Mapping colitis susceptibility in mouse models: distal chromosome 3 contains major loci related to Cdcs1

Inflammatory bowel disease (IBD) summarizes a group of chronic intestinal disorders with Crohn's disease and ulcerative colitis being most prominent. Though much effort is put into identification of causative factors, its etiology is still not understood. Risk factors for disease development include genetic predisposition and environmental triggers. Crucial for identification and analysis of relevant factors are mouse models. Experimental IBD in mice occurs spontaneously or is induced by chemicals, cell transfer, pathogens, or genetic mutation. These models were utilized for analyzing genetic contribution to disease and genotype-environmental interactions. In these studies, a variety of modifier loci were identified, thereby demonstrating the complexity of disease. A major contribution of distal chromosome 3 was independently replicated in several studies. The first colitogenic QTL in this region was detected using the IL-10-deficient mouse model and called cytokine deficiency-induced colitis susceptibility ( Cdcs) 1. This quantitative trait locus contains at least three subintervals with independent genetic factors. This locus or defined subintervals were replicated in at least seven studies, using models based on dysregulation of innate or adaptive immunity or pathogen control. In this review we illustrate the various models used for genetic mapping of susceptibility to experimental IBD and display Cdcs1-related loci as well as the mechanism of their contribution identified so far.

Download Full-text

The food additive EDTA aggravates colitis and colon carcinogenesis in mouse models

Scientific Reports ◽

10.1038/s41598-021-84571-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Rayko Evstatiev ◽

Adam Cervenka ◽

Tina Austerlitz ◽

Gunther Deim ◽

Maximilian Baumgartner ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Mouse Models ◽

Bowel Disease ◽

Intestinal Inflammation ◽

Food Additives ◽

Colorectal Carcinogenesis ◽

Testing Procedures ◽

Inflammatory Models ◽

Inflammatory Bowel

AbstractInflammatory bowel disease is a group of conditions with rising incidence caused by genetic and environmental factors including diet. The chelator ethylenediaminetetraacetate (EDTA) is widely used by the food and pharmaceutical industry among numerous other applications, leading to a considerable environmental exposure. Numerous safety studies in healthy animals have revealed no relevant toxicity by EDTA. Here we show that, in the presence of intestinal inflammation, EDTA is surprisingly capable of massively exacerbating inflammation and even inducing colorectal carcinogenesis at doses that are presumed to be safe. This toxicity is evident in two biologically different mouse models of inflammatory bowel disease, the AOM/DSS and the IL10−/− model. The mechanism of this effect may be attributed to disruption of intercellular contacts as demonstrated by in vivo confocal endomicroscopy, electron microscopy and cell culture studies. Our findings add EDTA to the list of food additives that might be detrimental in the presence of intestinal inflammation, but the toxicity of which may have been missed by regulatory safety testing procedures that utilize only healthy models. We conclude that the current use of EDTA especially in food and pharmaceuticals should be reconsidered. Moreover, we suggest that intestinal inflammatory models should be implemented in the testing of food additives to account for the exposure of this primary organ to environmental and dietary stress.

Download Full-text

P078 Efficacy of human anti-macrophage migration inhibitory factor antibodies in mouse models of inflammatory bowel disease

Journal of Crohn s and Colitis ◽

10.1016/s1873-9946(13)60100-2 ◽

2013 ◽

Vol 7 ◽

pp. S40

Author(s):

M. Thiele ◽

E. Magelky ◽

A. Schinagl ◽

D. Völkel ◽

P. Douillard ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Mouse Models ◽

Migration Inhibitory Factor ◽

Bowel Disease ◽

Macrophage Migration Inhibitory Factor ◽

Inhibitory Factor ◽

Macrophage Migration ◽

Inflammatory Bowel

Download Full-text

Distinct Effects of p38α Deletion in Myeloid Lineage and Gut Epithelia in Mouse Models of Inflammatory Bowel Disease

Gastroenterology ◽

10.1053/j.gastro.2010.01.005 ◽

2010 ◽

Vol 138 (4) ◽

pp. 1255-1265.e9 ◽

Cited By ~ 66

Author(s):

Motoyuki Otsuka ◽

Young Jun Kang ◽

Jianlin Ren ◽

Huiping Jiang ◽

Yinbin Wang ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Mouse Models ◽

Bowel Disease ◽

Myeloid Lineage ◽

Inflammatory Bowel

Download Full-text

The Oncogenic Potential of a Mutant TP53 Gene Explored in Two Spontaneous Lung Cancer Mice Models

10.21203/rs.3.rs-22164/v1 ◽

2020 ◽

Author(s):

Julian Ramelow ◽

Christopher Brooks ◽

Li GaO ◽

Abeer A Almiman ◽

Terence M Williams ◽

...

Keyword(s):

Lung Cancer ◽

Mouse Models ◽

Human Lung ◽

Lung Tumor ◽

Mutant Gene ◽

Genetic Mutation ◽

Tumor Formation ◽

Human Lung Cancer ◽

Oncogenic Potential ◽

Age Related

Abstract BackgroundLung cancer is the number one cancer killer worldwide. A major impediment to progress in the lung cancer treatment field is the lack of realistic mouse models that replicate the complexity of human malignancy and immune contexture within the tumor microenvironment. Such models are urgently needed. Mutations of the tumor suppressor gene TP53 are among the most common alterations in human lung cancers.MethodsPreviously, we developed a line of lung cancer mouse model where mutant human TP53-273H is expressed in a lung specific manner in FVB/N background. To investigate whether the human TP53 mutant has a similar oncogenic potential when it is expressed in another strain of mouse, we crossed the FVB/N-SPC-TP53-273H mice to A/J strain and created A/J-SPC-TP53-273H transgenic mice. We then compared lung tumor formation between A/J-SPC-TP53-273H and FVB/N-SPC-TP53-273H.ResultsWe found the TP53-273H mutant gene has a similar oncogenic potential in lung tumor formation in both mice strains, although A/J strain mice have been found to be a highly susceptible strain in terms of carcinogen-induced lung cancer. Both transgenic lines survived more than 18 months and developed age related lung adenocarcinomas. With micro CT imaging, we found the FVB-SPC-TP53-273H mice survived more than 8 weeks after initial detection of lung cancer, providing a sufficient window for evaluating new anti-cancer agents.ConclusionsOncogenic potential of the most common genetic mutation, TP53-273H, in human lung cancer is unique when it is expressed in different strains of mice. Our mouse models are useful tools for testing novel immune check point inhibitors or other therapeutic strategies in treatment of lung cancer.

Download Full-text

Abstract 17268: ApoA-I Mimetic Peptide 4F Suppresses the Elevation of Pro-Inflammatory Lipid Mediators in Mouse Models of Inflammatory Bowel Disease

Circulation ◽

10.1161/circ.138.suppl_1.17268 ◽

2018 ◽

Vol 138 (Suppl_1) ◽

Author(s):

David Meriwether ◽

Carmen Volpe ◽

Victor Grijalva ◽

Ellen O’Connor ◽

Nasrin Dorreh ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Mouse Models ◽

Inflammatory Mediators ◽

Bowel Disease ◽

Ex Vivo ◽

Early Stage ◽

Lipid Mediators ◽

Serosal Side ◽

Ussing Chambers ◽

Inflammatory Bowel

Introduction: Inflammatory bowel disease (IBD) has been linked to an increased prevalence of early stage vascular disease. ApoA-I mimetic peptides including 4F are potential therapeutic agents for the treatment of inflammatory diseases including atherosclerosis, and their mechanism of action appears localized to the intestine. We have reported that 4F protects against the development of disease in both the piroxicam-accelerated IL10-/- and myeloid COX2-/- mouse models of IBD. Hypothesis: We previously reported that plasma and lesion levels of oxidized products of linoleic and arachidonic acid correlate with disease in mouse models of atherosclerosis, and that 4F protects against disease in these models while inhibiting accumulation of these pro-inflammatory mediators. We thus sought to determine the complete lipid pro-inflammatory mediator profiles of both the COX2- and IL10-dependent models of IBD, while also determining the effect of 4F on the pro-inflammatory lipid profiles. Methods: We developed and validated a LC-ESI-MS/MS method for determining the levels of 40 lipid inflammatory mediators in both intestinal tissue and plasma, and we analyzed the effects of both disease and 4F upon these mediators in both IBD models. We also employed Ussing chambers to investigate ex vivo the direct effect of 4F on the clearance of pro-inflammatory lipid mediators from intestinal explants and serosal-side lipoproteins. Results: Disease in both models correlated with significantly elevated tissue and plasma levels of multiple lipid pro-inflammatory mediators, while the protective effects of 4F correlated with the significant suppression of most of these mediators. Of interest, 4F inhibited the disease dependent increase of 15HETE, 12HETE, 5HETE, 13HODE, LTB4, 6ketoPGF1α, PGF2α, and TXB2 in the COX2-/- model; and 15HETE, 12HETE, 13HODE, LTB4, and LTE4 in the IL10-/- model. Ex vivo, we showed that 4F could directly clear the pro-inflammatory mediators from inflamed intestinal explants, while also mediating their trans-intestinal efflux from serosal-side lipoproteins. Conclusions: 4F appears to protect against IBD in part by inhibiting the accumulation of pro-inflammatory lipid mediators, through a mechanism that involves the intestinal clearance of these mediators from tissue and plasma.

Download Full-text

Inflammatory Bowel Diseases: Host-Microbial-Environmental Interactions in Dysbiosis

Diseases ◽

10.3390/diseases8020013 ◽

2020 ◽

Vol 8 (2) ◽

pp. 13

Author(s):

Catherine Colquhoun ◽

Michelle Duncan ◽

George Grant

Keyword(s):

Inflammatory Bowel Diseases ◽

Early Life ◽

Secretory Iga ◽

Mucus Production ◽

Functional Changes ◽

Environmental Interactions ◽

Intestinal Dysbiosis ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Abundance And Diversity

Crohn’s Disease (CD) and Ulcerative Colitis (UC) are world-wide health problems in which intestinal dysbiosis or adverse functional changes in the microbiome are causative or exacerbating factors. The reduced abundance and diversity of the microbiome may be a result of a lack of exposure to vital commensal microbes or overexposure to competitive pathobionts during early life. Alternatively, many commensal bacteria may not find a suitable intestinal niche or fail to proliferate or function in a protective/competitive manner if they do colonize. Bacteria express a range of factors, such as fimbriae, flagella, and secretory compounds that enable them to attach to the gut, modulate metabolism, and outcompete other species. However, the host also releases factors, such as secretory IgA, antimicrobial factors, hormones, and mucins, which can prevent or regulate bacterial interactions with the gut or disable the bacterium. The delicate balance between these competing host and bacteria factors dictates whether a bacterium can colonize, proliferate or function in the intestine. Impaired functioning of NOD2 in Paneth cells and disrupted colonic mucus production are exacerbating features of CD and UC, respectively, that contribute to dysbiosis. This review evaluates the roles of these and other the host, bacterial and environmental factors in inflammatory bowel diseases.

Download Full-text