K.M., Viskocil, K., Vaughn, B.P.,
Hamilton, M.J., and Sadowsky, M.J. 2016. Inflammatory bowel
disease affects the outcome of fecal microbiota transplantation
for recurrent Clostridium difficile infection. Clin. Gastroenterol.
Hepatol. 14, 1433–1438.
Kim, C.H. 2009. FOXP3 and its role in the immune system. Adv.
Exp. Med. Biol. 665, 17–29.
Kılınç, B., Cirik, S., Turan, G., Tekogul, H., and Koru, E. 2013. Sea-
weed for food and industrial applications, In Muzzalupo, I. (ed.),
Food Industry. InTech, DOI: 10.5772/53172.
Kolmeder, C.A., Salojarvi, J., Ritari, J., de Been, M., Raes, J., Falony,
G., Vieira-Silva, S., Kekkonen, R.A., Corthals, G.L., Palva, A., et
al. 2016. Faecal metaproteomic analysis reveals a personalized
and stable functional microbiome and limited effects of a pro-
biotic intervention in adults. PLoS One 11, e0153294.
Kravtsov, E.G., Yermolayev, A.V., Anokhina, I.V., Yashina, N.V.,
Chesnokova, V.L., and Dalin, M.V. 2008. Adhesion characteri-
stics of lactobacillus is a criterion of the probiotic choice. Bull.
Exp. Biol. Med. 145, 232–234.
Kristensen, N.B., Bryrup, T., Allin, K.H., Nielsen, T., Hansen, T.H.,
and Pedersen, O. 2016. Alterations in fecal microbiota compo-
sition by probiotic supplementation in healthy adults: a system-
atic review of randomized controlled trials. Genome Med. 8, 52.
Landy, J., Ronde, E., English, N., Clark, S.K., Hart, A.L., Knight, S.C.,
Ciclitira, P.J., and Al-Hassi, H.O. 2016. Tight junctions in inflam-
matory bowel diseases and inflammatory bowel disease asso-
ciated colorectal cancer. World J. Gastroenterol. 22, 3117–3126.
Lavi, I., Levinson, D., Peri, I., Nimri, L., Hadar, Y., and Schwartz, B.
2010. Orally administered glucans from the edible mushroom Pleu-
rotus pulmonarius reduce acute inflammation in dextran sulfate
sodium-induced experimental colitis. Br. J. Nutr. 103, 393–402.
Lean, Q.Y., Eri, R.D., Fitton, J.H., Patel, R.P., and Gueven, N. 2015.
Fucoidan extracts ameliorate acute colitis. PLoS One 10, e0128453.
Li, H., Limenitakis, J.P., Fuhrer, T., Geuking, M.B., Lawson, M.A.,
Wyss, M., Brugiroux, S., Keller, I., Macpherson, J.A., Rupp, S.,
et al. 2015. The outer mucus layer hosts a distinct intestinal mi-
crobial niche. Nat. Commun. 6, 8292.
Licht, T.R., Hansen, M., Poulsen, M., and Dragsted, L.O. 2006. Die-

tary carbohydrate source influences molecular fingerprints of the
rat faecal microbiota. BMC Microbiol. 6, 98.
Liu, T., Zhang, L., Joo, D., and Sun, S.C. 2017. NF-kappaB signaling
in inflammation. Signal. Transduct. Target. Ther. 2, 17023.
Losurdo, G., Iannone, A., Contaldo, A., Ierardi, E., Di Leo, A., and
Principi, M. 2015. Escherichia coli nissle 1917 in ulcerative colitis
treatment: systematic review and meta-analysis. J. Gastrointestin.
Liver Dis. 24, 499–505.
Luo, Y., de Lange, K.M., Jostins, L., Moutsianas, L., Randall, J., Ken-
nedy, N.A., Lamb, C.A., McCarthy, S., Ahmad, T., Edwards, C.,
et al. 2017. Exploring the genetic architecture of inflammatory
bowel disease by whole-genome sequencing identifies associa-
tion at ADCY7. Nat. Genet. 49, 186–192.
Maldonado-Gomez, M.X., Martinez, I., Bottacini, F., O’Callaghan, A.,
Ventura, M., van Sinderen, D., Hillmann, B., Vangay, P., Knights,
D., Hutkins, R.W., et al. 2016. Stable engraftment of Bifidobac-
terium iongum AH1206 in the human gut depends on individu-
alized features of the resident microbiome. Cell Host Microbe
20, 515–526.
Marcobal, A., Southwick, A.M., Earle, K.A., and Sonnenburg, J.L.
2013. A refined palate: bacterial consumption of host glycans in
the gut. Glycobiology 23, 1038–1046.
Marteau, P. and Flourie, B. 2001. Tolerance to low-digestible car-
bohydrates: symptomatology and methods. Br. J. Nutr. 85 Suppl
1, S17–S21.
Maslowski, K.M. and Mackay, C.R. 2011. Diet, gut microbiota and
immune responses. Nat. Immunol. 12, 5–9.
Matsumoto, S., Nagaoka, M., Hara, T., Kimura-Takagi, I., Mistuyama,
K., and Ueyama, S. 2004. Fucoidan derived from Cladosiphon oka-
muranus Tokida ameliorates murine chronic colitis through the
down-regulation of interleukin-6 production on colonic epithelial
cells. Clin. Exp. Immunol. 136, 432–439.
Mazurak, N., Broelz, E., Storr, M., and Enck, P. 2015. Probiotic the-
rapy of the irritable bowel syndrome: Why is the evidence still
poor and what can be done about it? J. Neurogastroenterol. Motil.
21, 471–485.
McIlroy, J., Ianiro, G., Mukhopadhya, I., Hansen, R., and Hold, G.L.
2018. Review article: the gut microbiome in inflammatory bowel
disease-avenues for microbial management. Aliment. Pharmacol.
Ther. 47, 26–42.
Mimura, T., Rizzello, F., Helwig, U., Poggioli, G., Schreiber, S., Talbot,
I.C., Nicholls, R.J., Gionchetti, P., Campieri, M., and Kamm, M.A.
2004. Once daily high dose probiotic therapy (VSL#3) for main-
taining remission in recurrent or refractory pouchitis. Gut 53,
108–114.
Molodecky, N.A., Soon, I.S., Rabi, D.M., Ghali, W.A., Ferris, M.,
Chernoff, G., Benchimol, E.I., Panaccione, R., Ghosh, S., Barkema,
H.W., et al. 2012. Increasing incidence and prevalence of the in-
flammatory bowel diseases with time, based on systematic review.
Gastroenterology 142, 46–54 e42; quiz e30.
Mussatto, S.I. and Mancilha, I.M. 2007. Non-digestible oligosac-
charides: A review. Carbohydrate Polymers 68, 587–597.
Najafzadeh, M., Reynolds, P.D., Baumgartner, A., Jerwood, D., and
Anderson, D. 2007. Chaga mushroom extract inhibits oxidative
DNA damage in lymphocytes of patients with inflammatory bowel
disease. Biofactors 31, 191–200.
Ng, K.M., Ferreyra, J.A., Higginbottom, S.K., Lynch, J.B., Kashyap,
P.C., Gopinath, S., Naidu, N., Choudhury, B., Weimer, B.C.,
Monack, D.M., et al. 2013a. Microbiota-liberated host sugars fa-
cilitate post-antibiotic expansion of enteric pathogens. Nature
502, 96–99.
Ng, S.C., Tang, W., Ching, J.Y., Wong, M., Chow, C.M., Hui, A.J.,
Wong, T.C., Leung, V.K., Tsang, S.W., Yu, H.H., et al. 2013b.
Incidence and phenotype of inflammatory bowel disease based
on results from the Asia-pacific Crohn’s and colitis epidemiology
study. Gastroenterology 145, 158–165.e2.
O’Shea, C.J., O’Doherty, J.V., Callanan, J.J., Doyle, D., Thornton, K.,
Roles of probiotics in IBD 197
and Sweeney, T. 2016. The effect of algal polysaccharides lami-
narin and fucoidan on colonic pathology, cytokine gene expre-
ssion and Enterobacteriaceae in a dextran sodium sulfate-chal-
lenged porcine model. J. Nutr. Sci. 5, e15.
O’Sullivan, L., Murphy, B., McLoughlin, P., Duggan, P., Lawlor, P.G.,
Hughes, H., and Gardiner, G.E. 2010. Prebiotics from marine
macroalgae for human and animal health applications. Mar. Drugs
8, 2038–2064.
Ogura, Y., Bonen, D.K., Inohara, N., Nicolae, D.L., Chen, F.F., Ra-
mos, R., Britton, H., Moran, T., Karaliuskas, R., Duerr, R.H., et al.
2001. A frameshift mutation in NOD2 associated with suscepti-
bility to Crohn’s disease. Nature 411, 603–606.
Okolie, C.L., Rajendran, S.R.C.K., Udenigwe, C.C., Aryee, A.N.A.,
and Mason, B. 2017. Prospects of brown seaweed polysaccharides
(BSP) as prebiotics and potential immunomodulators. J. Food
Biochem. 41, e12392.
Ouwerkerk, J.P., de Vos, W.M., and Belzer, C. 2013. Glycobiome:
bacteria and mucus at the epithelial interface. Best Pract. Res.
Clin. Gastroenterol. 27, 25–38.
Pacheco, A.R., Barile, D., Underwood, M.A., and Mills, D.A. 2015.
The impact of the milk glycobiome on the neonate gut micro-
biota. Annu. Rev. Anim. Biosci. 3, 419–445.
Packey, C.D. and Sartor, R.B. 2008. Interplay of commensal and
pathogenic bacteria, genetic mutations, and immunoregulatory
defects in the pathogenesis of inflammatory bowel diseases. J.
Intern. Med. 263, 597–606.
Piche, T., des Varannes, S.B., Sacher-Huvelin, S., Holst, J.J., Cuber,
J.C., and Galmiche, J.P. 2003. Colonic fermentation influences
lower esophageal sphincter function in gastroesophageal reflux
disease. Gastroenterology 124, 894–902.
Pickard, J.M., Maurice, C.F., Kinnebrew, M.A., Abt, M.C., Schenten,
D., Golovkina, T.V., Bogatyrev, S.R., Ismagilov, R.F., Pamer, E.G.,
Turnbaugh, P.J., et al. 2014. Rapid fucosylation of intestinal epi-
thelium sustains host-commensal symbiosis in sickness. Nature
514, 638–641.
Pigneur, B. and Sokol, H. 2016. Fecal microbiota transplantation in
inflammatory bowel disease: the quest for the holy grail. Mucosal.
Immunol. 9, 1360–1365.
Powrie, F., Leach, M.W., Mauze, S., Menon, S., Caddle, L.B., and
Coffman, R.L. 1994. Inhibition of Th1 responses prevents inflam-
matory bowel disease in scid mice reconstituted with CD45RBhi
+
CD4 T cells. Immunity 1, 553–562.
Rios-Covian, D., Ruas-Madiedo, P., Margolles, A., Gueimonde, M.,
de Los Reyes-Gavilan, C.G., and Salazar, N. 2016. Intestinal short
chain fatty acids and their link with diet and human health. Front.
Microbiol. 7, 185.
Rivero-Urgell, M. and Santamaria-Orleans, A. 2001. Oligosaccha-
rides: application in infant food. Early Hum. Dev. 65 Suppl,
S43–S52.
Roberfroid, M.B. 2000. Prebiotics and probiotics: are they functional
foods? Am. J. Clin. Nutr. 71, S1682–S1687; discussion S1688–
S1690.
Sadowsky, M.J., Staley, C., Heiner, C., Hall, R., Kelly, C.R., Brandt,
L., and Khoruts, A. 2017. Analysis of gut microbiota - An ever
changing landscape. Gut Microbes 8, 268–275.
Sanchez, B., Delgado, S., Blanco-Miguez, A., Lourenco, A., Gueimonde,
M., and Margolles, A. 2017. Probiotics, gut microbiota, and their
influence on host health and disease. Mol. Nutr. Food Res. 61,
1600240.
Sanders, M.E. 2008. Probiotics: definition, sources, selection, and
uses. Clin Infect Dis 46 Suppl 2, S58–S61; discussion S144–S151.
Sanders, M.E. 2016. Probiotics and microbiota composition. BMC
Med. 14, 82.
Sangwan, V., Tomar, S.K., Singh, R.R., Singh, A.K., and Ali, B. 2011.
Galactooligosaccharides: novel components of designer foods.
J. Food Sci. 76, R103–R111.
Senthilkumar, K., Manivasagan, P., Venkatesan, J., and Kim, S.K.
198 Eom et al.
2013. Brown seaweed fucoidan: biological activity and apoptosis,
growth signaling mechanism in cancer. Int. J. Biol. Macromol.
60, 366–374.
Shanahan, F. 2017. Editorial: probiotics in inflammatory bowel
disease-wrong organisms, wrong disease, or flawed concepts?
Aliment. Pharmacol. Ther. 46, 632–633.
Shang, L., Fukata, M., Thirunarayanan, N., Martin, A.P., Arnaboldi,
P., Maussang, D., Berin, C., Unkeless, J.C., Mayer, L., Abreu, M.T.,
et al. 2008. Toll-like receptor signaling in small intestinal epithe-
lium promotes B-cell recruitment and IgA production in lamina
propria. Gastroenterology 135, 529–538.
Shi, L., Lin, Q., Yang, T., Nie, Y., Li, X., Liu, B., Shen, J., Liang, Y.,
Tang, Y., and Luo, F. 2016. Oral administration of Lentinus edodes
beta-glucans ameliorates DSS-induced ulcerative colitis in mice
via MAPK-Elk-1 and MAPK-PPARgamma pathways. Food Funct.
7, 4614–4627.
Sicard, J.F., Le Bihan, G., Vogeleer, P., Jacques, M., and Harel, J. 2017.
Interactions of intestinal bacteria with components of the in-
testinal mucus. Front. Cell. Infect. Microbiol. 7, 387.
Slavin, J. 2013. Fiber and prebiotics: mechanisms and health benefits.
Nutrients 5, 1417–1435.
Sonnenburg, E.D., Zheng, H., Joglekar, P., Higginbottom, S.K., Fir-
bank, S.J., Bolam, D.N., and Sonnenburg, J.L. 2010. Specificity of
polysaccharide use in intestinal bacteroides species determines
diet-induced microbiota alterations. Cell 141, 1241–1252.
Staley, C., Kelly, C.R., Brandt, L.J., Khoruts, A., and Sadowsky, M.J.
2016. Complete microbiota engraftment is not essential for re-
covery from recurrent Clostridium difficile infection following
fecal microbiota transplantation. MBio 7, e01965-16.
Strober, W. and Fuss, I.J. 2011. Proinflammatory cytokines in the
pathogenesis of inflammatory bowel diseases. Gastroenterology
140, 1756–1767.
Sun, Y. and O’Riordan, M.X. 2013. Regulation of bacterial patho-
genesis by intestinal short-chain fatty acids. Adv. Appl. Microbiol.
85, 93–118.
Sunkara, L.T., Jiang, W., and Zhang, G. 2012. Modulation of anti-
microbial host defense peptide gene expression by free fatty acids.
PLoS One 7, e49558.
Swennen, K., Courtin, C.M., and Delcour, J.A. 2006. Non-digestible
oligosaccharides with prebiotic properties. Crit. Rev. Food Sci.
Nutr. 46, 459–471.
Takaishi, H., Matsuki, T., Nakazawa, A., Takada, T., Kado, S., Asa-
hara, T., Kamada, N., Sakuraba, A., Yajima, T., Higuchi, H., et al.
2008. Imbalance in intestinal microflora constitution could be
involved in the pathogenesis of inflammatory bowel disease. Int.
J. Med. Microbiol. 298, 463–472.
Ten Bruggencate, S.J., Bovee-Oudenhoven, I.M., Lettink-Wissink,
M.L., Katan, M.B., and Van Der Meer, R. 2004. Dietary fructo-
oligosaccharides and inulin decrease resistance of rats to sal-
monella: protective role of calcium. Gut 53, 530–535.
Tojo, R., Suarez, A., Clemente, M.G., de los Reyes-Gavilan, C.G.,
Margolles, A., Gueimonde, M., and Ruas-Madiedo, P. 2014. Intes-
tinal microbiota in health and disease: role of bifidobacteria in
gut homeostasis. World J. Gastroenterol. 20, 15163–15176.
Vahabnezhad, E., Mochon, A.B., Wozniak, L.J., and Ziring, D.A. 2013.
Lactobacillus bacteremia associated with probiotic use in a pedi-
atric patient with ulcerative colitis. J. Clin. Gastroenterol. 47,
437–439.
Van den Abbeele, P., Belzer, C., Goossens, M., Kleerebezem, M., De
Vos, W.M., Thas, O., De Weirdt, R., Kerckhof, F.M., and Van de
Wiele, T. 2013. Butyrate-producing Clostridium cluster XIVa
species specifically colonize mucins in an in vitro gut model.
ISME J. 7, 949–961.
Van der Sluis, M., De Koning, B.A., De Bruijn, A.C., Velcich, A.,
Meijerink, J.P., Van Goudoever, J.B., Buller, H.A., Dekker, J.,
Van Seuningen, I., Renes, I.B., et al. 2006. Muc2-deficient mice
spontaneously develop colitis, indicating that MUC2 is critical
for colonic protection. Gastroenterology 131, 117–129.
Verghese, M., Walker, L.T., Shackelford, L., and Chawan, C.B. 2005.
Inhibitory effects of nondigestible carbohydrates of different chain
lengths on azoxymethane-induced aberrant crypt foci in Fisher
344 rats. Nutr. Res. 25, 859–868.
Videla, S., Vilaseca, J., Antolin, M., Garcia-Lafuente, A., Guarner, F.,
Crespo, E., Casalots, J., Salas, A., and Malagelada, J.R. 2001. Die-
tary inulin improves distal colitis induced by dextran sodium
sulfate in the rat. Am. J. Gastroenterol. 96, 1486–1493.
Weingarden, A., Gonzalez, A., Vazquez-Baeza, Y., Weiss, S., Hum-
phry, G., Berg-Lyons, D., Knights, D., Unno, T., Bobr, A., Kang, J.,
et al. 2015. Dynamic changes in short- and long-term bacterial
composition following fecal microbiota transplantation for re-
current Clostridium difficile infection. Microbiome 3, 10.
Wells, M.L., Potin, P., Craigie, J.S., Raven, J.A., Merchant, S.S., Helli-
well, K.E., Smith, A.G., Camire, M.E., and Brawley, S.H. 2017.
Algae as nutritional and functional food sources: revisiting our
understanding. J. Appl. Phycol. 29, 949–982.
Whelan, K. and Quigley, E.M. 2013. Probiotics in the management
of irritable bowel syndrome and inflammatory bowel disease.
Curr. Opin. Gastroenterol. 29, 184–189.
Yamamoto, S. and Ma, X. 2009. Role of Nod2 in the development
of Crohn’s disease. Microbes Infect. 11, 912–918.
Yamamoto, A., Itoh, T., Nasu, R., and Nishida, R. 2013. Effect of
sodium alginate on dextran sulfate sodium- and 2,4,6-trinitro-
benzene sulfonic acid-induced experimental colitis in mice. Phar-
macology 92, 108–116.
Yang, S.K., Yun, S., Kim, J.H., Park, J.Y., Kim, H.Y., Kim, Y.H., Chang,
D.K., Kim, J.S., Song, I.S., Park, J.B., et al. 2008. Epidemiology
of inflammatory bowel disease in the Songpa-Kangdong district,
Seoul, Korea, 1986-2005: a KASID study. Inflamm. Bowel Dis.
14, 542–549.
Zenewicz, L.A., Antov, A., and Flavell, R.A. 2009. CD4 T-cell dif-
ferentiation and inflammatory bowel disease. Trends Mol. Med.
15, 199–207.
Zhu, Y., Michelle Luo, T., Jobin, C., and Young, H.A. 2011. Gut mi-
crobiota and probiotics in colon tumorigenesis. Cancer Lett.
309, 119–127.