scholarly journals Skeletal Phenotype and Mechanisms of Bone Loss in Winnie Mice as a Model for Inflammatory Bowel Disease

2020 ◽  
Author(s):  
Ahmed Al Saedi ◽  
Shilpa Sharma ◽  
Ebrahim Bani Hassan ◽  
Lulu Chen ◽  
Ali Ghasem-Zadeh ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bone Loss ◽  
Mouse Model ◽  
Bone Formation ◽  
Intestinal Inflammation ◽  
Molecular Pathways ◽  
List Type ◽  
Skeletal Phenotype ◽  
Inflammatory Bowel ◽  
First Time

AbstractObjectiveWe aimed to investigate the skeletal phenotype of Winnie mouse model of spontaneous chronic colitis, which carries a mutation in the Muc2 gene and closely replicates IBD symptoms and pathophysiology. These mice have a high level of gut-derived serotonin (GDS), a potent osteoblastogenesis inhibitor. We explored the underlying mechanisms of bone loss associated with chronic intestinal inflammation.DesignWinnie male and female mice prior to colitis onset (6 weeks old) and progression (14 and 24 weeks) were compared to age- and sex-matched C57BL/6 controls. We assessed bone quality (static and dynamic histomorphometry, micro-CT, 3-point bending), intestinal inflammation (lipocalin-2), GDS levels, serum levels of calcium, phosphorus and vitamin D, ex vivo bone marrow analysis and molecular mechanisms inhibiting osteoblastogenesis.ResultsSignificant deterioration in trabecular and cortical microarchitecture, reductions in bone formation, mineral apposition rate, bone volume, osteoid volume and bone strength were observed in Winnie mice compared to C57BL/6 controls. Decreased osteoblast and increased osteoclast numbers were prominent in Winnie mice. We report for the first time that elevated GDS cross-talks with molecular pathways to inhibit bone formation in Winnie mice. Increased expression of 5-HTR1B and FOXO1 mRNAs, dissociation of FOXO1/CREB1 complex and association of FOXO1 with ATF4, promoting the transcriptional activity of FOXO1, results in suppression of osteoblast proliferation in Winnie mice compared to controls.ConclusionThese findings open avenues for the development of targeted therapies for IBD-related bone loss.Significance of this studyWhat is already known on this subject?- Osteoporosis is a common extraintestinal manifestation of inflammatory bowel disease (IBD).- Currently available treatments are not effective for IBD-associated bone loss.- The mechanisms of bone loss are poorly understood. A major limitation has been the lack of an appropriate animal model for IBD-associated bone loss.What are the new findings?- We report for the first-time the skeletal phenotype in Winnie mouse model of IBD- This study presents a novel mechanism of IBD-associated bone loss, involving elevated gut-derived serotonin crosstalk with molecular pathways inhibiting bone formation.How might it impact on clinical practice in the foreseeable future- These findings open avenues for the development of targeted therapies for IBD-related bone loss.

Characterization of Skeletal Phenotype and Associated Mechanisms With Chronic Intestinal Inflammation in the Winnie Mouse Model of Spontaneous Chronic Colitis

2021 ◽  
Author(s):  
Ahmed Al Saedi ◽  
Shilpa Sharma ◽  
Ebrahim Bani Hassan ◽  
Lulu Chen ◽  
Ali Ghasem-Zadeh ◽  
...  
Keyword(s):  
Bone Loss ◽  
Mouse Model ◽  
Bone Formation ◽  
Intestinal Inflammation ◽  
Bone Microarchitecture ◽  
Mineral Apposition Rate ◽  
Serotonin Level ◽  
Chronic Colitis ◽  
Skeletal Phenotype ◽  
Chronic Intestinal Inflammation

Abstract Background Osteoporosis is a common extraintestinal manifestation of inflammatory bowel disease (IBD). However, studies have been scarce, mainly because of the lack of an appropriate animal model of colitis-associated bone loss. In this study, we aimed to decipher skeletal manifestations in the Winnie mouse model of spontaneous chronic colitis, which carries a MUC2 gene mutation and closely replicates ulcerative colitis. In our study, Winnie mice, prior to the colitis onset at 6 weeks old and progression at 14 and 24 weeks old, were compared with age-matched C57BL/6 controls. We studied several possible mechanisms involved in colitis-associated bone loss. Methods We assessed for bone quality (eg, microcomputed tomography [micro-CT], static and dynamic histomorphometry, 3-point bending, and ex vivo bone marrow analysis) and associated mechanisms (eg, electrochemical recordings for gut-derived serotonin levels, real-time polymerase chain reaction [qRT-PCR], double immunofluorescence microscopy, intestinal inflammation levels by lipocalin-2 assay, serum levels of calcium, phosphorus, and vitamin D) from Winnie (6–24 weeks) and age-matched C57BL6 mice. Results Deterioration in trabecular and cortical bone microarchitecture, reductions in bone formation, mineral apposition rate, bone volume/total volume, osteoid volume/bone surface, and bone strength were observed in Winnie mice compared with controls. Decreased osteoblast and increased osteoclast numbers were prominent in Winnie mice compared with controls. Upregulation of 5-HTR1B gene and increased association of FOXO1 with ATF4 complex were identified as associated mechanisms concomitant to overt inflammation and high levels of gut-derived serotonin in 14-week and 24-week Winnie mice. Conclusions Skeletal phenotype of the Winnie mouse model of spontaneous chronic colitis closely represents manifestations of IBD-associated osteoporosis/osteopenia. The onset and progression of intestinal inflammation are associated with increased gut-derived serotonin level, increased bone resorption, and decreased bone formation.

scholarly journals Mouse model of ulcerative colitis using trinitrobenzene sulfonic acid

2015 ◽  
Vol 10 (4) ◽  
pp. 860
Author(s):  
Irfan Ahmad Rather ◽  
Vivek K. Bajpai ◽  
Nam Gyeong-Jun
Keyword(s):  
Ulcerative Colitis ◽  
Inflammatory Bowel Disease ◽  
Mouse Model ◽  
Bowel Disease ◽  
Sulfonic Acid ◽  
Intestinal Inflammation ◽  
Cost Effective ◽  
Trinitrobenzene Sulfonic Acid ◽  
Clinical Presentations ◽  
Inflammatory Bowel

<p>Animal model of intestinal inflammation is of paramount significance that aids in discerning the pathologies underlying ulcerative colitis and Crohn’s disease, the two clinical presentations of inflammatory bowel disease. The 2,4,6-trinitrobenzene sulfonic acid (TNBS) colitis model represents one such intestinal inflammation-prototype that is generated in susceptible strains of mice through intra-rectal instillation of compound TNBS. In this paper, we demonstrate the experimental induction of TNBS-mediated colitis in a susceptible strain of ICR mice. This can be done by the following steps: a) acclimation, b) induction and c) observation. TNBS-mouse model provides the information in shortest possible time and simultaneously represents a cost effective and highly reproducible model method of studying the pathogenesis of inflammatory bowel disease.</p><p><strong>Video Clips</strong></p><p><a href="https://youtube.com/v/6MsuIGzH3uA">Acclimation and induction of TNBS</a>:          4.5 min</p><p><a href="https://youtube.com/v/ya66SNwoVag">Observation and drug administration</a>:      1.5 min</p>

scholarly journals CDX2 upregulates SLC26A3 gene expression in intestinal epithelial cells

2017 ◽  
Vol 313 (3) ◽  
pp. G256-G264 ◽  
Author(s):  
Ishita Chatterjee ◽  
Anoop Kumar ◽  
Rosa María Castilla-Madrigal ◽  
Oscar Pellon-Cardenas ◽  
Ravinder K. Gill ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Transcriptional Regulation ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Intestinal Epithelial ◽  
Protein Levels ◽  
Homeobox Protein ◽  
Direct Binding ◽  
Inflammatory Bowel ◽  
First Time

SLC26A3 [downregulated in adenoma (DRA)] plays a key role in mammalian intestinal NaCl absorption, in that it mediates apical membrane Cl−/[Formula: see text] exchange. DRA function and expression are significantly decreased in diarrhea associated with inflammatory bowel disease. DRA is also considered to be a marker of cellular differentiation and is predominantly expressed in differentiated epithelial cells. Caudal-type homeobox protein-2 (CDX2) is known to regulate genes involved in intestinal epithelial differentiation and proliferation. Reduced expression of both DRA and CDX2 in intestinal inflammation prompted us to study whether the DRA gene is directly regulated by CDX2. Our initial studies utilizing CDX2 knockout (CDX2fV/fV;Cre+) mice showed a marked reduction in DRA mRNA and protein levels in proximal and distal colon. In silico analysis of the DRA promoter showed two consensus sites for CDX2 binding. Therefore, we utilized Caco-2 cells as an in vitro model to examine if DRA is a direct target of CDX2 regulation. siRNA-mediated silencing of CDX2 in Caco-2 cells resulted in a marked (~50%) decrease in DRA mRNA and protein levels, whereas ectopic overexpression of CDX2 upregulated DRA expression and also stimulated DRA promoter activity, suggesting transcriptional regulation. Electrophoretic mobility shift and chromatin immunoprecipitation assays demonstrated direct binding of CDX2 to one of the two putative CDX2 binding sites in the DRA promoter (+645/+663). In summary, our studies, for the first time, demonstrate transcriptional regulation of DRA expression by CDX2, implying that reduced expression of DRA in inflammatory bowel disease-associated diarrhea may, in part, be due to downregulation of CDX2 in the inflamed mucosa. NEW & NOTEWORTHY SLC26A3 [downregulated in adenoma (DRA)] mediates intestinal luminal NaCl absorption and is downregulated in inflammatory bowel disease-associated diarrhea. Since both DRA and caudal-type homeobox protein-2 (CDX2) are reduced in intestinal inflammation and the DRA promoter harbors CDX2 binding sites, we examined whether the DRA gene is regulated by CDX2. Our studies, for the first time, demonstrate transcriptional regulation of DRA expression by CDX2 via direct binding to the DRA promoter, suggesting that reduced expression of DRA in inflammatory bowel disease-associated diarrhea could, in part, be attributed to downregulation of CDX2.

O14. Bone loss observed in inflammatory bowel disease is associated with suppression of bone formation

Bone ◽  
1996 ◽  
Vol 19 (6) ◽  
pp. 688
Author(s):  
C.L. Lin ◽  
C. Moniz ◽  
T.J. Chambers ◽  
J.W.M. Chow
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bone Loss ◽  
Bone Formation ◽  
Bowel Disease ◽  
Inflammatory Bowel

scholarly journals Intestinal Inflammation and Altered Gut Microbiota Associated with Inflammatory Bowel Disease Render Mice Susceptible to Clostridioides difficile Colonization and Infection

mBio ◽  
2021 ◽  
Author(s):  
Lisa Abernathy-Close ◽  
Madeline R. Barron ◽  
James M. George ◽  
Michael G. Dieterle ◽  
Kimberly C. Vendrov ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Mouse Model ◽  
Gut Microbiota ◽  
Intestinal Inflammation ◽  
Antibiotic Use ◽  
Content Type ◽  
Clostridioides Difficile ◽  
Increased Risk ◽  
Inflammatory Bowel ◽  
The Relationship

The incidence of C. difficile infection (CDI) has increased significantly among patients with IBD, independently of antibiotic use, yet the relationship between IBD and increased risk for CDI remains to be understood. Our study sought to describe and utilize an antibiotic-independent mouse model to specifically explore the relationship between the IBD-associated gut and susceptibility to C. difficile colonization and CDI development.

scholarly journals GPR4 Deficiency Alleviates Intestinal Inflammation in a Mouse Model of Inflammatory Bowel Disease

2016 ◽  
Author(s):  
Edward J. Sanderlin ◽  
Nancy R. Leffler ◽  
Kvin Lertpiriyapong ◽  
Qi Cai ◽  
Heng Hong ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Mouse Model ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Vascular Endothelial Cells ◽  
Leukocyte Adhesion ◽  
Lymphoid Follicle ◽  
Wild Type ◽  
Inflammatory Bowel ◽  
Deficient Mice

AbstractGPR4 is a proton-sensing G protein-coupled receptor that can be activated by extracellular acidosis. It has recently been demonstrated that activation of GPR4 by acidosis increases the expression of numerous inflammatory and stress response genes in vascular endothelial cells (ECs) and also augments EC-leukocyte adhesion. Inhibition of GPR4 by siRNA or small molecule inhibitors reduces endothelial cell inflammation. As acidotic tissue microenvironments exist in many types of inflammatory disorders, including inflammatory bowel disease (IBD), we examined the role of GPR4 in IBD using a dextran sulfate sodium (DSS)-induced colitis mouse model. We observed that GPR4 mRNA expression was increased in mouse and human IBD tissues when compared to control intestinal tissues. To determine the function of GPR4 in IBD, wild-type and GPR4-deficient mice were treated with 3% DSS for 7 days to induce acute colitis. Our results showed that the severity of colitis was decreased in GPR4-deficient DSS-treated mice in comparison to wild-type DSS-treated mice. Clinical parameters, macroscopic disease indicators, and histopathological features were less severe in the DSS-treated GPR4-deficient mice than the DSS-treated wild-type mice. Inflammatory gene expression, leukocyte infiltration, and isolated lymphoid follicle (ILF) formation were reduced in intestinal tissues of DSS-treated GPR4-null mice. Collectively, our results suggest GPR4 provides a pro-inflammatory role in IBD as the absence of GPR4 ameliorates intestinal inflammation in the acute DSS-induced IBD mouse model.

The potent and selective RIPK2 inhibitor BI 706039 improves intestinal inflammation in the TRUC mouse model of Inflammatory Bowel Disease

2021 ◽  
Author(s):  
Joerg Ermann ◽  
Mederbek Matmusaev ◽  
Emma Haley ◽  
Clemens Braun ◽  
Felix Jost ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Mouse Model ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Intestinal Microbiome ◽  
Intestinal Immune System ◽  
Pharmacokinetic Properties ◽  
Inflammatory Bowel ◽  
The Impact ◽  
Human And Mouse

ABSTRACT Background and Aims : Mouse and human data implicates the NOD1 and NOD2 sensors of the intestinal microbiome and the associated signal transduction via the RIPK2 kinase as a potentially key signaling node for the development of Inflammatory Bowel Disease (IBD) and an attractive target for pharmacologic intervention. The TRUC mouse model of IBD has been strongly indicated for evaluating the impact of RIPK2 antagonism on intestinal inflammation based on previous studies with NOD1, NOD2 and RIPK2 knockout mice. Methods. We identified and profiled the BI 706039 molecule as a potent and specific functional inhibitor of both human and mouse RIPK2 and with favorable pharmacokinetic properties. We dosed BI 706039 in the spontaneous TRUC mouse model from aged day 28 through aged day 56. Results : Oral, daily administration of BI 706039 caused dose-responsive and significant improvement in colonic histopathological inflammation, colon weight and terminal levels of protein normalized fecal lipocalin (all p< 0.001). These observations correlated with dose-responsively increasing systemic levels of the BI 706039 compound, splenic molecular target engagement of RIPK2 and modulation of inflammatory genes in the colon. Conclusions : A relatively low oral dose of a potent and selective RIPK2 inhibitor can block the signaling interface between the intestinal microbiome and the intestinal immune system and significantly improve disease associated intestinal inflammation.

scholarly journals Intestinal inflammation and altered gut microbiota associated with inflammatory bowel disease renders mice susceptible to Clostridioides difficile colonization and infection

2020 ◽  
Author(s):  
Lisa Abernathy Close ◽  
Madeline R Barron ◽  
James M George ◽  
Michael G Dieterle ◽  
Kimberly C Vendrov ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Mouse Model ◽  
Gut Microbiota ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Helicobacter Hepaticus ◽  
Colonization Resistance ◽  
Distal Intestine ◽  
Clostridioides Difficile ◽  
Inflammatory Bowel

Clostridioides difficile has emerged as a noteworthy pathogen in patients with inflammatory bowel disease (IBD). Concurrent IBD and CDI is associated with increased morbidity and mortality compared to CDI alone. IBD is associated with alterations of the gut microbiota, an important mediator of colonization resistance to C. difficile. Here, we describe and utilize a mouse model to explore the role of intestinal inflammation in susceptibility to C. difficile colonization and subsequent disease severity in animals with underlying IBD. Helicobacter hepaticus, a normal member of the mouse gut microbiota, was used to trigger inflammation in the distal intestine akin to human IBD in mice that lack intact IL-10 signaling. Development of IBD resulted in a distinct intestinal microbiota community compared to non-IBD controls. We demonstrate that in this murine model, IBD was sufficient to render mice susceptible to C. difficile colonization. Mice with IBD were persistently colonized by C. difficile, while genetically identical non-IBD controls were resistant to C. difficile colonization. Concomitant IBD and CDI was associated with significantly worse disease than unaccompanied IBD. IL-10-deficient mice maintained gut microbial diversity and colonization resistance to C. difficile in experiments utilizing an isogenic mutant of H. hepaticus that does not trigger intestinal inflammation. These studies in mice demonstrate that the IBD-induced microbiota is sufficient for C. difficile colonization and that this mouse model requires intestinal inflammation for inducing susceptibility to CDI in the absence of other perturbations, such as antibiotic treatment.

scholarly journals Restored macrophage function ameliorates disease pathophysiology in a mouse model for IL10 receptor deficient very early onset inflammatory bowel disease

2021 ◽  
Author(s):  
Mania Ackermann ◽  
Adele Mucci ◽  
Amanda McCabe ◽  
Sandy Frei ◽  
Kayla Wright ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Mouse Model ◽  
Bowel Disease ◽  
Early Onset ◽  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Intraperitoneal Administration ◽  
Gene Correction ◽  
Hematopoietic Stem ◽  
Inflammatory Bowel

Abstract Background and aims Mutations in IL10 or the IL10-receptor lead to very early onset (VEO) inflammatory bowel disease (IBD), a life-threatening disease which is often unresponsive to conventional medication. Recent studies have demonstrated that defective IL-10 receptor signaling in innate immune cells is a key driver of severe intestinal inflammation in VEO-IBD. Specifically, IL10 unresponsiveness of macrophages, which govern the tight balance between pro- and anti-inflammatory responses in the intestinal system, plays a central role in the events leading to excessive inflammatory responses and the development of IBD. Methods and Results We here evaluated hematopoietic stem cell gene therapy in a VEO-IBD mouse model and demonstrate that the therapeutic response closely correlates with gene correction of the IL-10 signaling pathway in intestinal macrophages. This finding prompted us to evaluate the therapeutic efficacy of macrophage transplantation in the Il10rb -/- VEO-IBD mouse model. A 6-week regimen employing a combination of depletion of endogenous hyperinflammatory macrophages followed by intraperitoneal administration of wild-type macrophages significantly reduced colitis symptoms. Conclusion In summary, we show that the correction of the IL10 receptor-defect in macrophages either by genetic therapy or transfer of WT macrophages to the peritoneum can ameliorate disease-related symptoms and potentially represent novel treatment approaches for VEO-IBD patients.

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