Dataset Information

Inflammatory bowel disease therapies and gut function in a colitis mouse model.

ABSTRACT:

Background

Exclusive enteral nutrition (EEN) is a well-established approach to the management of Crohn's disease. Aim. To determine effects of EEN upon inflammation and gut barrier function in a colitis mouse model.

Methods

Interleukin-10-deficient mice (IL-10(-/-)) were inoculated with Helicobacter trogontum and then treated with EEN, metronidazole, hydrocortisone, or EEN and metronidazole combination. Blood and tissue were collected at 2 and 4 weeks with histology, mucosal integrity, tight junction integrity, inflammation, and H. trogontum load evaluated.

Results

H. trogontum induced colitis in IL-10(-/-) mice with histological changes in the cecum and colon. Elevated mucosal IL-8 mRNA in infected mice was associated with intestinal barrier dysfunction indicated by decreased transepithelial electrical resistance and mRNA of tight junction proteins and increased short-circuit current, myosin light chain kinase mRNA, paracellular permeability, and tumor necrosis factor- ? and myeloperoxidase plasma levels (P < 0.01 for all comparisons). EEN and metronidazole, but not hydrocortisone, treatments restored barrier function, maintained gut barrier integrity, and reversed inflammatory changes along with reduction of H. trogontum load (versus infected controls P < 0.05).

Conclusion

H. trogontum infection in IL-10(-/-) mice induced typhlocolitis with intestinal barrier dysfunction. EEN and metronidazole, but not hydrocortisone, modulate barrier dysfunction and reversal of inflammatory changes.

SUBMITTER: Nahidi L

PROVIDER: S-EPMC3763566 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

Inflammatory bowel disease therapies and gut function in a colitis mouse model.

Nahidi Lily L Leach Steven T ST Mitchell Hazel M HM Kaakoush Nadeem O NO Lemberg Daniel A DA Munday John S JS Huinao Karina K Day Andrew S AS

BioMed research international 20130806

<h4>Background</h4>Exclusive enteral nutrition (EEN) is a well-established approach to the management of Crohn's disease. Aim. To determine effects of EEN upon inflammation and gut barrier function in a colitis mouse model.<h4>Methods</h4>Interleukin-10-deficient mice (IL-10(-/-)) were inoculated with Helicobacter trogontum and then treated with EEN, metronidazole, hydrocortisone, or EEN and metronidazole combination. Blood and tissue were collected at 2 and 4 weeks with histology, mucosal integ ...[more]

PMID: 24027765

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Project description:Inflammatory bowel disease (IBD) is one of the immune-related gastrointestinal disorders, including ulcerative colitis and Crohn's disease, that affects the life quality of millions of people worldwide. IBD symptoms include abdominal pain, diarrhea, and rectal bleeding, which may result from the interactions among gut microbiota, food components, intestinal epithelial cells, and immune cells. It is of particular importance to assess how each key gene expressed in intestinal epithelial and immune cells affects inflammation in the colon. G protein-coupled taste receptors, including G protein subunit α-gustducin and other signaling proteins, have been found in the intestines. Here, we use α-gustducin as a representative and describe a dextran sulfate sodium (DSS)-induced IBD model to evaluate the effect of gustatory gene mutations on gut mucosal immunity and inflammation. This method combines gene knockout technology with the chemically induced IBD model, and thus can be applied to assess the outcome of gustatory gene nullification as well as other genes that may exuberate or dampen the DSS-induced immune response in the colon. Mutant mice are administered with DSS for a certain period during which their body weight, stool, and rectal bleeding are monitored and recorded. At different timepoints during administration, some mice are euthanized, then the sizes and weights of their spleens and colons are measured and gut tissues are collected and processed for histological and gene expression analyses. The data show that the α-gustducin knockout results in excessive weight loss, diarrhea, intestinal bleeding, tissue damage, and inflammation vs. wild-type mice. Since the severity of induced inflammation is affected by mouse strains, housing environment, and diet, optimization of DSS concentration and administration duration in a pilot experiment is particularly important. By adjusting these factors, this method can be applied to assess both anti- and pro-inflammatory effects.

Project description:BACKGROUND:Ionizing Radiation (IR) is a known pro-inflammatory agent and in the process of development of biomarkers for radiation biodosimetry, a chronic inflammatory disease condition could act as a confounding factor. Hence, it is important to develop radiation signatures that can distinguish between IR-induced inflammatory responses and pre-existing disease. In this study, we compared the gene expression response of a genetically modified mouse model of inflammatory bowel disease (Il10-/-) with that of a normal wild-type mouse to potentially develop transcriptomics-based biodosimetry markers that can predict radiation exposure in individuals regardless of pre-existing inflammatory condition. RESULTS:Wild-type (WT) and Il10-/- mice were exposed to whole body irradiation of 7?Gy X-rays. Gene expression responses were studied using high throughput whole genome microarrays in peripheral blood 24?h post-irradiation. Analysis resulted in identification of 1962 and 1844 genes differentially expressed (p <?0.001, FDR?<?10%) after radiation exposure in Il10-/- and WT mice respectively. A set of 155 genes was also identified as differentially expressed between WT and Il10-/- mice at the baseline pre-irradiation level. Gene ontology analysis revealed that the 155 baseline differentially expressed genes were mainly involved in inflammatory response, glutathione metabolism and collagen deposition. Analysis of radiation responsive genes revealed that innate immune response and p53 signaling processes were strongly associated with up-regulated genes, whereas B-cell development process was found to be significant amongst downregulated genes in the two genotypes. However, specific immune response pathways like MHC based antigen presentation, interferon signaling and hepatic fibrosis were associated with radiation responsive genes in Il10-/- mice but not WT mice. Further analysis using the IPA prediction tool revealed significant differences in the predicted activation status of T-cell mediated signaling as well as regulators of inflammation between WT and Il10-/- after irradiation. CONCLUSIONS:Using a mouse model we established that an inflammatory disease condition could affect the expression of many radiation responsive genes. Nevertheless, we identified a panel of genes that, regardless of disease condition, could predict radiation exposure. Our results highlight the need for consideration of pre-existing conditions in the population in the process of development of reliable biodosimetry markers.

Dataset Information

Inflammatory bowel disease therapies and gut function in a colitis mouse model.

Background

Methods

Results

Conclusion

Publications

Inflammatory bowel disease therapies and gut function in a colitis mouse model.

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