Muc2-Deficient Mice Spontaneously Develop Colitis, Indicating That MUC2 Is Critical for Colonic Protection

Sluis, Maria van der; Koning, Barbara A E de; Bruijn, Adrianus C. J. M. de; Velcich, Anna; Meijerink, Jules P.P.; Goudoever, Johannes B. van; Büller, Hans A.; Dekker, Jan; Seuningen, Isabelle Van; Renes, Ingrid B.; Einerhand, Alexandra W. C.

doi:10.1053/j.gastro.2006.04.020

Cited by 1,365 publications

(1,114 citation statements)

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“…SCFAs increase cell metabolism by more than 80% and the production and secretion of mucins by the colon epithelium more than twentyfold 8,33 . Experimental models that inhibit the oxidation of SCFAs or that use animals that have been silenced for the MUC-2 gene are capable of causing inflammation of the colon mucosa to appear, with histological similarities to diversion colitis 10,27,37,34 . All these points reinforce the important role played by SCFAs in relation to the capacity of the colon epithelium to produce mucins and consequently to protect the mucosa against aggression coming from the intestinal lumen 8 .…”

Section: Discussionmentioning

confidence: 99%

Quantification by computerized morphometry of tissue levels of sulfomucins and sialomucins in diversion colitis in rats

et al. 2010

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PURPOSE: To quantify the intensity of sulfomucin and sialomucin expression in the colon mucosa, by means of computer-assisted image processing, comparing segments with and without fecal stream and correlating with the duration of fecal transit exclusion. METHODS: Forty-five Wistar rats were subjected to diversion of the fecal stream in the left colon by means of constructing a proximal colostomy and distal mucosal fistula. They were distributed randomly into three experimental groups of 15 animals, of which 10 were subjected to colon diversion (experimental subgroup) and five were only subjected to laparotomy, without colon diversion (control subgroup). The three experimental groups were formed according to the sacrifice date, which was to be performed six weeks after the surgical procedure (Group A), 12 weeks (Group B) and 18 weeks (Group C). The sulfomucin and sialomucin expression in the colon mucosa was evaluated using the histochemical technique of high iron diamine-alcian blue (HID-AB). The tissue expression was quantified for each animal, in the segments with and without fecal stream, at a location where there were four complete contiguous crypts in two random fields, with the aid of the computer-assisted image analysis software. The final value was taken to be the mean reading from the two fields selected, in the segments with and without fecal stream. To compare the expressions of the two mucin subtypes in the segments with and without fecal stream, the paired Student t test was used. To analyze variance according to duration of exclusion, ANOVA with the Newman-Keuls post-test was used, setting the significance level at 5% (p<0.05). RESULTS: There were significant reductions in tissue sulfomucin and sialomucin content in the colon without fecal stream, independent of the duration of exclusion considered. There was increased tissue sulfomucin content and decreased tissue sialomucin in the segments without fecal stream, with increasing duration of exclusion. CONCLUSIONS: Diversion of the fecal transit decreased the tissue sulfomucin and sialomucin content in the segments without fecal stream. Notwithstanding the reduction in the levels of both subtypes of acid mucin in the segments without fecal stream, there was increased tissue sulfomucin content and decreased tissue sialomucin with increasing duration of intestinal diversion.

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Section: Discussionmentioning

confidence: 99%

Quantification by computerized morphometry of tissue levels of sulfomucins and sialomucins in diversion colitis in rats

et al. 2010

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“…6 The Muc2 gene has been implicated as crucial in colonic mucosal defense, based on observations that Muc-2-deficient mice exhibit lowgrade mucosal inflammation in the basal state, and have an increased susceptibility to colitis. 11,22,29,30 MUC-2 is not a major form of mucin in the healthy stomach of humans or rodents, but has been shown to be expressed in gastric carcinoma. 9,10 The results of the present study, however, clearly demonstrate that Muc-2-deficient mice exhibit impaired gastric mucosal repair.…”

Section: Discussionmentioning

confidence: 99%

“…9 Studies in mice suggest that deficiency of Muc-2 may contribute to the onset and perpetuation of colitis. 11 Given the importance of mucin in health and in different pathological conditions, and the possibility that Muc-2 is expressed in injured or inflamed stomach, we speculated that mice deficient in Muc-2 might display impaired healing of mucosal injury. We investigated this using both acute and chronic models of gastric injury.…”

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confidence: 99%

Muc-2–Deficient Mice Display a Sex-Specific, COX-2–Related Impairment of Gastric Mucosal Repair

Wallace

Vong

Dharmani

et al. 2011

The American Journal of Pathology

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Mucus is known to contribute significantly to the prevention and repair of mucosal damage throughout the gastrointestinal tract. Although not normally expressed in the stomach, mucin-2 (MUC-2, encoded by the MUC2 gene) is expressed in certain disease states. The aim of this study was to determine in a mouse model whether the absence of Muc-2 would result in impaired susceptibility to and healing of gastric mucosal injury. Acute gastric damage was induced in mice deficient in Muc-2 and in wild-type controls, through oral administration of indomethacin. Chronic gastric ulcers were induced by serosal application of acetic acid. The extent of injury and the extent of healing of the damage over time were examined in both models. Indomethacin administration caused similar levels of gastric damage in Muc-2-deficient and wild-type mice, but the erosions healed more slowly in the former. Acetic acid-induced gastric ulcers were initially similar in size in Muc-2-deficient and wildtype mice of both sexes, but ulcer healing was significantly impaired in male Muc-2-deficient mice. Induction of cyclooxygenase-2 in the stomach, in response to indomethacin-or acetic acid-induced ulceration, was significantly reduced in male Muc-2-deficient mice. This phenomenon, and the sex specificity, was also apparent in bone marrow-derived macrophages stimulated with endotoxin. These results demonstrate a marked impairment of gastric mucosal repair in male Muc-2-deficient mice that may be related to an insufficient induction of cyclooxygenase-2, an enzyme known to contribute to mucosal repair.

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“…However, ''depletion of goblet cells'' is a common pathologic finding in IBD [42]. Loss of proper mucin secretion may directly lead to chronic inflammation, as it has been shown that MUC2 deficient mice spontaneously develop chronic colitis [43]. Besides mucin production, goblet cells secretes cytokines such as IL-7 [44] and thus may exert immunoregulatory functions, and can also deliver luminal antigens to the underlying DCs [45].…”

Section: Role Of Iecs In the Pathogenesis Of Ibdmentioning

confidence: 99%

“…Expression of specific ion channels such as Bestrophin2 may support the proper function of the mucus layer [44,45]. Goblet cells can also interact with the lamina propria immune cells through antigen delivery or cytokine production [42,43]. c Mucus layer covers the mice colonic surface and constitutes the goblet cell-mediated barrier function.…”

Section: Mechanism Of Epithelial Repair In Ibdmentioning

confidence: 99%

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

2015

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In the past decades, continuous effort has been paid to deeply understanding the pathophysiology of inflammatory bowel diseases (IBD), such as ulcerative colitis or Crohn's disease. As the disease typically arises as chronic inflammation of the gastrointestinal mucosa, research has been focused on how such an uncontrolled, deleterious immune response may arise and persist in a certain cohort of patients. Based on those immunologic analyses, the establishment of anti-TNF-a therapy, and the following series of biologic agents achieved great success and dramatically changed the therapeutic strategy of IBD patients. However, to guarantee long-term remission of the disease, the therapeutic standard has been raised to achieve ''mucosal healing'', which requires complete repair of the gastrointestinal mucosa. Recent studies have revealed the unexpected importance of epithelial cells in the pathophysiology of IBD. The general barrier function as well as the cell lineage-specific functions have been deeply attributed to the development of chronic intestinal inflammation. Also, the groundbreaking establishment of the in vitro intestinal stem cell culture system has opened up a way of developing stem cell transplantation therapy to treat otherwise refractory ulcers that may persist in IBD patients. In this review, we would like to focus on the role of epithelial cells in the pathophysiology of IBD, and also give a perspective to the upcoming development of regenerative therapies that may become one of the therapeutic choices to achieve mucosal healing in refractory patients of IBD.

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Muc2-Deficient Mice Spontaneously Develop Colitis, Indicating That MUC2 Is Critical for Colonic Protection

Cited by 1,365 publications

References 39 publications

Quantification by computerized morphometry of tissue levels of sulfomucins and sialomucins in diversion colitis in rats

Quantification by computerized morphometry of tissue levels of sulfomucins and sialomucins in diversion colitis in rats

Muc-2–Deficient Mice Display a Sex-Specific, COX-2–Related Impairment of Gastric Mucosal Repair

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

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