Review
Copyright ©2014 Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 28, 2014; 20(28): 9468-9475
Published online Jul 28, 2014. doi: 10.3748/wjg.v20.i28.9468
Ulcerative colitis as a polymicrobial infection characterized by sustained broken mucus barrier
Shui-Jiao Chen, Xiao-Wei Liu, Jian-Ping Liu, Xi-Yan Yang, Fang-Gen Lu
Shui-Jiao Chen, Xiao-Wei Liu, Jian-Ping Liu, Xi-Yan Yang, Fang-Gen Lu, Department of Gastroenterology, 2nd Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China
Author contributions: Chen SJ and Liu XW wrote the paper; Liu JP, Yang XY and Lu FG outlined the review; all authors approved the final version of the manuscript.
Supported by National Natural Science Foundation of China, No. 81270471
Correspondence to: Dr. Fang-Gen Lu, Department of Gastroenterology, 2nd Xiangya Hospital of Central South University, 139 Middle Renmin Road, Furong, Changsha 410011, Hunan Province, China. lufanggenyao@163.com
Telephone: +86-731-85295035 Fax: +86-731-88944818
Received: January 18, 2014
Revised: February 24, 2014
Accepted: April 30, 2014
Published online: July 28, 2014

Abstract

To reduce medication for patients with ulcerative colitis (UC), we need to establish the etiology of UC. The intestinal microbiota of patients with inflammatory bowel disease (IBD) has been shown to differ from that of healthy controls and abundant data indicate that it changes in both composition and localization. Small intestinal bacterial overgrowth is significantly higher in IBD patients compared with controls. Probiotics have been investigated for their capacity to reduce the severity of UC. The luminal surfaces of the gastrointestinal tract are covered by a mucus layer. This normally acts as a barrier that does not allow bacteria to reach the epithelial cells and thus limits the direct contact between the host and the bacteria. The mucus layer in the colon comprises an inner layer that is firmly adherent to the intestinal mucosa, and an outer layer that can be washed off with minimal rinsing. Some bacteria can dissolve the protective inner mucus layer. Defects in renewal and formation of the inner mucus layer allow bacteria to reach the epithelium and have implications for the causes of colitis. In this review, important elements of UC pathology are thought to be the intestinal bacteria, gut mucus, and the mucosa-associated immune system.

Key Words: Ulcerative colitis, Mucus, Infection, Bacteria, Etiology

Core tip: Long-term or even life-long medication bothers patients with ulcerative colitis (UC). Existing treatment ignores the cause of UC, so establishing the etiology of UC is the key to resolving this problem. UC can be viewed as a polymicrobial infection that is characterized by a sustained broken mucus barrier with subsequent bacterial migration toward the mucosa and proliferation of complex bacterial biofilms on the epithelial surface. Regulation of mucus secretion and viscosity, suppression of bacterial biofilms, probiotics and immunostimulation should be increasingly considered to treat UC.


Citation: Chen SJ, Liu XW, Liu JP, Yang XY, Lu FG. Ulcerative colitis as a polymicrobial infection characterized by sustained broken mucus barrier. World J Gastroenterol 2014; 20(28): 9468-9475
INTRODUCTION

Ulcerative colitis (UC) belongs to a subgroup of inflammatory bowel diseases (IBDs), is characterized as chronic inflammation, and has become a global health threat[1,2]. High disease-recurrence rates, long-term or even life-long medication bothers patients with UC[3-5]. Existing treatment ignores the cause of UC, and is unable to cure UC, which is why patients need long-term medication; therefore, establishing the etiology of UC is the key to resolving this problem. Important elements of IBD pathology are thought to be genetics, the intestinal microbiome, the gut mucosa, and the mucosa-associated immune system[6,7]. Studies using dextran sulfate sodium (DSS) models of colitis also suggest that the key contributors in disease pathogenesis include alteration in the mucosal barrier integrity and function[8,9]. The human gastrointestinal tract is a vast surface inhabited by a complex and diverse community of micro-organisms[10], and the intestinal mucus is an efficient system for protecting the epithelium from bacteria by promoting their clearance and separating them from the mucosal immune cells, thereby inhibiting inflammation and infection[11]. UC is an immune-mediated disorder that results from an abnormal interaction between colonic bacteria and mucosal immune cells in a genetically susceptible host[12]. In this review, UC is thought to be a polymicrobial infection characterized by sustained broken mucus barrier.

ROLE OF MUCUS AND BACTERIA IN UC

The gastrointestinal tract is covered by a layer of mucus that protects the epithelium from luminal antigens and provides lubrication to advance the bolus[13]. A well-developed mucus barrier and not the epithelial cell layer is the first line of defense against a variety of enteric pathogens[14,15]. Leukocytes migrate into and patrol within the mucus layer, executing the surveillance function without any collateral damage. The sticky outer mucus surface offers the opportunity for probiotic strains to grow and build protective interlaced layers, preventing bacterial accumulation and microcolony formation on the colorectal surface[16,17]. Before bacteria can adhere and invade the mucosa, they must first traverse the mucus barrier[17]. The inflammation takes place only after the mucus barrier is broken and the defense is overwhelmed. UC is caused by a weakening in gut barrier, mainly due to increased infiltration of gut bacteria and the resultant recruitment of neutrophils and formation of crypt abscess[18]. Understanding the role of mucus and bacteria and their interaction will help us to establish the etiology of UC more clearly (Table 1).

Table 1 Interaction of mucus and bacteria.
Effect of mucus on bacteriaEffect of bacteria on mucus
Limits the direct contact between the host and bacteriaMaintenance of the mucus layer is stimulated by bacterial fermentation products
Serves as a source of nutrients for bacterial growthMediate the expression of MUC2
Contributes to the selection of the species-specific colon floraDissolve the protective inner mucus layer
Contains several proteins that limit bacterial growth and penetration
Role of mucus in UC

Mucus production and secretion is a continuously ongoing process with a renewal of the inner protective mucus in the distal colon within an hour. Rapid renewal of the mucus barrier prevents microbial contact with the epithelial cells. Alteration of the adherent mucus barrier is a predisposing factor for early onset of epithelial cell damage in DSS colitis[19]. Sulfation of the mucins is significantly reduced in UC patients, and suggest that colonic mucins plays an important role in maintaining the normal physiological function of the colon and the possible role of mucus in the pathogenesis of UC[20]. Phosphatidylcholine (PC) accounts for > 70% of total phospholipids within the intestinal mucus layer, and the mucus PC content is reduced by about 70% in UC[21]. MUC2 is the major mucin in the large intestine[22,23], which is secreted by goblet cells, and the expression of it correlated with the activity of disease and the extent of the inflammatory process in the large intestine[24]. Individuals with UC have decreased numbers of goblet cells and reduced mucus thickness at presentation[25], and goblet cell abnormalities play an etiological role in UC. DSS models of colitis were characterized by depletion of goblet cell and adherent mucin[19]. In UC, the cooperation of aberrant expression of Hes1 and the disappearance of caudal type homeobox 2 (CDX2) caused Hath1 suppression, resulting in goblet cell depletion[26], and the present study suggests that Hes1 is essential for Hath1 gene suppression via Notch signaling. Gersemann et al[27] also pointed that in UC, the protective mucus layer, acting as a physical and chemical barrier between the gut epithelium and the luminal microbes, is thinner and in part denuded as compared to controls, and this could be caused by a missing induction of the goblet cell differentiation factors Hath1 and KLF4, leading to immature goblet cells. This goblet cell differentiation in UC can lead to defects in renewal and formation of the inner mucus layer and may enable the luminal microbes to invade the mucosa and trigger the inflammation[16,27,28]. So we can easily reach the conclusion that understanding the regulation of goblet cell differentiation and the intestinal mucus turnover and renewal of the inner protective mucus layer is important for novel ways to improve treatment of UC[16,21].

Role of bacteria in UC

UC is a multifactorial disease that is dependent on host genetics, environment, immune response and intestinal microbiota. The dysregulation of the gut microbiota plays an important role in the pathogenesis of UC[29]. The immunoregulatory function of the intestinal microbiota consists of priming the mucosal immune system and maintenance of intestinal epithelial homeostasis. Epithelial barrier dysfunction brings about increased bacterial translocation through the lamina propria[30,31]. Ineffective bacterial clearance leads to excessive Toll-like receptor (TLR) stimulation, secretion of proinflammatory cytokines and activation of innate and T-cell-mediated immune responses. TLR-2 can bind a wide range of ligands, including lipoteichoic acid from Gram-positive bacteria, bacterial lipopeptides and glycolipids, and fungal β glucan (zymosan). TLR-4 can bind lipopolysaccharide from Gram-negative bacteria. Flagellin has innate qualities through its repetitive structures that are able to bind TLR-5, and also is a polypeptide that is internalized, processed and presented by professional antigen-presenting cells (APCs). Thus, the earliest phases of an immune response are dependent upon the recognition and interpretation of the antigenic composition of the milieu by T cells and APCs as revealed by innate and adaptive immune responses. TLR-9 is able to recognize bacterial DNA[32-34], and the stimulation of TLR-9 causes activation of nuclear factor-κB signaling, and leads to immune response and mucosal inflammation. These features could help to explain the mechanism of UC.

Defects in renewal and formation of the inner mucus layer allow bacteria to reach the epithelium and have implications for the causes of colitis[28]. Neutrophils and mononuclear cells infiltrate the lamina propria and activate nuclear factor-κB translocation, which in turn increases proinflammatory cytokines such as interleukin (IL)-1β, IL-6 and tumor necrosis factor-α, and inhibits the production of anti-inflammatory cytokines such as IL-10[35]. Fusobacterium varium (F. varium) was present in the colonic mucosa of a high proportion (84%) of UC patients[36] and contribute to the clinical activity in UC[37]. L. crispatus CCTCC M206119 strain is involved in exacerbation of intestinal inflammation in DSS-colitis mice, and may interact directly with colonic epithelial cells or lamina propria mononuclear cells after disruption of the mucosal barrier and balance of gut flora by DSS administration. Campylobacter spp.[38], Escherichia coli[39-41], Enterohepatic Helicobacter[42,43], and Bacteroides ovatus[44] are also responsible for the induction of intestinal inflammation.

However, not all the bacteria promote inflammation; Pediococcus acidilactici[45], Lactobacillus spp.[45], and Bacteroides spp.[46] show a variety of beneficial immunomodulatory effects in UC. Their products, rather than live bacteria, may be capable of inducing immunoregulatory effects, and may restore the dysregulated functions of immune cells[47]. Some recent studies have demonstrated that TLR signaling in intestinal sites can also inhibit inflammatory responses and maintain colonic homeostasis[48,49].

Effect of mucus layer on bacteria

The mammalian gastrointestinal tract harbors a vast microbial ecosystem, known as the microbiota. Gut microbiota includes around 1000 different species and > 15000 different strains of bacteria, for a total weight of about 1 kg. The luminal surfaces of the gastrointestinal tract are covered by a mucus layer composed mainly of mucins, which are high-molecular-weight glycoproteins characterized by extended serine, threonine, and proline-rich domains in the protein core[50]. This layer is a biochemically complex medium, rich in carbohydrates, antimicrobial peptides and other proteins, as well as lipids and electrolytes[51]. The inner mucus layer normally acts as a barrier that does not allow bacteria to reach the epithelial cells and thus limits the direct contact between the host and bacteria[52]. The mucus layer covering the gastrointestinal tract also has been reported to serve as a source of nutrients for bacterial growth. Thus, its presence influences intestinal colonization by attracting bacteria that have the ability to survive and multiply within the mucus layer[53,54]. We have also found that the numerous O-glycans on the MUC2 mucin serve as nutrients for the bacteria as well as attachment sites, and as such, probably contribute to the selection of the species-specific colon flora[44]. Overproduction of MUC2 may alter adherence and invasion of Shigella dysenteriae into human colonic epithelial cells. At the same time, the mucus also contains several proteins that limit bacterial growth and penetration, such as the antibacterial proteins and IgA[10,20]. These are important for the assembly and stability of the microbiota.

Effect of bacteria on mucus

The mucus barrier, however, can be compromised by environmental or genetic factors as well as specific pathogens such as Serpulina, Fusobacterium, Enterobacteriaceae, or Gardnerella. These bacteria can specifically form adherent biofilms on the epithelial surface, compromising the mucus barrier and allowing migration of other indigenous bacteria into the mucosa. The commensal bacteria in the colon live and thrive in the outer loose mucus layer, and can dissolve this layer[55]. Nevertheless, the association of the microbiota with the mucus is not well understood and requires further investigation.

The importance of bacterial exposure to produce a functional mucus barrier is demonstrated by germ-free animals in which the inner mucus layer is thin[56], but can be restored by exposure to bacterial components[56]. Maintenance of the mucus layer is also known to be stimulated by bacterial fermentation products[57]. In conclusion, the bacteria can influence mucus production[56]. Proteins secreted by probiotic bacteria of antimicrobial substances can enhance the mucosal barrier function and compete with enteropathogens for adhesion sites[58,59]. The composition of short-chain fatty acids in the intestine is determined by the composition of the microbiota, and butyrate can mediate MUC2 mRNA via activator protein-1 and acetylation/methylation of histones at the MUC2 promoter. The microbiota can also mediate MUC2 mRNA[58], and MUC2 can potentially be modulated in several other ways either during infection, such as at the level of gene expression, or even at the level of secretion into the intestinal lumen. Each regulatory step may influence the biological function of MUC2, which in turn influences how the host responds to enteric pathogens[16]. MUC2 is reportedly overexpressed in response to bacterial components, such as lipopolysaccharide or lipoteichoic acid, in cultured intestinal or airway epithelial cells and also bladder epithelial cells[13,60].

Bacteria can also dissolve the protective inner mucus layer, potentially triggering colitis. MUC2 is the major colonic secretory mucin. We found that bacteria can produce proteases capable of dissolving the inner protective mucus layer by specific cleavages in the MUC2 mucin and that this cleavage can be modulated by site-specific O-glycosylation. However, because of O-glycosylation, the mucin domains are highly resistant to proteases and are not expected to be cleaved by proteases[52]. However, MUC2 glycosylation can still be metabolized by intestinal commensal or pathogenic bacteria, serving as an energy source, suggesting a role in intestinal microbiota selection[20,61]. The 980-amino-acid-long C-terminal part of MUC2 has two cleavage sites. One is localized to the NR2QA sequence within the VWD4 domain where the cleavage site is surrounded by numerous cysteines that are involved in disulfide bond formation. The second cleavage site is localized prior to the first cysteine in the MUC2 C-terminal VWD4 domain. The enzyme secreted by Entamoeba histolytica can dissolve the guanidinium-chloride-insoluble mucus gel that we now know is the major constituent of the inner firm mucus layer[10]. Porphyromonas gingivalis also secretes a protease as an active enzyme to cleave MUC2, and this enzyme was isolated and identified as Arg-gingipain B. Citrobacter rodentium colonizes the outer mucus layer in high numbers, lacks a functional flagellum and is thus non-motile, and therefore likely utilizes specific mucinases or glycosidases to digest mucin in order to overcome the mucus barrier[16,20].

CHANGES OF BACTERIAS IN UC

The intestinal microbiota of IBD patients has been shown to differ from that of healthy controls; abundant data indicate that the microbiota in IBD patients changes in both composition and localization[62,63], and the changes are not a product of colitis, which has previously been reported[64]. These support an integrative view of microbial ecology relevant to IBD[65], and butyrate-producing bacteria could be important to gut homeostasis[66,67]. The diversity of fecal microbiota is significantly lower in UC patients. Bacteroides[68], Clostridium subcluster XIVab[66], Lactobacillus spp.[67], Akkermansia muciniphila[69] and Clostridium leptum[70] are decreased in UC patients, and the number of Enterococcus[68], Escherichia coli[71], Actinobacteria[72], Proteobacteria[73] and Campylobacter ureolyticus[73] are higher in UC patients than in healthy subjects. Sulfate-reducing bacterium levels are also raised in UC[74], and are crucial for induction of DSS colitis in mice. Some research has proposed that F. varium might be one of the elusive pathogenic factors in UC[6]. Data also showed that the amount and composition of bacteria clearly differed between the mucus layers in animals not treated with DSS, with significantly higher loads of bacteria in the outer mucus layer[75], and Lactobacillus crispatus CCTCC M206119 strain is involved in exacerbation of intestinal inflammation in DSS-colitis mice[76]. Recently, we also found that small intestinal bacterial overgrowth was significantly higher in IBD patients as compared to controls[35]. Despite the requirement of commensal bacteria for normal intestinal function, an abnormal host response to commensal bacteria has been implicated as a crucial factor in the pathogenesis of IBD[77,78]. Recent research has shown that some commensal and pathogenic bacterias are closely related to UC, but it is difficult to draw a definitive conclusion in evaluating the role of microflora in pathogenesis of UC, and to find specific micro-organisms associated with the pathogenesis of UC.

USE OF PROBIOTICS IN UC

Bacteria are closely related to UC, and recently some studies have investigated the use of probiotics in UC[47,79,80]. Probiotics contain viable organisms; sufficient amounts of which reach the intestine in an active state, thus exerting positive health effects[81]. Their mechanisms of action are still unclear, but several have been postulated to contribute to the anti-inflammatory effect of probiotics in the gut, including competitive exclusion of pathogens. Probiotics may potentially alter the intestinal microbiome exogenously or provide an option to deliver microbial metabolic products to alter the chronicity of intestinal mucosal inflammation[82]. Bifidobacteria and lactobacilli produce harmful substances for Gram-positive and Gram-negative bacteria, and they compete with pathogens (i.e., Clostridium, Bacteriodetes, Staphylococcus, and Enterobacter) for cell adhesion[83,84]. Production of antimicrobial agents (e.g., IgA) and organic acids, modulation of lymphocyte and dendritic cell function[85,86], enhancement of the epithelial barrier function, modulation of the membrane permeability and mucosal immune system, and keeping pathogens away from the intestinal mucosal surface are also included. Probiotics have been investigated for their capacity to reduce the severity of UC (Table 2). The efficacy of VSL#3 (Bifidobacterium breve, Bifidobacterium infantis, Bifidobacterium longum, Lactobacillus paracasei, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus bulgaricus, and Streptococcus thermophilus) in UC patients has also been demonstrated[94-96]. Also, some natural anti-inflammatory effects have recently been shown for Lactobacillus salivarius, L. plantarum, Lactobacillus casei Shirota, Lactobacillus reuteri and Bifidobacterium based on experimental colitis models[76,97-99].

Table 2 Probiotics have undergone investigation for their capacity to reduce the severity of ulcerative colitis.
ProbioticsMethodConclusion
B. infantis 35624[87]Oral administration of B. infantis 35624 for 6-8 wk is taken by patients with ulcerative colitisThis microbe can reduce systemic pro-inflammatory biomarkers in UC
L. reuteri ATCC 55730[88]Mild to moderate UC were received an enema solution containing 10 (10) CFU of L. reuteri ATCC 55730 for 8 wk, in addition to oral mesalazineIn children with active distal ulcerative colitis, rectal infusion of L. reuteri is effective in improving mucosal inflammation and changing mucosal expression levels of some cytokines involved in the mechanisms of inflammatory bowel disease
B. breve strain[89]Mild to moderate UC ingested 1 g of the probiotic powder [10 (9) CFU/g] three times a day, and 5.5 g of GOS once a day for one yearAdministration of live B. breve strain Yakult and GOS can improve the clinical condition of patients with UC
L. delbruekii and L. fermentum[90]Mild to moderate UC were treated with sulfasalazine 2400 mg/d with a probiotic preparation (which contained powder with 10 (9) CFU of L. delbruekii and L. fermentum, for eight consecutive weeksOral supplementation with probiotics could be helpful in maintaining remission and preventing relapse of UC
L. casei DG[91]Mild left-sided UC were received oral 5-ASA and rectal L. casei DGManipulation of mucosal microbiota by L. casei DG and its effects on the mucosal immune system seem to be required to mediate the beneficial activities of probiotics in UC patients
EcN[92]Moderate distal UC were randomly assigned to treatment with either 40, 20, or 10 mL enemas (n = 24, 23, 23) containing 10 (8) EcN/mL (n = 20). The study medication was taken once daily for 2, 4, 8 wkEcN is a well tolerated treatment alternative in moderate distal UC
B. longum[93]The probiotic group ingested one daily capsule consisting of B. longum 2 × 10 (9) CFUPatients with UC on probiotic therapy experienced greater quality-of-life changes than before
CONCLUSION

UC is mainly due to increased infiltration of gut bacteria and the resultant recruitment of neutrophils and formation of crypt abscess[18], and can be viewed as a polymicrobial infection that is characterized by a sustained broken mucus barrier with subsequent bacterial migration toward the mucosa and proliferation of complex bacterial biofilms on the epithelial surface. Regulation of the mucus secretion and viscosity, suppression of bacterial biofilms, probiotics and immunostimulation should be increasingly considered to treat UC and evaluated in the future[17].

Footnotes

P- Reviewers: Day AS, Nakase H, Sipos F S- Editor: Ma YJ L- Editor: O'Neill M E- Editor: Wang CH

References
1.  Ooi CJ, Fock KM, Makharia GK, Goh KL, Ling KL, Hilmi I, Lim WC, Kelvin T, Gibson PR, Gearry RB. The Asia-Pacific consensus on ulcerative colitis. J Gastroenterol Hepatol. 2010;25:453-468.  [PubMed]  [DOI]
2.  Sood A, Midha V. Epidemiology of inflammatory bowel disease in Asia. Indian J Gastroenterol. 2007;26:285-289.  [PubMed]  [DOI]
3.  Kannan N, Guruvayoorappan C. Protective effect of Bauhinia tomentosa on acetic acid induced ulcerative colitis by regulating antioxidant and inflammatory mediators. Int Immunopharmacol. 2013;16:57-66.  [PubMed]  [DOI]
4.  Criscuoli V, Modesto I, Orlando A, Cottone M. Mesalazine for the treatment of inflammatory bowel disease. Expert Opin Pharmacother. 2013;14:1669-1678.  [PubMed]  [DOI]
5.  Kane SV. Systematic review: adherence issues in the treatment of ulcerative colitis. Aliment Pharmacol Ther. 2006;23:577-585.  [PubMed]  [DOI]
6.  Kellermayer R. Genetic drift. “Omics”as the filtering gateway between environment and phenotype: The inflammatory bowel diseases example. Am J Med Genet A. 2010;152A:3022-3025.  [PubMed]  [DOI]
7.  Packey CD, Sartor RB. Interplay of commensal and pathogenic bacteria, genetic mutations, and immunoregulatory defects in the pathogenesis of inflammatory bowel diseases. J Intern Med. 2008;263:597-606.  [PubMed]  [DOI]
8.  Baumgart DC, Sandborn WJ. Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet. 2007;369:1641-1657.  [PubMed]  [DOI]
9.  Hendrickson BA, Gokhale R, Cho JH. Clinical aspects and pathophysiology of inflammatory bowel disease. Clin Microbiol Rev. 2002;15:79-94.  [PubMed]  [DOI]
10.  Johansson ME, Larsson JM, Hansson GC. The two mucus layers of colon are organized by the MUC2 mucin, whereas the outer layer is a legislator of host-microbial interactions. Proc Natl Acad Sci USA. 2011;108 Suppl 1:4659-4665.  [PubMed]  [DOI]
11.  Fu J, Wei B, Wen T, Johansson ME, Liu X, Bradford E, Thomsson KA, McGee S, Mansour L, Tong M. Loss of intestinal core 1-derived O-glycans causes spontaneous colitis in mice. J Clin Invest. 2011;121:1657-1666.  [PubMed]  [DOI]
12.  Hansson GC. Role of mucus layers in gut infection and inflammation. Curr Opin Microbiol. 2012;15:57-62.  [PubMed]  [DOI]
13.  Kim DY, Takeuchi K, Ishinaga H, Kishioka C, Suzuki S, Basbaum C, Majima Y. Roxithromycin suppresses mucin gene expression in epithelial cells. Pharmacology. 2004;72:6-11.  [PubMed]  [DOI]
14.  Dharmani P, Srivastava V, Kissoon-Singh V, Chadee K. Role of intestinal mucins in innate host defense mechanisms against pathogens. J Innate Immun. 2009;1:123-135.  [PubMed]  [DOI]
15.  Lindén SK, Florin TH, McGuckin MA. Mucin dynamics in intestinal bacterial infection. PLoS One. 2008;3:e3952.  [PubMed]  [DOI]
16.  Bergstrom KS, Kissoon-Singh V, Gibson DL, Ma C, Montero M, Sham HP, Ryz N, Huang T, Velcich A, Finlay BB. Muc2 protects against lethal infectious colitis by disassociating pathogenic and commensal bacteria from the colonic mucosa. PLoS Pathog. 2010;6:e1000902.  [PubMed]  [DOI]
17.  Swidsinski A, Loening-Baucke V, Herber A. Mucosal flora in Crohn’s disease and ulcerative colitis - an overview. J Physiol Pharmacol. 2009;60 Suppl 6:61-71.  [PubMed]  [DOI]
18.  Qin X. Etiology of inflammatory bowel disease: a unified hypothesis. World J Gastroenterol. 2012;18:1708-1722.  [PubMed]  [DOI]
19.  Dharmani P, Leung P, Chadee K. Tumor necrosis factor-α and Muc2 mucin play major roles in disease onset and progression in dextran sodium sulphate-induced colitis. PLoS One. 2011;6:e25058.  [PubMed]  [DOI]
20.  Kawashima H. Roles of the gel-forming MUC2 mucin and its O-glycosylation in the protection against colitis and colorectal cancer. Biol Pharm Bull. 2012;35:1637-1641.  [PubMed]  [DOI]
21.  Stremmel W. [Mucosal protection by phosphatidylcholine as new therapeutic concept in ulcerative colitis]. Z Gastroenterol. 2013;51:384-389.  [PubMed]  [DOI]
22.  Kim YS, Ho SB. Intestinal goblet cells and mucins in health and disease: recent insights and progress. Curr Gastroenterol Rep. 2010;12:319-330.  [PubMed]  [DOI]
23.  Shirazi T, Longman RJ, Corfield AP, Probert CS. Mucins and inflammatory bowel disease. Postgrad Med J. 2000;76:473-478.  [PubMed]  [DOI]
24.  Dorofeyev AE, Vasilenko IV, Rassokhina OA, Kondratiuk RB. Mucosal barrier in ulcerative colitis and Crohn’s disease. Gastroenterol Res Pract. 2013;2013:431231.  [PubMed]  [DOI]
25.  Gersemann M, Wehkamp J, Stange EF. Innate immune dysfunction in inflammatory bowel disease. J Intern Med. 2012;271:421-428.  [PubMed]  [DOI]
26.  Zheng X, Tsuchiya K, Okamoto R, Iwasaki M, Kano Y, Sakamoto N, Nakamura T, Watanabe M. Suppression of hath1 gene expression directly regulated by hes1 via notch signaling is associated with goblet cell depletion in ulcerative colitis. Inflamm Bowel Dis. 2011;17:2251-2260.  [PubMed]  [DOI]
27.  Gersemann M, Stange EF, Wehkamp J. From intestinal stem cells to inflammatory bowel diseases. World J Gastroenterol. 2011;17:3198-3203.  [PubMed]  [DOI]
28.  Johansson ME. Fast renewal of the distal colonic mucus layers by the surface goblet cells as measured by in vivo labeling of mucin glycoproteins. PLoS One. 2012;7:e41009.  [PubMed]  [DOI]
29.  Håkansson A, Tormo-Badia N, Baridi A, Xu J, Molin G, Hagslätt ML, Karlsson C, Jeppsson B, Cilio CM, Ahrné S. Immunological alteration and changes of gut microbiota after dextran sulfate sodium (DSS) administration in mice. Clin Exp Med. 2014;Epub ahead of print.  [PubMed]  [DOI]
30.  Stremmel W, Gauss A. Lecithin as a therapeutic agent in ulcerative colitis. Dig Dis. 2013;31:388-390.  [PubMed]  [DOI]
31.  Ohkusa T, Yoshida T, Sato N, Watanabe S, Tajiri H, Okayasu I. Commensal bacteria can enter colonic epithelial cells and induce proinflammatory cytokine secretion: a possible pathogenic mechanism of ulcerative colitis. J Med Microbiol. 2009;58:535-545.  [PubMed]  [DOI]
32.  Hotte NS, Salim SY, Tso RH, Albert EJ, Bach P, Walker J, Dieleman LA, Fedorak RN, Madsen KL. Patients with inflammatory bowel disease exhibit dysregulated responses to microbial DNA. PLoS One. 2012;7:e37932.  [PubMed]  [DOI]
33.  Lee J, Mo JH, Katakura K, Alkalay I, Rucker AN, Liu YT, Lee HK, Shen C, Cojocaru G, Shenouda S. Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells. Nat Cell Biol. 2006;8:1327-1336.  [PubMed]  [DOI]
34.  Jijon H, Backer J, Diaz H, Yeung H, Thiel D, McKaigney C, De Simone C, Madsen K. DNA from probiotic bacteria modulates murine and human epithelial and immune function. Gastroenterology. 2004;126:1358-1373.  [PubMed]  [DOI]
35.  Rana SV, Sharma S, Malik A, Kaur J, Prasad KK, Sinha SK, Singh K. Small intestinal bacterial overgrowth and orocecal transit time in patients of inflammatory bowel disease. Dig Dis Sci. 2013;58:2594-2598.  [PubMed]  [DOI]
36.  Ohkusa T, Sato N, Ogihara T, Morita K, Ogawa M, Okayasu I. Fusobacterium varium localized in the colonic mucosa of patients with ulcerative colitis stimulates species-specific antibody. J Gastroenterol Hepatol. 2002;17:849-853.  [PubMed]  [DOI]
37.  Koido S, Ohkusa T, Kajiura T, Shinozaki J, Suzuki M, Saito K, Takakura K, Tsukinaga S, Odahara S, Yukawa T. Long-term alteration of intestinal microbiota in patients with ulcerative colitis by antibiotic combination therapy. PLoS One. 2014;9:e86702.  [PubMed]  [DOI]
38.  Mukhopadhya I, Thomson JM, Hansen R, Berry SH, El-Omar EM, Hold GL. Detection of Campylobacter concisus and other Campylobacter species in colonic biopsies from adults with ulcerative colitis. PLoS One. 2011;6:e21490.  [PubMed]  [DOI]
39.  Kalischuk LD, Inglis GD, Buret AG. Campylobacter jejuni induces transcellular translocation of commensal bacteria via lipid rafts. Gut Pathog. 2009;1:2.  [PubMed]  [DOI]
40.  Lamb-Rosteski JM, Kalischuk LD, Inglis GD, Buret AG. Epidermal growth factor inhibits Campylobacter jejuni-induced claudin-4 disruption, loss of epithelial barrier function, and Escherichia coli translocation. Infect Immun. 2008;76:3390-3398.  [PubMed]  [DOI]
41.  Sepehri S, Khafipour E, Bernstein CN, Coombes BK, Pilar AV, Karmali M, Ziebell K, Krause DO. Characterization of Escherichia coli isolated from gut biopsies of newly diagnosed patients with inflammatory bowel disease. Inflamm Bowel Dis. 2011;17:1451-1463.  [PubMed]  [DOI]
42.  Bohr UR, Glasbrenner B, Primus A, Zagoura A, Wex T, Malfertheiner P. Identification of enterohepatic Helicobacter species in patients suffering from inflammatory bowel disease. J Clin Microbiol. 2004;42:2766-2768.  [PubMed]  [DOI]
43.  Thomson JM, Hansen R, Berry SH, Hope ME, Murray GI, Mukhopadhya I, McLean MH, Shen Z, Fox JG, El-Omar E. Enterohepatic helicobacter in ulcerative colitis: potential pathogenic entities? PLoS One. 2011;6:e17184.  [PubMed]  [DOI]
44.  Saitoh S, Noda S, Aiba Y, Takagi A, Sakamoto M, Benno Y, Koga Y. Bacteroides ovatus as the predominant commensal intestinal microbe causing a systemic antibody response in inflammatory bowel disease. Clin Diagn Lab Immunol. 2002;9:54-59.  [PubMed]  [DOI]
45.  Bullock NR, Booth JC, Gibson GR. Comparative composition of bacteria in the human intestinal microflora during remission and active ulcerative colitis. Curr Issues Intest Microbiol. 2004;5:59-64.  [PubMed]  [DOI]
46.  Noor SO, Ridgway K, Scovell L, Kemsley EK, Lund EK, Jamieson C, Johnson IT, Narbad A. Ulcerative colitis and irritable bowel patients exhibit distinct abnormalities of the gut microbiota. BMC Gastroenterol. 2010;10:134.  [PubMed]  [DOI]
47.  Mann ER, You J, Horneffer-van der Sluis V, Bernardo D, Omar Al-Hassi H, Landy J, Peake ST, Thomas LV, Tee CT, Lee GH. Dysregulated circulating dendritic cell function in ulcerative colitis is partially restored by probiotic strain Lactobacillus casei Shirota. Mediators Inflamm. 2013;2013:573576.  [PubMed]  [DOI]
48.  Rachmilewitz D, Katakura K, Karmeli F, Hayashi T, Reinus C, Rudensky B, Akira S, Takeda K, Lee J, Takabayashi K. Toll-like receptor 9 signaling mediates the anti-inflammatory effects of probiotics in murine experimental colitis. Gastroenterology. 2004;126:520-528.  [PubMed]  [DOI]
49.  Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell. 2004;118:229-241.  [PubMed]  [DOI]
50.  Liévin-Le Moal V, Servin AL. The front line of enteric host defense against unwelcome intrusion of harmful microorganisms: mucins, antimicrobial peptides, and microbiota. Clin Microbiol Rev. 2006;19:315-337.  [PubMed]  [DOI]
51.  Johansson ME, Thomsson KA, Hansson GC. Proteomic analyses of the two mucus layers of the colon barrier reveal that their main component, the Muc2 mucin, is strongly bound to the Fcgbp protein. J Proteome Res. 2009;8:3549-3557.  [PubMed]  [DOI]
52.  van der Post S, Subramani DB, Bäckström M, Johansson ME, Vester-Christensen MB, Mandel U, Bennett EP, Clausen H, Dahlén G, Sroka A. Site-specific O-glycosylation on the MUC2 mucin protein inhibits cleavage by the Porphyromonas gingivalis secreted cysteine protease (RgpB). J Biol Chem. 2013;288:14636-14646.  [PubMed]  [DOI]
53.  Collado MC, Derrien M, Isolauri E, de Vos WM, Salminen S. Intestinal integrity and Akkermansia muciniphila, a mucin-degrading member of the intestinal microbiota present in infants, adults, and the elderly. Appl Environ Microbiol. 2007;73:7767-7770.  [PubMed]  [DOI]
54.  Sonnenburg JL, Angenent LT, Gordon JI. Getting a grip on things: how do communities of bacterial symbionts become established in our intestine? Nat Immunol. 2004;5:569-573.  [PubMed]  [DOI]
55.  Johansson ME, Phillipson M, Petersson J, Velcich A, Holm L, Hansson GC. 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.  [PubMed]  [DOI]
56.  Petersson J, Schreiber O, Hansson GC, Gendler SJ, Velcich A, Lundberg JO, Roos S, Holm L, Phillipson M. Importance and regulation of the colonic mucus barrier in a mouse model of colitis. Am J Physiol Gastrointest Liver Physiol. 2011;300:G327-G333.  [PubMed]  [DOI]
57.  Gaudier E, Rival M, Buisine MP, Robineau I, Hoebler C. Butyrate enemas upregulate Muc genes expression but decrease adherent mucus thickness in mice colon. Physiol Res. 2009;58:111-119.  [PubMed]  [DOI]
58.  Burger-van Paassen N, Vincent A, Puiman PJ, van der Sluis M, Bouma J, Boehm G, van Goudoever JB, van Seuningen I, Renes IB. The regulation of intestinal mucin MUC2 expression by short-chain fatty acids: implications for epithelial protection. Biochem J. 2009;420:211-219.  [PubMed]  [DOI]
59.  Sánchez B, Urdaci MC, Margolles A. Extracellular proteins secreted by probiotic bacteria as mediators of effects that promote mucosa-bacteria interactions. Microbiology. 2010;156:3232-3242.  [PubMed]  [DOI]
60.  Zen Y, Harada K, Sasaki M, Tsuneyama K, Katayanagi K, Yamamoto Y, Nakanuma Y. Lipopolysaccharide induces overexpression of MUC2 and MUC5AC in cultured biliary epithelial cells: possible key phenomenon of hepatolithiasis. Am J Pathol. 2002;161:1475-1484.  [PubMed]  [DOI]
61.  García-Miguel M, González MJ, Quera R, Hermoso MA. Innate immunity modulation by the IL-33/ST2 system in intestinal mucosa. Biomed Res Int. 2013;2013:142492.  [PubMed]  [DOI]
62.  Willing B, Halfvarson J, Dicksved J, Rosenquist M, Järnerot G, Engstrand L, Tysk C, Jansson JK. Twin studies reveal specific imbalances in the mucosa-associated microbiota of patients with ileal Crohn’s disease. Inflamm Bowel Dis. 2009;15:653-660.  [PubMed]  [DOI]
63.  Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, Nielsen T, Pons N, Levenez F, Yamada T. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464:59-65.  [PubMed]  [DOI]
64.  Lupp C, Robertson ML, Wickham ME, Sekirov I, Champion OL, Gaynor EC, Finlay BB. Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae. Cell Host Microbe. 2007;2:119-129.  [PubMed]  [DOI]
65.  Tong M, Li X, Wegener Parfrey L, Roth B, Ippoliti A, Wei B, Borneman J, McGovern DP, Frank DN, Li E. A modular organization of the human intestinal mucosal microbiota and its association with inflammatory bowel disease. PLoS One. 2013;8:e80702.  [PubMed]  [DOI]
66.  Wang W, Chen L, Zhou R, Wang X, Song L, Huang S, Wang G, Xia B. Increased proportions of Bifidobacterium and the Lactobacillus group and loss of butyrate-producing bacteria in inflammatory bowel disease. J Clin Microbiol. 2014;52:398-406.  [PubMed]  [DOI]
67.  Kumari R, Ahuja V, Paul J. Fluctuations in butyrate-producing bacteria in ulcerative colitis patients of North India. World J Gastroenterol. 2013;19:3404-3414.  [PubMed]  [DOI]
68.  Nemoto H, Kataoka K, Ishikawa H, Ikata K, Arimochi H, Iwasaki T, Ohnishi Y, Kuwahara T, Yasutomo K. Reduced diversity and imbalance of fecal microbiota in patients with ulcerative colitis. Dig Dis Sci. 2012;57:2955-2964.  [PubMed]  [DOI]
69.  Vigsnæs LK, Brynskov J, Steenholdt C, Wilcks A, Licht TR. Gram-negative bacteria account for main differences between faecal microbiota from patients with ulcerative colitis and healthy controls. Benef Microbes. 2012;3:287-297.  [PubMed]  [DOI]
70.  Kabeerdoss J, Sankaran V, Pugazhendhi S, Ramakrishna BS. Clostridium leptum group bacteria abundance and diversity in the fecal microbiota of patients with inflammatory bowel disease: a case-control study in India. BMC Gastroenterol. 2013;13:20.  [PubMed]  [DOI]
71.  Pilarczyk-Zurek M, Chmielarczyk A, Gosiewski T, Tomusiak A, Adamski P, Zwolinska-Wcislo M, Mach T, Heczko PB, Strus M. Possible role of Escherichia coli in propagation and perpetuation of chronic inflammation in ulcerative colitis. BMC Gastroenterol. 2013;13:61.  [PubMed]  [DOI]
72.  Lepage P, Häsler R, Spehlmann ME, Rehman A, Zvirbliene A, Begun A, Ott S, Kupcinskas L, Doré J, Raedler A. Twin study indicates loss of interaction between microbiota and mucosa of patients with ulcerative colitis. Gastroenterology. 2011;141:227-236.  [PubMed]  [DOI]
73.  Verma R, Verma AK, Ahuja V, Paul J. Real-time analysis of mucosal flora in patients with inflammatory bowel disease in India. J Clin Microbiol. 2010;48:4279-4282.  [PubMed]  [DOI]
74.  Khalil NA, Walton GE, Gibson GR, Tuohy KM, Andrews SC. In vitro batch cultures of gut microbiota from healthy and ulcerative colitis (UC) subjects suggest that sulphate-reducing bacteria levels are raised in UC and by a protein-rich diet. Int J Food Sci Nutr. 2014;65:79-88.  [PubMed]  [DOI]
75.  Dicksved J, Schreiber O, Willing B, Petersson J, Rang S, Phillipson M, Holm L, Roos S. Lactobacillus reuteri maintains a functional mucosal barrier during DSS treatment despite mucus layer dysfunction. PLoS One. 2012;7:e46399.  [PubMed]  [DOI]
76.  Zhou FX, Chen L, Liu XW, Ouyang CH, Wu XP, Wang XH, Wang CL, Lu FG. Lactobacillus crispatus M206119 exacerbates murine DSS-colitis by interfering with inflammatory responses. World J Gastroenterol. 2012;18:2344-2356.  [PubMed]  [DOI]
77.  Sartor RB. Clinical applications of advances in the genetics of IBD. Rev Gastroenterol Disord. 2003;3 Suppl 1:S9-17.  [PubMed]  [DOI]
78.  Kim SC, Tonkonogy SL, Albright CA, Tsang J, Balish EJ, Braun J, Huycke MM, Sartor RB. Variable phenotypes of enterocolitis in interleukin 10-deficient mice monoassociated with two different commensal bacteria. Gastroenterology. 2005;128:891-906.  [PubMed]  [DOI]
79.  Hedin C, Whelan K, Lindsay JO. Evidence for the use of probiotics and prebiotics in inflammatory bowel disease: a review of clinical trials. Proc Nutr Soc. 2007;66:307-315.  [PubMed]  [DOI]
80.  Jonkers D, Penders J, Masclee A, Pierik M. Probiotics in the management of inflammatory bowel disease: a systematic review of intervention studies in adult patients. Drugs. 2012;72:803-823.  [PubMed]  [DOI]
81.  de Vrese M, Schrezenmeir J. Probiotics, prebiotics, and synbiotics. Adv Biochem Eng Biotechnol. 2008;111:1-66.  [PubMed]  [DOI]
82.  Mack DR. Probiotics in inflammatory bowel diseases and associated conditions. Nutrients. 2011;3:245-264.  [PubMed]  [DOI]
83.  Servin AL. Antagonistic activities of lactobacilli and bifidobacteria against microbial pathogens. FEMS Microbiol Rev. 2004;28:405-440.  [PubMed]  [DOI]
84.  Collado MC, Meriluoto J, Salminen S. Role of commercial probiotic strains against human pathogen adhesion to intestinal mucus. Lett Appl Microbiol. 2007;45:454-460.  [PubMed]  [DOI]
85.  Dotan I, Rachmilewitz D. Probiotics in inflammatory bowel disease: possible mechanisms of action. Curr Opin Gastroenterol. 2005;21:426-430.  [PubMed]  [DOI]
86.  Sturm A, Rilling K, Baumgart DC, Gargas K, Abou-Ghazalé T, Raupach B, Eckert J, Schumann RR, Enders C, Sonnenborn U. Escherichia coli Nissle 1917 distinctively modulates T-cell cycling and expansion via toll-like receptor 2 signaling. Infect Immun. 2005;73:1452-1465.  [PubMed]  [DOI]
87.  Groeger D, O’Mahony L, Murphy EF, Bourke JF, Dinan TG, Kiely B, Shanahan F, Quigley EM. Bifidobacterium infantis 35624 modulates host inflammatory processes beyond the gut. Gut Microbes. 2013;4:325-339.  [PubMed]  [DOI]
88.  Oliva S, Di Nardo G, Ferrari F, Mallardo S, Rossi P, Patrizi G, Cucchiara S, Stronati L. Randomised clinical trial: the effectiveness of Lactobacillus reuteri ATCC 55730 rectal enema in children with active distal ulcerative colitis. Aliment Pharmacol Ther. 2012;35:327-334.  [PubMed]  [DOI]
89.  Ishikawa H, Matsumoto S, Ohashi Y, Imaoka A, Setoyama H, Umesaki Y, Tanaka R, Otani T. Beneficial effects of probiotic bifidobacterium and galacto-oligosaccharide in patients with ulcerative colitis: a randomized controlled study. Digestion. 2011;84:128-133.  [PubMed]  [DOI]
90.  Hegazy SK, El-Bedewy MM. Effect of probiotics on pro-inflammatory cytokines and NF-kappaB activation in ulcerative colitis. World J Gastroenterol. 2010;16:4145-4151.  [PubMed]  [DOI]
91.  D’Incà R, Barollo M, Scarpa M, Grillo AR, Brun P, Vettorato MG, Castagliuolo I, Sturniolo GC. Rectal administration of Lactobacillus casei DG modifies flora composition and Toll-like receptor expression in colonic mucosa of patients with mild ulcerative colitis. Dig Dis Sci. 2011;56:1178-1187.  [PubMed]  [DOI]
92.  Matthes H, Krummenerl T, Giensch M, Wolff C, Schulze J. Clinical trial: probiotic treatment of acute distal ulcerative colitis with rectally administered Escherichia coli Nissle 1917 (EcN). BMC Complement Altern Med. 2010;10:13.  [PubMed]  [DOI]
93.  Fujimori S, Gudis K, Mitsui K, Seo T, Yonezawa M, Tanaka S, Tatsuguchi A, Sakamoto C. A randomized controlled trial on the efficacy of synbiotic versus probiotic or prebiotic treatment to improve the quality of life in patients with ulcerative colitis. Nutrition. 2009;25:520-525.  [PubMed]  [DOI]
94.  Bibiloni R, Fedorak RN, Tannock GW, Madsen KL, Gionchetti P, Campieri M, De Simone C, Sartor RB. VSL#3 probiotic-mixture induces remission in patients with active ulcerative colitis. Am J Gastroenterol. 2005;100:1539-1546.  [PubMed]  [DOI]
95.  Miele E, Pascarella F, Giannetti E, Quaglietta L, Baldassano RN, Staiano A. Effect of a probiotic preparation (VSL#3) on induction and maintenance of remission in children with ulcerative colitis. Am J Gastroenterol. 2009;104:437-443.  [PubMed]  [DOI]
96.  Lee JH, Moon G, Kwon HJ, Jung WJ, Seo PJ, Baec TY, Lee JH, Kim HS. [Effect of a probiotic preparation (VSL#3) in patients with mild to moderate ulcerative colitis]. Korean J Gastroenterol. 2012;60:94-101.  [PubMed]  [DOI]
97.  Osman N, Adawi D, Ahrne S, Jeppsson B, Molin G. Modulation of the effect of dextran sulfate sodium-induced acute colitis by the administration of different probiotic strains of Lactobacillus and Bifidobacterium. Dig Dis Sci. 2004;49:320-327.  [PubMed]  [DOI]
98.  Rochat T, Bermúdez-Humarán L, Gratadoux JJ, Fourage C, Hoebler C, Corthier G, Langella P. Anti-inflammatory effects of Lactobacillus casei BL23 producing or not a manganese-dependant catalase on DSS-induced colitis in mice. Microb Cell Fact. 2007;6:22.  [PubMed]  [DOI]
99.  Geier MS, Butler RN, Giffard PM, Howarth GS. Lactobacillus fermentum BR11, a potential new probiotic, alleviates symptoms of colitis induced by dextran sulfate sodium (DSS) in rats. Int J Food Microbiol. 2007;114:267-274.  [PubMed]  [DOI]