P075 Muc5ac expression protects the colonic barrier in experimental colitis

Abstract Background The mucus gel layer (MGL) lining the colon is integral to exclusion of bacteria and maintaining intestinal homeostasis in health and disease. MGL defects allowing bacteria to directly contact the colonic surface are commonly observed in ulcerative colitis (UC). The major macromolecular component of the colonic MGL is the secreted gel-forming mucin, MUC2, whose expression is essential for homeostasis in health. In UC, another gel-forming mucin, MUC5AC is induced. In mice, Muc5ac is protective during intestinal helminth infection. Here, we tested the expression and functional role of MUC5AC/Muc5ac in colitis patient biopsies and murine colitis. Methods We measured MUC5AC/Muc5ac expression in UC patient biopsies and during acute dextran sulphate sodium (DSS) colitis. We performed DSS-colitis in mice deficient in Muc5ac (Muc5ac−/−) to model the potential functional role of Muc5ac in colitis. To assess MGL integrity, we quantified bacterial–epithelial interaction and translocation to mesenteric lymph nodes (MLNs). Antibiotic treatment was performed to directly investigate the role of colonic bacteria in our murine colitis studies. Results Colonic MUC5AC/Muc5ac mRNA expression increased significantly in active UC and murine colitis. Muc5ac−/− mice experienced worsened injury and inflammation in DSS-colitis compared with controls. This was associated with increased bacterial–epithelial contact and translocation to the MLN. Antibiotic treatment normalised colitis severity in Muc5ac−/− mice to that of antibiotic treated controls. Conclusion We demonstrate for the first time that MUC5AC/Muc5ac induction in acute colitis controls injury by reducing bacterial breach of the MGL. Therefore, developing strategies to induce MUC5AC expression may protect the intestinal barrier in UC.

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Muc5ac Expression Protects the Colonic Barrier in Experimental Colitis

Inflammatory Bowel Diseases ◽

10.1093/ibd/izaa064 ◽

2020 ◽

Vol 26 (9) ◽

pp. 1353-1367

Author(s):

Kristine E Olli ◽

Caroline Rapp ◽

Lauren O’Connell ◽

Colm B Collins ◽

Eoin N McNamee ◽

...

Keyword(s):

Lymph Nodes ◽

Antibiotic Treatment ◽

Functional Role ◽

Intestinal Helminth ◽

Rrna Gene ◽

Mesenteric Lymph Nodes ◽

Murine Colitis ◽

Dss Colitis ◽

Mesenteric Lymph

Abstract Background The mucus gel layer (MGL) lining the colon is integral to exclusion of bacteria and maintaining intestinal homeostasis in health and disease. Some MGL defects allowing bacteria to directly contact the colonic surface are commonly observed in ulcerative colitis (UC). The major macromolecular component of the colonic MGL is the secreted gel-forming mucin MUC2, whose expression is essential for homeostasis in health. In UC, another gel-forming mucin, MUC5AC, is induced. In mice, Muc5ac is protective during intestinal helminth infection. Here we tested the expression and functional role of MUC5AC/Muc5ac in UC biopsies and murine colitis. Methods We measured MUC5AC/Muc5ac expression in UC biopsies and in dextran sulfate sodium (DSS) colitis. We performed DSS colitis in mice deficient in Muc5ac (Muc5ac-/-) to model the potential functional role of Muc5ac in colitis. To assess MGL integrity, we quantified bacterial-epithelial interaction and translocation to mesenteric lymph nodes. Antibiotic treatment and 16S rRNA gene sequencing were performed to directly investigate the role of bacteria in murine colitis. Results Colonic MUC5AC/Muc5ac mRNA expression increased significantly in active UC and murine colitis. Muc5ac-/- mice experienced worsened injury and inflammation in DSS colitis compared with control mice. This result was associated with increased bacterial-epithelial contact and translocation to the mesenteric lymph nodes. However, no change in microbial abundance or community composition was noted. Antibiotic treatment normalized colitis severity in Muc5ac-/- mice to that of antibiotic-treated control mice. Conclusions MUC5AC/Muc5ac induction in the acutely inflamed colon controls injury by reducing bacterial breach of the MGL.

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Antepartum Antibiotic Treatment Increases Offspring Susceptibility to Experimental Colitis: A Role of the Gut Microbiota

PLoS ONE ◽

10.1371/journal.pone.0142536 ◽

2015 ◽

Vol 10 (11) ◽

pp. e0142536 ◽

Cited By ~ 43

Author(s):

Peris Mumbi Munyaka ◽

N. Eissa ◽

Charles Noah Bernstein ◽

Ehsan Khafipour ◽

Jean-Eric Ghia

Keyword(s):

Gut Microbiota ◽

Antibiotic Treatment ◽

Experimental Colitis

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Mo1034 INTESTINAL PROTECTION INDUCED BY TREATMENT WITH ALKALINE PHOSPHATASE ON THE SEVERITY OF EXPERIMENTAL COLITIS IN OBESE MICE SUBJECTED TO FORCED TREADMILL RUNNING. ROLE OF PROINFLAMMATORY BIOMARKERS, INTESTINAL BARRIER PROTEINS AND OXIDATIVE STRESS

Gastroenterology ◽

10.1016/s0016-5085(20)32582-8 ◽

2020 ◽

Vol 158 (6) ◽

pp. S-763

Author(s):

Dagmara Wojcik ◽

Aleksandra Danielak ◽

Agnieszka Mazur-Bialy ◽

Marcin Surmiak ◽

Marcin Magierowski ◽

...

Keyword(s):

Oxidative Stress ◽

Alkaline Phosphatase ◽

Intestinal Barrier ◽

Experimental Colitis ◽

Treadmill Running ◽

Obese Mice ◽

And Oxidative Stress

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Role of M-CSF-dependent macrophages in colitis is driven by the nature of the inflammatory stimulus

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00453.2007 ◽

2008 ◽

Vol 294 (3) ◽

pp. G770-G777 ◽

Cited By ~ 39

Author(s):

Jean-Eric Ghia ◽

Francesca Galeazzi ◽

David C. Ford ◽

Cory M. Hogaboam ◽

Bruce A. Vallance ◽

...

Keyword(s):

Inflammatory Responses ◽

Critical Factor ◽

Experimental Colitis ◽

Dss Colitis ◽

Inflammatory Protein ◽

Tnf Α ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Macrophage Subset

Although macrophages are considered a critical factor in determining the severity of acute inflammatory responses in the gut, recent evidence has indicated that macrophages may also play a counterinflammatory role. In this study, we examined the role of a macrophage subset in two models of colitis. Macrophage colony-stimulating factor (M-CSF)-deficient osteopetrotic mice (op/op) and M-CSF-expressing heterozygote (+/?) mice were studied following the induction of colitis by either dinitrobenzene sulfonic acid (DNBS) or dextran sulfate sodium (DSS). DNBS induced a severe colitis in M-CSF-deficient op/op mice compared with +/? mice. This was associated with increased mortality and more severe macroscopic and microscopic injury. Colonic tissue myeloperoxidase (MPO) activity as well as concentrations of TNF-α, IL-1β, and IL-6 were higher and IL-10 lower in op/op mice with DNBS colitis. The severity of inflammation and mortality was attenuated in op/op mice that had received human recombinant M-CSF prior to the induction of colitis. In contrast, op/op mice appeared less vulnerable to colitis induced by DSS. Macroscopic damage, microscopic injury, MPO activity, and tissue concentrations of TNF-α, IL-1β, and IL-6 were all lower in op/op mice compared with +/? mice with DSS colitis, and no changes were seen in IL-10. Macrophage inflammatory protein-1α concentrations were increased in op/op but not +/? mice following colitis induced by DNBS but not DSS. These results indicate that M-CSF-dependent macrophages may play either a pro- or counterinflammatory role in acute experimental colitis, depending on the stimulus used to induce colitis.

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Bactericidal Permeability Increasing Protein Deficiency Aggravates Acute Colitis in Mice by Increasing the Serum Levels of Lipopolysaccharide

Frontiers in Immunology ◽

10.3389/fimmu.2020.614169 ◽

2021 ◽

Vol 11 ◽

Author(s):

Qingli Kong ◽

Zhe Lv ◽

Yun Kang ◽

Yunqing An ◽

Zhenlong Liu ◽

...

Keyword(s):

Abdominal Cavity ◽

Experimental Colitis ◽

Serum Levels ◽

Mucosal Damage ◽

Rt Pcr ◽

Acute Colitis ◽

Fecal Microbiome ◽

Murine Colitis ◽

Number Of Bacteria

ObjectiveThe objective of this study was to understand the role of bactericidal permeability increasing protein (BPI) in the pathogenesis of experimental murine colitis.MethodsWe used the Cre-LoxP system to generate BPI knockout (BPI KO) mice. Acute colitis was induced in BPI KO mice and wild-type (WT) mice by subjecting the mice to 5% dextran sulfate sodium (DSS). Mice were observed for symptoms of experimental colitis. The survival of BPI KO mice to infection with Acinetobacter baumannii, a gram-negative bacterium, was also assessed.ResultsSouthern blot, RT-PCR, and western blot results showed that the 2nd and 3rd exons of the murine Bpi gene were knocked out systemically, confirming successful construction of the BPI KO mouse. BPI KO mice subjected to DSS showed increased symptoms of experimental colitis, increased colonic mucosal damage, increased epithelial permeability, elevated levels of serum LPS, and a disrupted fecal microbiome as compared with WT mice. Furthermore, BPI KO mice challenged intraperitoneally with A. baumannii died sooner than WT mice, and the total number of bacteria in the abdominal cavity, spleen, and liver was increased in BPI KO mice as compared to WT mice.ConclusionsWe successfully generated BPI KO mice. The BPI KO mice developed worse colitis than WT mice by increased colitis symptoms and colonic mucosal damage, elevated levels of serum LPS, and a disrupted microbiome. BPI could be a potential target for treatment of ulcerative colitis in humans.

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Mo1774 Prenatal Antibiotic Treatment Increases Offspring's Susceptibility to Experimental Colitis: A Role of the Gut Microbiota

Gastroenterology ◽

10.1016/s0016-5085(15)32404-5 ◽

2015 ◽

Vol 148 (4) ◽

pp. S-708 ◽

Cited By ~ 4

Author(s):

Peris M. Munyaka ◽

Azin Khafipour ◽

Hongxing Wang ◽

Nour Eissa ◽

Ehsan Khafipour ◽

...

Keyword(s):

Gut Microbiota ◽

Antibiotic Treatment ◽

Experimental Colitis

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Matrix metalloproteinase 9-induced increase in intestinal epithelial tight junction permeability contributes to the severity of experimental DSS colitis

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00256.2015 ◽

2015 ◽

Vol 309 (12) ◽

pp. G988-G997 ◽

Cited By ~ 48

Author(s):

Prashant Nighot ◽

Rana Al-Sadi ◽

Manmeet Rawat ◽

Shuhong Guo ◽

D. Martin Watterson ◽

...

Keyword(s):

Epithelial Cell ◽

Protein Expression ◽

Barrier Function ◽

Intestinal Inflammation ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Intestinal Epithelial ◽

Dss Colitis

Recent studies have implicated a pathogenic role for matrix metalloproteinases 9 (MMP-9) in inflammatory bowel disease. Although loss of epithelial barrier function has been shown to be a key pathogenic factor for the development of intestinal inflammation, the role of MMP-9 in intestinal barrier function remains unclear. The aim of this study was to investigate the role of MMP-9 in intestinal barrier function and intestinal inflammation. Wild-type (WT) and MMP-9−/−mice were subjected to experimental dextran sodium sulfate (DSS) colitis by administration of 3% DSS in drinking water for 7 days. The mouse colonic permeability was measured in vivo by recycling perfusion of the entire colon using fluorescently labeled dextran. The DSS-induced increase in the colonic permeability was accompanied by an increase in intestinal epithelial cell MMP-9 expression in WT mice. The DSS-induced increase in intestinal permeability and the severity of DSS colitis was found to be attenuated in MMP-9−/−mice. The colonic protein expression of myosin light chain kinase (MLCK) and phospho-MLC was found to be significantly increased after DSS administration in WT mice but not in MMP-9−/−mice. The DSS-induced increase in colonic permeability and colonic inflammation was attenuated in MLCK−/−mice and MLCK inhibitor ML-7-treated WT mice. The DSS-induced increase in colonic surface epithelial cell MLCK mRNA was abolished in MMP-9−/−mice. Lastly, increased MMP-9 protein expression was detected within the colonic surface epithelial cells in ulcerative colitis cases. These data suggest a role of MMP-9 in modulation of colonic epithelial permeability and inflammation via MLCK.

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Butyrate increases IL-23 production by stimulated dendritic cells

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00540.2011 ◽

2012 ◽

Vol 303 (12) ◽

pp. G1384-G1392 ◽

Cited By ~ 64

Author(s):

Bradford E. Berndt ◽

Min Zhang ◽

Stephanie Y. Owyang ◽

Tyler S. Cole ◽

Teresa W. Wang ◽

...

Keyword(s):

Dendritic Cells ◽

Epigenetic Modification ◽

Experimental Colitis ◽

Short Chain Fatty Acids ◽

Dss Colitis ◽

Deacetylase Inhibitor ◽

Mucosal Homeostasis ◽

Dc Maturation

The gut microbiota is essential for the maintenance of intestinal immune homeostasis and is responsible for breaking down dietary fiber into short-chain fatty acids (SCFAs). Butyrate, the most abundant bioactive SCFA in the gut, is a histone deacetylase inhibitor (HDACi), a class of drug that has potent immunomodulatory properties. This characteristic of butyrate, along with our previous discovery that conventional dendritic cells (DCs) are required for the development of experimental colitis, led us to speculate that butyrate may modulate DC function to regulate gut mucosal homeostasis. We found that butyrate, in addition to suppressing LPS-induced bone marrow-derived DC maturation and inhibiting DC IL-12 production, significantly induced IL-23 expression. The upregulation of mRNA subunit IL-23p19 at the pretranslational level was consistent with the role of HDACi on the epigenetic modification of gene expression. Furthermore, the mechanism of IL-23p19 upregulation was independent of Stat3 and ZBP89. Coculture of splenocytes with LPS-stimulated DCs pretreated with or without butyrate was performed and showed a significant induction of IL-17 and IL-10. We demonstrated further the effect of butyrate in vivo using dextran sulfate sodium (DSS)-induced colitis and found that the addition of butyrate in the drinking water of mice worsened DSS-colitis. This is in contrast to the daily intraperitoneal butyrate injection of DSS-treated mice, which mildly improved disease severity. Our study highlights a novel effect of butyrate in upregulating IL-23 production of activated DCs and demonstrates a difference in the host response to the oral vs. systemic route of butyrate administration.

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