Ontology highlight
ABSTRACT:
PROVIDER: PRJNA703330 | ENA |
REPOSITORIES: ENA
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Project description:BACKGROUND & AIMS: Inflammatory Bowel Disease (IBD) is a chronic inflammatory condition driven by loss of homeostasis between the mucosal immune system, the commensal gut microbiota, and the intestinal epithelium. Our overarching goal is to understand how these components of the intestinal ecosystem cooperate to control homeostasis and to identify novel signal transduction pathways that become dysregulated in IBD. METHODS: We have applied a multi-scale systems biology approach to a mouse model of chronic colitis. We combined quantitative measures of epithelial hyperplasia and immune infiltration with multivariate analysis of inter- and intra-cellular signaling molecules in order to generate a tissue level model of the inflamed disease state. We utilized the computational model to identify signaling pathways that were dysregulated in the context of colitis and then validated model predictions by measuring the effect of small molecule pathway inhibitors on colitis. RESULTS: Our data-driven computational model identified mTOR signaling as a potential driver of inflammation and mTOR inhibition reversed the molecular, immunological, and epithelial manifestations of colitis. Inhibition of Notch signaling, which induces epithelial differentiation, had the same effect, suggesting that the epithelial proliferation/differentiation state plays a key role in maintaining homeostasis of the colon. Confirming this, we found that colonic organoids grown ex vivo showed a similar relationship between proliferation and cytokine expression, even in the absence of gut bacteria and immune cells. CONCLUSIONS: Our study provides a tissue-level systems biology perspective of murine colitis and suggests that mTOR plays a key role in regulating colonic homeostasis by controlling epithelial proliferation/differentiation state. We used microarrays to examine changes in global gene expression patterns associated with chronic inflammation induced by the T cell transfer model of Inflammatory Bowel Disease.
2018-02-05 | GSE87317 | GEO
Project description:IBD is characterized by chronic recurrences of intestinal inflammation and intestinal immune disturbances.Bacteroides vulgatus can alleviate DSS-induced colitis in mice, but the mechanism is unknown. The aim of this study was to examine the changes in gene expression in the intestinal tissue of mice with colitis following treatment with Bacteroides vulgatus by RNA sequencing.
2023-12-06 | GSE246118 | GEO
Project description:Histone deacetylases (Hdac) remove acetyl groups from proteins, influencing global and specific gene expression. Hdacs control inflammation, as shown by Hdac inhibitor-dependent protection from DSS-induced murine colitis. While tissue-specific Hdac knockouts show redundant and specific functions, little is known of their intestinal epithelial cell (IEC) role. We have shown previously that dual Hdac1/Hdac2 IEC-specific loss disrupts cell proliferation and determination, with decreased secretory cell numbers and altered barrier function. We thus investigated how compound Hdac1/Hdac2 or Hdac2 IEC-specific deficiency alters the inflammatory response. Floxed Hdac1 and Hdac2 and villin-Cre mice were interbred. Compound Hdac1/Hdac2 IEC-deficient mice showed chronic basal inflammation, with increased basal Disease Activity Index (DAI) and deregulated Reg gene colonic expression. DSS-treated dual Hdac1/Hdac2 IEC-deficient mice displayed increased DAI, histological score, intestinal permeability and inflammatory gene expression. In contrast to double knockouts, Hdac2 IEC-specific loss did not affect IEC determination and growth, nor result in chronic inflammation. However, Hdac2 disruption protected against DSS colitis, as shown by decreased DAI, intestinal permeability and caspase-3 cleavage. Hdac2 IEC-specific deficient mice displayed increased expression of IEC gene subsets, such as colonic antimicrobial Reg3b and Reg3g mRNAs, and decreased expression of immune cell function-related genes. Our data show that Hdac1 and Hdac2 are essential IEC homeostasis regulators. IEC-specific Hdac1 and Hdac2 may act as epigenetic sensors and transmitters of environmental cues and regulate IEC-mediated mucosal homeostatic and inflammatory responses. Different levels of IEC Hdac activity may lead to positive or negative outcomes on intestinal homeostasis during inflammation Total RNAs from the colon of three control and three Hdac2 IEC-specific knockout mice were isolated with the Rneasy kit (Qiagen, Mississauga, ON, Canada).
2014-02-08 | E-GEOD-54785 | biostudies-arrayexpress
Project description:In this study, we attempted to dissect the dynamic changes during inflammation using well-prepared scRNA-seq dataset. Specifically, we tried to characterize the pathology and the biological mechanism underlying the ulcerative colitis separately for the acute and chronic colitis. We observed a significant reduction in epithelial populations during acute colitis, indicating tissue damage, with a partial recovery observed in chronic inflammation. Analyses of cell-cell interactions demonstrated shifts in networking patterns among different cell types during disease progression. Notably, macrophage phenotypes exhibited diversity, with a pronounced polarization towards the pro-inflammatory M1 phenotype in chronic condition, suggesting the role of macrophage heterogeneity in disease progression. Analysis of the intestinal microbiome revealed significant alterations in composition and metabolism pathways, particularly the nicotinamide pathway. Additionally, dysbiosis was linked to dysregulation of NAD homeostasis through NAMPT, providing insights into potential therapeutic strategies. The study also highlighted the role of T cell differentiation in the context of dysbiosis and its implications in colitis progression, emphasizing the need for targeted interventions to modulate the inflammatory response and immune balance in colitis.
2024-05-08 | GSE264408 | GEO
Project description:The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that buoys intestinal immune responses. AHR induces its own negative regulator, the AHR repressor (AHRR). Here we show that AHRR is vital to sustain intestinal intraepithelial lymphocytes (IEL). Fewer IEL of all types were present in the absence of AHRR. Single cell RNA sequencing (scRNAseq) revealed an oxidative cell stress profile in Ahrr–/– IEL. Ahrr deficiency unleashed AHR-induced expression of CYP1A1, an oxidative enzyme that generates reactive oxygen species; this resulted in elevated intracellular content of reactive oxygen species, lipid peroxidation and ferroptosis in Ahrr–/– IEL. Dietary supplementation with selenium or Vitamin-E (Vit-E) to restore redox homeostasis rescued Ahrr–/– IEL. Loss of IEL in Ahrr deficient mice caused susceptibility to Clostridium difficile infection and dextran sodium sulfate-induced colitis. We conclude that AHR signaling must be tightly regulated to prevent oxidative stress and ferroptosis of IEL to preserve intestinal immune responses.
2023-01-19 | GSE199960 | GEO
Project description:The mucosal epithelium plays a key role in regulating immune homeostasis. Dysregulation of epithelial barrier function is associated with mucosal inflammation. Expression of claudin-2, a pore-forming tight junction protein, is highly upregulated during inflammatory bowel disease (IBD) and, due to its association with epithelial permeability, has been postulated to promote inflammation. Furthermore, claudin-2 also regulates colonic epithelial cell proliferation and intestinal nutrient absorption. However, the precise role of claudin-2 in regulating colonic epithelial and immune homeostasis remains unclear. Here, we demonstrate, using Villin-Claudin-2 transgenic (Cl-2TG) mice, that increased colonic claudin-2 expression unexpectedly protects mice against experimentally induced colitis and colitis-associated cancer. Notably, Cl-2TG mice exhibited increased colon length and permeability as compared with wild type (WT) littermates. However, despite their leaky colon, Cl-2TG mice subjected to experimental colitis were immune compromised, with reduced induction of TLR-2, TLR-4, Myd-88 expression and NF-kB and STAT3 activation. Most importantly, colonic macrophages in Cl-2TG mice exhibited an anergic phenotype. Claudin-2 overexpression also increased colonocyte proliferation and provided protection against colitis-induced colonocyte death. Taken together, our findings have revealed a critical role of claudin-2 in regulating colonic homeostasis, suggesting novel therapeutic strategies for inflammatory conditions of the gastrointestinal tract. 8-10 weeks old male Villin-Claudin-2 transgenic mice and WT littermates were provided either normal drinking water (control) or Dextran Sodium Sulfate (DSS: 4% w/v) for 10 days. 3 replicates each.
2013-09-15 | E-GEOD-46006 | biostudies-arrayexpress
Project description:STAT3 is a pleiotropic transcription factor with important functions in cytokine signalling in a variety of tissues. However, the role of STAT3 in the intestinal epithelium is not well understood. Here we demonstrate that development of colonic inflammation is associated with the induction of STAT3 activity in intestinal epithelial cells (IEC). Studies in genetically engineered mice showed that epithelial STAT3 activation in DSS colitis is dependent on IL-22 rather than IL-6. IL-22 was secreted by colonic CD11c+ cells in response to Toll-like receptor stimulation. Conditional knockout mice with an IEC specific deletion of STAT3 activity were highly susceptible to experimental colitis, indicating that epithelial STAT3 regulates gut homeostasis. STAT3IEC-KO mice, upon induction of colitis, showed a striking defect of epithelial restitution. Gene chip analysis indicated that STAT3 regulates the cellular stress response, apoptosis and pathways associated with wound healing in IEC. Consistently, both IL-22 and epithelial STAT3 were found to be important in wound-healing experiments in vivo. In summary, our data suggest that intestinal epithelial STAT3 activation regulates immune homeostasis in the gut by promoting IL-22-dependent mucosal wound healing. 4 samples of colon epithelium were analyzed from 4 mice (2 per group Stat3flfl VillinCre- and Stat3flfl VillinCre+, respectively) after they had been treated with DSS (2.5%) for 5 days
2009-05-08 | E-GEOD-15955 | biostudies-arrayexpress
Project description:immune cells in intestinal lamina propria play important roles in pathogenesis of DSS colitis. Here, we used single cell RNA sequencing (scRNA-seq) to reveale the intestinal immune landscape of DSS colitis and study the effects of Ring1A on intestinal immune cells.
2023-09-13 | GSE210866 | GEO
Project description:Hepcidin is demonstrated to be the key iron regulatory hormone, produced by the liver. Here we show an unexpected role of hepcidin as a master initiator of the local and systemic inflammatory response. We found that hepcidin was highly expressed in the colon of two major idiopathic inflammatory bowel diseases : Crohn's disease (CD) and ulcerative colitis (UC). Thanks to the generation of intestinal specific hepcidin KO mice (Hepc{delta}int), we found in a DSS-induced colitis model that hepcidin mediated the induction of key inflammatory cytokines and was protective against intestinal injury. In a model of LPS-induced acute inflammation, intestinal hepcidin expression was increased through a TLR4 dependent pathway andwas required for intestinal neutrophil infiltration and inflammation. Strikingly, intestinal hepcidin was absolutely required for the systemic production of key inflammatory cytokines (IL-6, CXCL1, TNF-alpha ...) as well as for the setting of the hypoferremia of inflammation. In a sepsis model, Hepc{delta}int mice were protected against LPS-induced mortality. Mechanistically, we showed that hepcidin was a direct neutrophil chemoattractant and a proinflammatory molecule in macrophages through a Myd88 dependent pathway. Altogether, we demonstrated that Hepcidin is a key new essential component of the immune system and may be a promising target in many inflammatory diseases. We used microarrays to detail the global program of gene expression of BMDM treat with hepcidin for 1 hour.
2016-07-16 | E-GEOD-71073 | biostudies-arrayexpress