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Chronic colitis in Bacteroides Thetaiotaomicron-Monoassociated HLA-B27 Transgenic rats alters expression of receptor and metabolic genes in luminal bacteria.

ABSTRACT: Background: Inflammatory bowel diseases (IBD) may be caused in part by aberrant immune responses to commensal intestinal microbes including Bacteroides thetaiotaomicron (B.theta). Healthy, germ-free HLA-B27 transgenic (Tg) rats develop chronic colitis when colonized with complex gut commensal bacteria whereas non-transgenic (nTg) rats remain disease-free. However, the role of B.theta, a well-characterized anaerobic commensal bacterium, in causing disease in Tg rats is unknown nor is much known about how microbes respond to host inflammation. Methods: Tg and nTg rats were monoassociated with a human isolate of B.theta. Colonic inflammation was quantified by blinded histological scoring and real-time RT-PCR assays of pro-inflammatory cytokines. Cecal bacterial concentrations were measured by quantitative plating. Whole genome transcriptional profiling of B.theta recovered from ceca was performed using custom GeneChips and data analyzed using dChip, Significance Analysis of Microarrays, and Gene Set Enrichment Analysis (GSEA) software. Results: B.theta monoassociated Tg rats had significantly more colonic inflammation and increased colonic levels of pro-inflammatory cytokine mRNAs compared to nTg controls. Transcriptional profiles of cecal B.theta were significantly different in Tg vs. nTg rats. GSEA revealed that the Gene Ontology molecular function of receptor activity, which is comprised mainly of genes that encode nutrient binding proteins, was significantly enriched with genes upregulated in B.theta from Tg rats. KEGG canonical pathways of ribosome, oxidative phosphorylation, pyrimidine metabolism, purine metabolism, peptidoglycan biosynthesis, and metabolism were significantly enriched with genes downregulated in B.theta from Tg rats. Numbers of viable bacteria/gram cecal contents in Tg vs. nTg rats were not significantly different. Conclusions: B.theta induces mild colitis in HLA-B27 Tg rats, which is associated with changes in the expression of microbial metabolic and nutrient binding pathways, but no difference in concentrations of luminal bacteria. Mechanistic studies of differentially expressed B.theta genes may reveal novel pathways that contribute to IBD.

ORGANISM(S): Parabacteroides distasonis Phocaeicola vulgatus Bacteroides thetaiotaomicron Lachnospira eligens Agathobacter rectalis Methanobrevibacter smithii

PROVIDER: GSE34966 | GEO | 2012/01/11

SECONDARY ACCESSION(S): PRJNA150943

REPOSITORIES: GEO

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Project description:Background: Inflammatory bowel diseases (IBD) may be caused in part by aberrant immune responses to commensal intestinal microbes including Bacteroides thetaiotaomicron (B.theta). Healthy, germ-free HLA-B27 transgenic (Tg) rats develop chronic colitis when colonized with complex gut commensal bacteria whereas non-transgenic (nTg) rats remain disease-free. However, the role of B.theta, a well-characterized anaerobic commensal bacterium, in causing disease in Tg rats is unknown nor is much known about how microbes respond to host inflammation. Methods: Tg and nTg rats were monoassociated with a human isolate of B.theta. Colonic inflammation was quantified by blinded histological scoring and real-time RT-PCR assays of pro-inflammatory cytokines. Cecal bacterial concentrations were measured by quantitative plating. Whole genome transcriptional profiling of B.theta recovered from ceca was performed using custom GeneChips and data analyzed using dChip, Significance Analysis of Microarrays, and Gene Set Enrichment Analysis (GSEA) software. Results: B.theta monoassociated Tg rats had significantly more colonic inflammation and increased colonic levels of pro-inflammatory cytokine mRNAs compared to nTg controls. Transcriptional profiles of cecal B.theta were significantly different in Tg vs. nTg rats. GSEA revealed that the Gene Ontology molecular function of receptor activity, which is comprised mainly of genes that encode nutrient binding proteins, was significantly enriched with genes upregulated in B.theta from Tg rats. KEGG canonical pathways of ribosome, oxidative phosphorylation, pyrimidine metabolism, purine metabolism, peptidoglycan biosynthesis, and metabolism were significantly enriched with genes downregulated in B.theta from Tg rats. Numbers of viable bacteria/gram cecal contents in Tg vs. nTg rats were not significantly different. Conclusions: B.theta induces mild colitis in HLA-B27 Tg rats, which is associated with changes in the expression of microbial metabolic and nutrient binding pathways, but no difference in concentrations of luminal bacteria. Mechanistic studies of differentially expressed B.theta genes may reveal novel pathways that contribute to IBD. The fully-sequenced human fecal isolate of B.theta (VPI-5482) was grown on Brain-Heart Infusion (BHI) agar and in BHI broth under strict anaerobic conditions using pre-reduced media. Adult germ-free HLA-B27/b2 microglobulin transgenic rats and adult germ-free non-transgenic littermate were monoassociated with B.theta for six weeks in gnotobiotic isolators at the National Gnotobiotic Rodent Resource Center at UNC Chapel Hill. Bacterial RNA was isolated from rat cecal contents and hybridized on Affymetrix human gut microbiota community GeneChip.

Project description:Leber2015 - Mucosal immunity and gut microbiome interaction during C. difficile infection This model is described in the article: Systems Modeling of Interactions between Mucosal Immunity and the Gut Microbiome during Clostridium difficile Infection. Leber A, Viladomiu M, Hontecillas R, Abedi V, Philipson C, Hoops S, Howard B, Bassaganya-Riera J. PLoS ONE 2015; 10(7): e0134849 Abstract: Clostridium difficile infections are associated with the use of broad-spectrum antibiotics and result in an exuberant inflammatory response, leading to nosocomial diarrhea, colitis and even death. To better understand the dynamics of mucosal immunity during C. difficile infection from initiation through expansion to resolution, we built a computational model of the mucosal immune response to the bacterium. The model was calibrated using data from a mouse model of C. difficile infection. The model demonstrates a crucial role of T helper 17 (Th17) effector responses in the colonic lamina propria and luminal commensal bacteria populations in the clearance of C. difficile and colonic pathology, whereas regulatory T (Treg) cells responses are associated with the recovery phase. In addition, the production of anti-microbial peptides by inflamed epithelial cells and activated neutrophils in response to C. difficile infection inhibit the re-growth of beneficial commensal bacterial species. Computational simulations suggest that the removal of neutrophil and epithelial cell derived anti-microbial inhibitions, separately and together, on commensal bacterial regrowth promote recovery and minimize colonic inflammatory pathology. Simulation results predict a decrease in colonic inflammatory markers, such as neutrophilic influx and Th17 cells in the colonic lamina propria, and length of infection with accelerated commensal bacteria re-growth through altered anti-microbial inhibition. Computational modeling provides novel insights on the therapeutic value of repopulating the colonic microbiome and inducing regulatory mucosal immune responses during C. difficile infection. Thus, modeling mucosal immunity-gut microbiota interactions has the potential to guide the development of targeted fecal transplantation therapies in the context of precision medicine interventions. This model is hosted on BioModels Database and identified by: BIOMD0000000583. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Background and Aims: We have shown in several controlled rat and human infection studies that dietary calcium improves intestinal resistance and strengthens the mucosal barrier. Reinforcement of gut barrier function is also relevant for inflammatory bowel disease (IBD). Therefore, we investigated the effect of supplemental calcium on spontaneous colitis development in HLA-B27 transgenic rats, an experimental animal model of IBD. Methods: HLA-B27 transgenic rats were fed a purified high-fat diet containing either a low or high calcium content (30 and 120 mmol CaHPO4/kg diet, respectively) for almost 7 weeks. Inert chromium ethylenediamine-tetraacetic acid (CrEDTA) was added to the diets to quantify intestinal permeability by measuring urinary CrEDTA excretion. Relative fecal dry-weight was determined to quantify diarrhea. Colonic inflammation was determined histologically, and by measuring mucosal interleukin-1M-NM-2. In addition, colonic mucosal gene expression of individual rats was analyzed, using whole genome microarrays. Interesting results were verified by Q-PCR. Results: The high-calcium diet significantly prevented the increase in intestinal permeability and diarrhea with time in HLA-B27 rats developing colitis as compared to the low-calcium group. The histological colitis score and mucosal interleukin-1M-NM-2 levels were lower in high-calcium fed rats. Supplemental calcium prevented the colitis-induced increase in the expression of extracellular matrix remodeling genes (e.g. matrix metalloproteinases, procollagens and fibronectin), which was confirmed by Q-PCR. Conclusions: Dietary calcium inhibits colitis development in HLA-B27 transgenic rats. Calcium prevents the colitis-related increase in intestinal permeability, diminishes diarrhea, and lowers the inflammatory response in the mucosa, resulting in less extracellular matrix breakdown. Keywords: nutritional intervention Female HLA-B27/M-NM-22-microglobulin transgenic rats on an inbred Fisher 344 background (n=8 in experimental group and n=9 in control group) (Taconic Farms, Inc, Germantown, NY), 8-10 weeks old and with a mean body weight of 128 g at the start of the experiment, were housed individually in metabolic cages. Animals were kept in a temperature- and humidity-controlled environment and in a 12-h light-dark cycle. Rats were fed a purified M-bM-^@M-^XhumanizedM-bM-^@M-^Y Western diet which contained in the control situation (per kg): 200 g acid casein, 326 g corn starch, 174 g glucose, 160 g palm oil, 40 g corn oil, 50 g cellulose and 5.16 g CaHPO4.2H2O (corresponding to 30 mmol calcium/kg diet; Sigma-Aldrich, St Louis, MO). Vitamins and minerals (other than calcium) were added to all diets according to the recommendations of the American Institute of Nutrition 1993.17 The experimental diet contained more calcium (120 mmol calcium/kg diet) at the expense of glucose. All samples were individually labelled and hybridized (Cy5). Equal amounts of Cy3 cRNA of all animals were pooled to serve as standard reference pool.

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Chronic colitis in Bacteroides Thetaiotaomicron-Monoassociated HLA-B27 Transgenic rats alters expression of receptor and metabolic genes in luminal bacteria.

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