CLINICAL REVIEW
Mucin Function in Inflammatory Bowel Disease
An Update
Doron Boltin, MBBS, Tsachi T. Perets, PhD, Alex Vilkin, MD, and Yaron Niv, MD, AGAF, FACG
Abstract: MUC2 is the primary component of the mucin barrier
that separates the intestinal microbiota and the intestinal epi-
thelium. This mucous barrier is affected by both luminal/microbial
factors and host/immune factors, both of which have genetic and
environmental determinants. The complex interactions between
these players in health and disease states are not fully understood.
Inflammatory bowel disease (IBD) has both genetic and environ-
mental etiologies that lead to the breakdown of the epithelial
barrier. In this review, we explore the up-to-date evidence that
implicates mucin in the pathogenesis of IBD. In IBD, quantitative
changes in mucin secretion occur, as well as structural changes
in mucin’s glycoprotein core and the sulfation and sialylation of
mucin’s oligosaccharide residues. These changes are associated
with a diminished functionality of the mucous barrier. We identify
the various genetic mutations associated with these changes and
outline the animal models that have enhanced the current under-
standing of the genetic basis for IBD. Further study is needed to
better characterize the immune and genetic influences on mucin
expression and secretion and role of endoplasmic reticulum stress
and a defective unfolded protein response in mediating these
changes.
Key Words: mucosal barrier, inflammatory bowel disease, intestinal
epithelium, goblet cell, mucin, MUC2, unfolded protein response,
ER stress
(J Clin Gastroenterol 2013;47:106–111)
T he mucosa of the gastrointestinal (GI) tract is a complex
microenvironment involving an epithelial barrier, immune
cells, and microbes. A delicate balance is maintained in the
healthy colon. Luminal microbes are physically separated
from the host immune system by a barrier consisting of epi-
thelium and mucus.
Ulcerative colitis (UC) and Crohn’s disease (CD) are
the 2 major forms of inflammatory bowel disease (IBD).
The pathogenesis of IBD, although not fully elucidated,
involves an inappropriate host response to an altered
commensal flora with a dysfunctional mucous barrier.
Mucins are the primary constituent of the mucous
layer lining the GI tract. Mucins are high–molecular-weight
glycoproteins, which are heavily glycosylated with O-linked
oligosaccharides and N-glycan chains, linked to a protein
backbone. There are at least 21 mucin (MUC) genes known
in the human genome. These genes encode 2 groups of
mucins: secreted mucins and membrane-bound mucins.
From the Department of Gastroenterology, Rabin Medical Center and
Tel Aviv University, Tel Aviv, Israel.
The authors declare that they have nothing to disclose.
Reprints: Yaron Niv, MD, AGAF, FACG, Department of Gastro-
enterology, Rabin Medical Center and Tel Aviv University, 39
Jabotinski Street, Tel Aviv 49100, Israel (e-mail nivyaron80
@gmail.com; yniv@clalit.org.il).
Copyright r 2013 by Lippincott Williams & Wilkins
106 | www.jcge.com
The predominant mucins in the normal colorectum are
MUC1, MUC2, MUC3A, MUC3B, MUC4, MUC13, and
MUC17.1 MUC2 is the primary secretory, gel-forming
component of intestinal mucus, produced in goblet cells.
MUC1, MUC3A, MUC3B, MUC4, MUC13, and MUC17
are membrane bound and are involved in cell signaling,
adhesion, growth, and immune modulation. Largely, the
degree of mucin glycosylation determines the extent of
mucosal protection. Colonic mucins typically have up to 12
monosaccharides per chain. These oligosaccharides may be
linear, branched, acidic, or neutral, such that there is a huge
scope for variation.1
As we will outline, the loss of integrity of the mucosal
barrier in IBD due to changes in mucin secretion may be
related to host immune changes, luminal microbial factors,
or directly acting genetic or environmental determinants.
If so, then it stands to reason that disequilibrium of the
mucous barrier may be central to the pathogenesis of IBD.
MUCIN AND INFLAMMATION
Acute Inflammation
Acute intestinal infection leads to increased goblet cell
differentiation and an upregulation of mucin synthesis and
secretion. Regulation of mucin synthesis is complex, mul-
tifactorial, and incompletely understood. Both microbial
and immune factors affect mucin production in variable
and inconsistent manners. For example, bacterial products
from gram positive (lipoteichoic acid) and gram-negative
(lipopolysaccharides and flagellin A) bacteria can induce
mucin production.2,3 Upregulation of mucin in the face of
pathogens allows for the mucous protective layer to remain
intact on the one hand, and for the offending pathogens to
be flushed downstream, on the other. MUC17, for example,
is instrumental in limiting the epithelial adhesion and
invasion of enteroinvasive Escherichia coli.4 Muc1-deficient
mice are highly susceptible to invasive Campylobacter jejuni
infection.5
The effect of parasites on intestinal goblet cells and
mucin has been well studied. In the acute setting, Nippos-
trongylus brasiliensis and Trichinella spiralis cause goblet
cell hyperplasia and increased mucin secretion, mediated by
a Th2 immune response.6 In mouse models, the nematode
Trichuris muris causes increases Muc2 production, whereas
in Muc2-deficient mice nematode expulsion is significantly
delayed.7 In addition, T. muris leads to de novo MUC5AC
expression in the cecum of infected mice and may be
essential for nematode expulsion.8
However, for invasive intestinal pathogens to be
effective, they must bind and breach intestinal mucin. Many
enteric pathogens possess adhesion molecules with specific
receptors on the mucin molecule. For example, Crypto-
sporidium parvum and Entamoeba histolytica both expresses
J Clin Gastroenterol  Volume 47, Number 2, February 2013
J Clin Gastroenterol  Volume 47, Number 2, February 2013 Mucin Expression in IBD

a surface Gal/GalNAc lectin that can adhere to intestinal

mucin.9 In addition, E. histolytica secretes cysteine pro- TABLE 1. Changes in Intestinal Mucin Structure and Expression
in IBD
teases that specifically target the C-terminal domain of
MUC2, thereby disrupting the mucous barrier.10 Enter- CD UC References
otoxigenic E. coli use type 1 pili and Fy pili to bind mucin Mucus thickness Increased Decreased Senapati and
saccharides. Giardia, Salmonella, and Yersinia species use colleagues1,15
similar mechanisms to facilitate colonization.11 Oligosaccharide Decreased Decreased Raouf et al16
An array of proinflammatory cytokines promote chain length
mucin expression, including interleukin (IL)-4, IL-9, IL-13, Goblet cell Unchanged Decreased Senapati and
and tumor necrosis factor (TNF)-a. These are activated numbers colleagues1,15
largely by NF-kB in a CD4 T-cell response.2,3 MUC1 has Sulfation Unchanged Decreased Van Klinken
et al17
been shown to activate the NF-kB pathway in cancer cell Glycosylation Unknown Decreased Larsson et al18
lines; however, contradictory data exist.12 The precise role Sialylation Increased Increased Parker et al19
of MUC1 as an inflammatory mediator is unclear and is the MUC1 Decreased Increased Buisine and
subject of ongoing research. colleagues20,21
MUC2 mRNA Unchanged/ Decreased Moehle et al22
Chronic Inflammation decreased
Chronic intestinal infection leads to the ultimate MUC2 protein Decreased DecreasedVan and
depletion of goblet cells and reduction in mucin synthesis colleagues17,23
and secretion, allowing pathogens to access the underlying MUC3A Decreased Unchanged Buisine and
epithelium. Qualitative changes in mucin structure are also colleagues20,24
MUC3B Decreased Unchanged Buisine et al20
seen, as in chronic N. brasiliensis infection where increased MUC4 Decreased Increased Myerscough
oligosaccharide sialylation aids worm expulsion and impedes et al15
parasite attachment.13 MUC5AC Detectable Detectable Longman and
colleagues21,25
MUCIN AND CD MUC6 Detectable Unknown Buisine et al25
MUC13 Increased Increased Myerscough
Mucin Structure et al15
MUC17 Unknown Decreased Senapati et al26
The mucous layer is thicker in CD subjects compared Anti-MUC1 Undetectable Detectable Takaishi and
with controls, possibly corresponding with goblet cell antibodies colleagues27,28
hyperplasia14 (Table 1). Oligosaccharide chain length is Major mucolytic Ruminococcus Ruminococcus Png et al29
reduced by 50%, yet sialylation is increased.16,19 Detectable bacteria gnavus torques
MUC2 protein is increased in CD, irrespective of inflam-
mation. This probably does not reflect increased MUC2 CD indicates Crohn’s disease; IBD, inflammatory bowel disease; UC,
ulcerative colitis.
synthesis, but rather decreased posttranscriptional sulfation
and glycosylation. The overall effect is a mucin gel with
altered viscoelastic properties and reduced barrier function.
predisposition to CD.32 Chromosome 7q22 encompasses
Mucin Phenotype the chromosomal locus for MUC3A, MUC3B, MUC12,
Over 20 years ago, before individual mucins were and MUC17.33 Kyo et al24 demonstrated that single-
characterized, Prindiville et al30 already described goblet cell nucleotide polymorphisms within the cytoplasmic C-
heterogeneity in CD patients, with quantitative differences terminus of MUC3A, involving a tyrosine residue, may
in mucin-directed monoclonal antibodies. Macroscopically predispose to CD. Allelic polymorphisms in the MUC1 and
normal ileal mucosa in patients with CD probably has MUC2 genes have also been linked to CD.22,33
a mucin phenotype identical to normal controls.25 However,
some groups have described a reduction in MUC3, MUC4,
and MUC5B mRNA expression in both inflamed and Microbial Factors
noninflamed mucosa (although MUC1 mRNA was reduced Bacteria have long been investigated as environmental
only in inflamed ileal mucosa).20 In active ileal CD, Buisine factors in the pathogensis of IBD. Support for this includes
et al25 demonstrated MUC5AC and MUC6 expression the intracellular pathways that recognize microbial molec-
(normally restricted to gastric mucosa) and a marked ular patterns, such as NOD2 in CD, the clinical role
absence of MUC2. These gastric metaplastic cells have been of antibiotics in the treatment of both CD and UC, and
coined as ulcer-associated cell lineage, which in addition to more.34 Sulfation and sialylation play a role in the resist-
expressing gastric mucins are presumed to express peptides ance of mucin to bacterial degradation. About 1% of
(such as epidermal growth factor and the trefoil factor normal colonic bacteria secrete glycosidases and sulfatases
family peptide) involved in mucosal repair and ulcer healing. capable of degrading mucin oligosaccharides, allowing the
Ulcer-associated cell lineage is associated with decreased enteric microflora to exploit mucin carbohydrate as an
expression of the intestine-specific transcription factor CDX-2 energy source.35 In healthy controls, this normal process of
and increased expression of transcription factor PDX-1 that mucin breakdown is in equilibrium with continual mucin
regulates development of gastric mucosa.31 synthesis. Bacteria are normally present in the outer
mucous layer but are absent from the inner layer.36 In a
Genetic Factors dextran sulfate sodium colitis model, this inner layer
High concordance rates of CD among sibling pairs becomes permeable to bacterial, granting them access the
and twins suggest a genetic etiology. Genome-wide linkage colonic epithelium. This suggests that altered mucin per-
studies have identified 71 susceptibility loci that confer a meability with subsequent bacterial colonization of the

r 2013 Lippincott Williams & Wilkins www.jcge.com | 107

Boltin et al
inner mucous layer is an early step in the development of
colitis.37
In IBD, total mucosa-associated bacteria are in-
creased, even in the absence of acute inflammation. Png
et al29 recently identified Ruminococcus gnavus as the major
mucolyic bacteria in CD. In contrast, mucolytic bacteria
present in healthy controls (such as Akkermansia mucini-
phila) are reduced in IBD patients. This suggests that A.
muciniphila is associated with a protective or anti-inflam-
matory role in health, which is lost in IBD.
In normal colons, there are different quantities of
sialomucins and sulfomucins in the right and left colons,
with the greatest bulk present in the rectum. Mucin species
vary according to the presence of sulfate-reducing bacteria.
A higher sulfomucin proportion correlates with higher
quantities of Desulfobacter, Desulfobulbus, and Desulfoto-
maculum. Nevertheless, although mucin composition may
influence bacterial sulfate respiration in the normal human
colon, the absolute numbers of bacteria seem to be
unchanged.38
MUCIN AND ULCERATIVE COLITIS
Mucin Structure
In contrast to CD where thickening of the mucous layer
is observed, UC is associated with a paucity of intestinal
mucin corresponding to goblet cell depletion.15 O-glycans
normally account for 80% of the mucus mass and alterations
in O-glycans lead to a dysfunctional mucous barrier. Larsson
and colleagues recently demonstrated an aberrant glyco-
sylation profile of MUC2 in active UC, where upregulation
of sialyltransferase results in increased sialosyl-GalNAc-S/T
on MUC2, with smaller glycans produced. This strongly
correlated with disease activity. Patients in remission had
glycosylation patterns similar to healthy controls.18 An and
colleagues engineered mice lacking core 3-b1,3-N-acetylglu-
cosaminyltransferase, the enzyme required for the synthesis
of core 3-derived O-glycans. These mice displayed a reduc-
tion in Muc2 protein, increased intestinal permeability, and
an increased susceptibility to colitis and colorectal cancer
(CRC).23 It has also been shown that mice with epithelial
cell–specific deficiency of core-1–derived O-glycans develop
spontaneous colitis resembling UC, indicating a possible
causal role. Absence of core-1 O-glycan exposes a Tn antigen
that is detectable in the epithelium of some UC patients.
Loss of core-1 O-glycan and the presence of Tn antigen is
associated with somatic mutations in the gene encoding for
the galactosyltransferase-specific chaperone, Cosmc, which is
essential for core 1 glycosylation.39
As in CD, mucin sialylation is increased in UC.19
Although sulfate incorporation into MUC2 is reduced,
sulfated mucins are preferentially secreted, so the net
quantity of sulfated MUC2 is unchanged.17
Mucin Phenotype
MUC2 is the predominant secreted mucin in UC, as in
the healthy colon. In active UC, the quantity of MUC2
production and secretion is reduced, yet the percentage of
MUC2 in the mucus gel is unchanged.17 MUC1 expression
may be reduced; however, mRNA and protein expression may
be increased with severe disease.21 MUC17 expression is
reduced,26 MUC3 is unchanged, and MUC13 is increased in
active UC. MUC4 is similarly increased, especially when
associated with neoplasia.15 Aberrant expression of MUC5AC
is observed in UC, as in CD.40
108 | www.jcge.com
J Clin Gastroenterol  Volume 47, Number 2, February 2013
Genetic Factors
Genome-wide linkage studies have identified 49 sus-
ceptibility loci that confer a predisposition to CD.41 Homo-
zygotes and heterozygotes for an MUC3A allele with
altered 51-bp repeat units confer a significantly increased
risk of UC.42 This mutant MUC3A is underglycosylated
and undersulfated, rendering it vulnerable to degradation
by bacterial proteases. Interestingly, the chromosomal
locus 7q22 that encodes the MUC3A (as well as MUC3B,
MUC12, and MUC17) gene has been identified as a sus-
ceptibility locus for IBD.42 Allelic variants of MUC2 have
been investigated in the sera of UC patients; however, no
differences in allele length were observed.43 Moehle et al22
described a downregulation in MUC12 mRNA expression
and allelic polymorphisms in MUC4 and MUC13 in UC.
Microbial Factors
In contrast to CD and non-IBD controls, the major
mucolytic bacterium in UC is Ruminococcus torques.29
As mentioned, sulfation of mucin glycoproteins confers
resistance to bacterial enzymatic breakdown of the mucous
layer. However, some virulent bacteria secrete sulfatases
that remove the sulfate ester and thus render the mucin
molecule susceptible to degradation by bacterial glyco-
sidases. In UC, there is increased bacterial sulfatase activ-
ity, particularly in active disease. Sulfatase activity mirrors
disease activity.44
Immune Factors
Both cell-mediated and humoral immunity play a role
in the pathogenesis of UC. Patients have an array of auto-
antibodies, some of which are directed against colonocyte
antigens. Anti-S (soluble-mucin) and anti-M (membrane-
bound mucin) antibodies are present in the sera of UC
patients but not in patients with CD, infectious colitis, or in
healthy controls.27 The first colonocyte antigen to be char-
acterized was, in fact, MUC1. Anti-MUC1 antibodies, tar-
geting the tandem repeat domain of MUC1 core protein,
have been detected in the sera of UC patients.28 This
underscores the role of autoimmune mechanisms in disease
pathogenesis.
Nishida et al45 recently demonstrated that in Th1 and
Th2 mouse colitis models, Muc1 regulates a Th17-type
response. Th17 cytokines may stimulate Muc1 production,
and Muc1 in turn downregulates the Th17 response to
dampen inflammation. When this negative feedback loop is
interrupted, as observed in Muc/TCR double knockout
mice, Th17 driven colitis ensues.
Environmental Factors
Smoking is a powerful epidemiological factor in UC.
The protection conferred by nicotine seems to be mediated
mainly by IL-8, as well as IL-1b, IL-2, IL-10, and TNF-a.46
Transdermal nicotine in UC subjects does not affect mucin
gene transcription but has been associated with increased
colonic mucus.47
Neoplasia
In normal colonic mucosa, sulfomucins predominate
over sialomucins; yet in mucosa adjacent to and remote
from neoplasia in UC, the reverse is true. A predominance
of sialomucins has therefore been postulated as a marker of
premalignancy. Sialomucins associated with dysplasia and
carcinoma in UC are phenotypically different to those
found in normal mucosa.48
r 2013 Lippincott Williams & Wilkins
J Clin Gastroenterol  Volume 47, Number 2, February 2013
Others have found decreased O-acylated sialomucins
in both UC-associated and sporadic CRC. A similar
decrease in O-acylated sialic acid variants were observed in
dysplastic mucosa in UC. However, some evidence suggests
that these may be nonspecific changes related to inflam-
mation, rather than signs of premalignancy.49 These early,
contradictory works rely on outdated laboratory methods
with wide interlaboratory variability and must be consid-
ered in this light.
Recently, increased expression of MUC6 was observed
in UC-associated neoplasia compared with sporadic neo-
plasms.50 This suggests that gastric-type mucins could play
an important role in the initial step of UC-associated
tumorigenesis.
The most convincing body of evidence implicating
aberrant mucin expression in the pathogenesis of colitis-
associated neoplasia comes from murine models. IL-10 /
mice crossed to human MUC1-transgenic mice are a model
for intestinal inflammation and exhibit increased MUC1
expression and rapid progression to CRC.51 These data
suggest that MUC1 might act as an oncogene. Indeed,
elsewhere, the cytoplasmic domain of MUC1 has been
shown to interact with b-catenin (an integral component
of the Wnt signaling pathway involved in cellular pro-
liferation) or inhibit apoptosis, through various mecha-
nisms.52 Therefore, also, murine models with altered Muc2
develop spontaneous colitis-associated CRC. Velcich and
colleagues engineered Muc2 / mice that developed
aberrant intestinal crypt morphology and altered cell
maturation and migration. These mice frequently devel-
oped adenomas in the small intestine that progressed to
invasive adenocarcinoma and rectal tumors. This implies
that Muc2 is involved in the suppression of CRC.53 Further
studies have found that Muc2 deficiency results in carci-
nogenesis independently of deregulated Wnt signaling,
through unknown mechanisms.54
CELLULAR SIGNALING AND MUCIN
REGULATION IN IBD
The intestinal epithelium, being a highly secretory
organ, must constantly cope with the accumulation of
unfolded or misfolded proteins in the endoplasmic retic-
ulum (ER), also referred to as “ER stress.”55 The unfolded
protein response (UPR) is engaged in response to ER stress.
Increasingly, the UPR is recognized as having a key role in
the proper function of the intestinal epithelium. The
mechanisms by which the UPR acts include upregulation of
ER size, synthesis of proteins to assist folding (chaperones),
and in extreme cases, induction of apoptosis (Fig. 1).
Several studies have reported increased markers of ER
stress in ileal and colonic tissue from CD and UC subjects.
Kaser et al55 reported that genetic deletion of the UPR
transcription factor XPB1 causes a spontaneous colitis in
murine models. Furthermore, genetic variants of XBP1 are
associated with both CD and UC, suggesting a role of
defective UPR in IBD pathogenesis.
ARG2 is an ER protein involved in assisting proper
protein folding. Arg2 / (knockout) mice exhibit increased
ER stress within the intestinal epithelium.56 Furthermore,
these mice exhibit disrupted MUC2 synthesis and decreased
mucus production. This would suggest that the UPR pro-
tein ARG2 is directly involved in MUC2 assembly and that
ER stress can cause defective MUC2 production.
r 2013 Lippincott Williams & Wilkins
Mucin Expression in IBD
Endoplasmic reticulum
ERAD
Ribosome Proteosome
P
PERK UPR ATF-6
IRE-1
Supression of
protein synthesis
NFκB
Inflammation XPB-1 JNK
ER Biosynthesis
ARG-2 biosynthesis
Nucleus
(protein chaperone)
FIGURE 1. Nascent mucin polypeptides are translated directly
from the ribosome into the endoplasmic reticulum (ER). In the
absence of ER stress, the mucin protein (P) is glycosylated and
folded before the mucin molecule is transferred to the Golgi.
Malfolding leads to ER stress and activates a set of signaling
pathways, collectively termed the unfolded protein response
(UPR). Three UPR branches (IRE1, PERK, and ATF6) promote cell
survival by reducing misfolded protein levels. Misfolded proteins
are removed from the ER as proteosomes by retrotranslocation as
part of the ER-associated degradation (ERAD) system. UPR sig-
naling may also promote apoptotic cell death if ER stress is not
alleviated.
Muc2 / (knockout) mice develop a spontaneous
colitis and display compensatory production of gastric
MUC6.53 Heazlewood et al57 studied 2 strains of mice
(Winnie and Eeyore) with induced spontaneous single mis-
sense mutations in Muc2 oligomerization domains. These
mutant mice showed aberrant Muc2 biosynthesis, less
stored mucin in goblet cells, a diminished mucous barrier,
increased susceptibility to colitis, increased production of
Th1 and Th2 cytokines, and increased intestinal perme-
ability. A Muc2 non-glycosylated precursor accumulated,
leading to ER stress and ultimate goblet cell apoptosis.
These findings suggest that ER stress–related MUC2
depletion may have a role in the pathogenesis of UC in
humans.
It has recently been demonstrated that fatty acid
synthase (FAS), a key enzyme involved in lipogenesis, has a
central role in the regulation of Muc2. FAS facilitates
S-palmitoylation of Muc2 at its N terminus, thereby ena-
bling proper mucin secretion and function. FAS-deficient
mice have a defective mucous barrier, and diabetic mice
with lower FAS levels have a depleted mucous layer, which
is restored after insulin treatment.58
Autophagy refers to a related intracellular pathway
involving lysosome-dependent catabolism of proteins and
organelles for recycling. Polymorphisms in the presumptive
autophagy gene, ATG16L1, have been associated with
CD and a phenotypic impairment in the Paneth cell
granule exocytosis.59,60 The Paneth cell granules contain
antibacterial peptides and lysozyme. Hypomorphism for
ATG16L1 leads to lysozyme-deficient mucus. These data
demonstrate the effect of autophagy protein deficiency on
intestinal mucus, in a manner parallel but distinct from the
role of mucin on intestinal mucus.
www.jcge.com | 109
Boltin et al
CONCLUSIONS
Mucins determine the viscoelastic properties of the
mucous barrier in the GI tract. Acute and chronic inflam-
matory processes cause disequilibrium in the microenviron-
ment of the mucous barrier, involving altered commensal
microbes and defective innate and adaptive host immune
responses. Future therapies in IBD should aim to strengthen
the mucous barrier through upregulation/downregulation of
MUC genes, manipulation of posttranscriptional processing,
or targeting the mucin molecule itself. Further studies are
required to identify epitopes on the mucin molecule that
anchor microbes and could be potential targets for probiotic
or antibiotic drugs. The role of the UPR in IBD patho-
genesis must be further explored. Better understanding the
changes in mucin gene expression in IBD-associated neo-
plasia could have ramifications for early detection and
therapeutic interventions.
REFERENCES
1. Senapati S, Das S, Batra SK. Mucin-interacting proteins: from
function to therapeutics. Trends Biochem Sci. 2010;35:236–245.
2. Theodoropoulos G, Carraway KL. Molecular signaling in the
regulation of mucins. J Cell Biochem. 2007;102:1103–1116.
3. Andrianifahanana M, Moniaux N, Batra SK. Regulation of
mucin expression: mechanistic aspects and implications for
cancer and inflammatory diseases. Biochim Biophys Acta.
2006;1765:189–222.
4. Moncada DM, Kammanadiminti SJ, K Chadee. Mucin and
Toll-like receptors in host defense against intestinal parasites.
Trends Parasitol. 2003;19:305–311.
5. McAuley JL, Linden SK, Png CW, et al. MUC1 cell surface
mucin is a critical element of the mucosal barrier to infection.
J Clin Invest. 2007;117:2313–2324.
6. Knight PA, Brown JK, Pemberton AD. Innate immune
response mechanisms in the intestinal epithelium: potential
roles for mast cells and goblet cells in the expulsion of adult
Trichinella spiralis. Parasitology. 2008;135:655–670.
7. Hasnain SZ, Wang H, Ghia JE, et al. Mucin gene deficiency in
mice impairs host resistance to an enteric parasitic infection.
Gastroenterology. 2010;138:1763–1771.
8. Hasnain SZ, Evans CM, Roy M, et al. Muc5ac: a critical
component mediating the rejection of enteric nematodes. J Exp
Med. 2011;208:893–900.
9. Goldston AM, Powell RR, Koushik AB, et al. Exposure to
host ligands correlates with co-localization of Gal/GalNAc
lectin subunits in lipid rafts and PIP2 signaling in Entamoeba
histolytica. Eukaryot Cell. 2012;11:743–751.
10. Lidell ME, Moncada DM, Chadee K, et al. Entamoeba
histolytica cysteine proteases cleave the MUC2 mucin in its
C-terminal domain and dissolve the protective colonic
mucus gel. Proc Natl Acad Sci USA. 2006;103:9298–9303.
11. Podolsky DK, Gerken G, Eyking A, et al. Colitis-associated
variant of TLR2 causes impaired mucosal repair because of
TFF3 deficiency. Gastroenterology. 2009;137:209–220.
12. Ahmad R, Raina D, Trivedi V, et al. MUC1 oncoprotein
activates the IkappaB kinase beta complex and constitutive
NF-kappaB signalling. Nat Cell Biol. 2007;9:1419–1427.
13. Karlsson NG, Olson FJ, Jovall PA, et al. Identification of
transient glycosylation alterations of sialylated mucin oligo-
saccharides during infection by the rat intestinal parasite
Nippostrongylus brasiliensis. Biochem J. 2000;350:805–814.
14. Pullan RD, Thomas GA, Rhodes M, et al. Thickness of
adherent mucus gel on colonic mucosa in humans and its
relevance to colitis. Gut. 1994;35:353–359.
15. Myerscough N, Warren B, M Gough, et al. Expression of mucin
gene in ulcerative colitis. Biochem Soc Trans. 1995;23:536S.
16. Raouf AH, Tsai HH, Parker N, et al. Sulphation of colonic
mucin in ulcerative colitis and Crohn’s disease. Clin Sci.
1992;83:623–626.
110 | www.jcge.com
J Clin Gastroenterol  Volume 47, Number 2, February 2013
17. Van Klinken BJ, Van der Wal JW, Einerhand AW, et al.
Sulphation and secretion of the predominant secretory human
colonic mucin MUC2 in ulcerative colitis. Gut. 1999;44:
387–393.
18. Larsson JM, Karlsson H, Crespo JG, et al. Altered O-
glycosylation profile of MUC2 mucin occurs in active ulcer-
ative colitis and is associated with increased inflammation.
Inflamm Bowel Dis. 2011;17:2299–2307.
19. Parker N, Tsai HH, Ryder SD, et al. Increased rate of
sialylation of colonic mucin by cultured ulcerative colitis
mucosal explants. Digestion. 1995;56:52–56.
20. Buisine MP, Desreumaux P, Debailleul V, et al. Abnormalities
in mucin gene expression in Crohn’s disease. Inflamm Bowel
Dis. 1999;5:24–32.
21. Longman RJ, Poulsom R, Corfield AP, et al. Alterations in the
composition of the supramucosal defense barrier in relation to
disease severity of ulcerative colitis. J Histochem Cytochem.
2006;54:1335–1348.
22. Moehle C, Ackermann N, Langmann T, et al. Aberrant
intestinal expression and allelic variants of mucin genes
associated with inflammatory bowel disease. J Mol Med.
2006;84:1055–1066.
23. An G, Wei B, Xia B, et al. Increased susceptibility to colitis and
colorectal tumors in mice lacking core 3-derived O-glycans.
J Exp Med. 2007;204:1417–1429.
24. Kyo K, Muto T, Nagawa H, et al. Associations of distinct
variants of the intestinal mucin gene MUC3A with ulcerative
colitis and Crohn’s disease. J Hum Genet. 2001;46:5–20.
25. Buisine MP, Desreumaux P, Leteurtre E, et al. Mucin gene
expression in intestinal epithelial cells in Crohn’s disease. Gut.
2001;49:544–551.
26. Senapati S, Ho SB, Sharma P, et al. Expression of intestinal
MUC17 membrane-bound mucin in inflammatory and neo-
plastic diseases of the colon. J Clin Pathol. 2010;63:702–707.
27. Takaishi H, Ohara S, Hotta K, et al. Circulating autoanti-
bodies against purified colonic mucin in ulcerative colitis.
J Gastroenterol. 2000;35:20–27.
28. Hinoda Y, Nakagawa N, Nakamura H, et al. Detection of a
circulating antibody against a peptide epitope on a mucin core
protein, MUC1, in ulcerative colitis. Immunol Lett. 1993;35:
163–168.
29. Png CW, Lindén SK, Gilshenan KS, et al. Mucolytic bacteria
with increased prevalence in IBD mucosa augment in vitro
utilization of mucin by other bacteria. Am J Gastroenterol.
2010;105:2420–2428.
30. Prindiville M, Cantrell M, Gershwin ME. Characterization
and heterogeneity of monoclonal antibodies directed to
intestinal mucin derived from Crohn’s disease small bowel.
Hybridoma. 1991;10:269–280.
31. Kaneko Y, Nakamura T, Hayama M, et al. Altered expression
of CDX-2, PDX-1 and mucin core proteins in “Ulcer-
associated cell lineage (UACL)” in Crohn’s disease. J Mol
Histol. 2008;39:161–168.
32. Franke A, McGovern DP, Barrett JC, et al. Genome-wide
meta-analysis increases to 71 the number of confirmed Crohn’s
disease susceptibility loci. Nat Genet. 2010;42:1118–1125.
33. Satsangi J, Parkes M, Louis E. Two-stage genome-wide
search in inflammatory bowel disease: evidence for suscepti-
bility loci on chromosomes 3, 7 and 12. Nat Genet. 1996;14:
199–202.
34. Sabbah A, Chang TH, Harnack R, et al. Activation of innate
immune antiviral responses by Nod2. Nat Immunol.
2009;10:1073–1080.
35. Hoskins LC. Mucin glycoprotein degradation by mucin
oligosaccharide-degrading strains of human faecal bacteria.
Characterisation of saccharide cleavage products and their
potential role in nutritional support of larger faecal bacterial
populations. Microb Ecol Health Dis. 1992;5:193–207.
36. Johansson ME, Phillipson M, Petersson J, et al. The inner
of the two Muc2 mucin-dependent mucus layers in colon
is devoid of bacteria. Proc Natl Acad Sci USA. 2008;105:
15064–15069.
r 2013 Lippincott Williams & Wilkins
J Clin Gastroenterol  Volume 47, Number 2, February 2013
37. Johansson ME, Gustafsson JK, Sjöberg KE, et al. Bacteria
penetrate the inner mucus layer before inflammation in the
dextran sulfate colitis model. PLoS One. 2010;18:e12238.
38. Croix JA, Carbonero F, Nava GM, et al. On the relationship
between sialomucin and sulfomucin expression and hydro-
genotrophic microbes in the human colonic mucosa. PLoS
One. 2011;6:e24447.
39. Fu J, Wei B, Wen T, et al. Loss of intestinal core 1-derived O-
glycans causes spontaneous colitis in mice. J Clin Invest.
2011;121:1657–1666.
40. Forgue-Lafitte ME, Fabiani B, Levy PP, et al. Abnormal
expression of M1/MUC5AC mucin in distal colon of patients
with diverticulitis, ulcerative colitis and cancer. Int J Cancer.
2007;121:1543–1549.
41. McGovern DP, Gardet A, Törkvist L, et al. Genome-
wide association identifies multiple ulcerative colitis
susceptibility loci. Nat Genet. 2010;42:332–337.
42. Kyo K, Parkes M, Takei Y, et al. Association of ulcerative
colitis with rare VNTR alleles of the human intestinal mucin
gene, MUC3. Hum Mol Genet. 1999;8:307–311.
43. Swallow DM, Vinall LE, Gum JR, et al. Ulcerative colitis
is not associated with differences in MUC2 mucin allele length.
J Med Genet. 1999;36:859–860.
44. Tsai HH, Dwarakanath AD, Hart CA, et al. Increased faecal
mucin sulphatase activity in ulcerative colitis: a potential target
for treatment. Gut. 1995;36:570–576.
45. Nishida A, Lau CW, Zhang M, et al. The membrane-bound
mucin muc1 regulates T helper 17-cell responses and colitis
in mice. Gastroenterology. 2012;142:865–874.
46. Bhatti MA, Hodgson HJF. Nicotine down-regulates IL-8
production and tissue expression in inflammatory bowel
disease. Gastroenterology. 1997;112:A934.
47. Louvet B, Buisine MP, Desreumaux P, et al. Transdermal
nicotine decreases mucosal IL-8 expression but has no effect on
mucin gene expression in ulcerative colitis. Inflamm Bowel Dis.
1999;5:174–181.
48. Agawa S, Muto T, Morioka Y. Mucin abnormality of colonic
mucosa in ulcerative colitis associated with carcinoma and/or
dysplasia. Dis Colon Rectum. 1988;31:387–389.
r 2013 Lippincott Williams & Wilkins
Mucin Expression in IBD
49. Issaacson P, Attwood PRA. Failure to demonstrate specificity
of the morphological and histochemical changes in mucosa
adjacent to colonic carcinoma. J Clin Pathol. 1979;32:214–218.
50. Tatsumi N, Kushima R, Vieth M, et al. Cytokeratin 7/20 and
mucin core protein expression in ulcerative colitis-associated
colorectal neoplasms. Virchows Arch. 2006;448:756–762.
51. Beatty PL, Plevy SE, Sepulveda AR, et al. Cutting edge:
transgenic expression of human MUC1 in IL-10 / mice
accelerates inflammatory bowel disease and progression to
colon cancer. J Immunol. 2007;179:735–739.
52. Wei X, Xu H, Kufe D. Human MUC1 oncoprotein regulates
p53-responsive gene transcription in the genotoxic stress
response. Cancer Cell. 2005;7:167–178.
53. Velcich A, Yang W, Heyer J, et al. Colorectal cancer in mice
genetically deficient in the mucin Muc2. Science. 2002;295:
1726–1729.
54. Yang K, Popova NV, Yang WC, et al. Interaction of Muc2 and
Apc on Wnt signaling and in intestinal tumorigenesis: potential
role of chronic inflammation. Cancer Res. 2008;68:7313–7322.
55. Kaser A, Lee AH, Franke A, et al. XBP1 links ER stress to
intestinal inflammation and confers genetic risk for human
inflammatory bowel disease. Cell. 2008;134:743–756.
56. Zhao F, Edwards R, Dizon D, et al. Disruption of Paneth and
goblet cell homeostasis and increased endoplasmic reticulum
stress in Agr2 / mice. Dev Biol. 2010;338:270–279.
57. Heazlewood CK, Cook MC, Eri R, et al. Aberrant mucin
assembly in mice causes endoplasmic reticulum stress and
spontaneous inflammation resembling ulcerative colitis. PLoS
Med. 2008;5:e54.
58. Wei X, Yang Z, Rey FE, et al. Fatty acid synthase modulates
intestinal barrier function through palmitoylation of mucin 2.
Cell Host Microbe. 2012;11:140–152.
59. Cadwell K, Liu JY, Brown SL, et al. A key role for autophagy
and the autophagy gene Atg16l1 in mouse and human
intestinal Paneth cells. Nature. 2008;456:259–263.
60. Hampe J, Franke A, Rosenstiel P, et al. A genome-wide
association scan of nonsynonymous SNPs identifies a suscept-
ibility variant for Crohn disease in ATG16L1. Nat Genet.
2007;39:207–211.
www.jcge.com | 111