Dataset Information

Examining the brain's response to intestinal permeability and inflammation in the dextran sulfate sodium-induced colitis model.

ABSTRACT: The gut and brain are increasingly linked in human disease, with neuropsychiatric conditions classically long attributed to the brain showing an involvement of the intestine and inflammatory bowel diseases displaying an ever-lengthening list of neurological comorbidities. To identify molecular systems that underpin this gut-brain connection and thus discover therapeutic targets, experimental models of gut dysfunction must be evaluated for brain effects. In the present study, we examine disturbances along the gut-brain axis in a widely used murine model of colitis, the dextran sodium sulfate (DSS) model, using high-throughput transcriptomics and an unbiased network analysis strategy coupled with standard outcome measures, yielding a comprehensive approach to identify key disease processes in both colon and brain. We examine the reproducibility of colitis induction with this model and its resulting genetic programs during different phases of disease, finding that DSS-induced colitis is largely reproducible with a few site-specific molecular features. We focus on the circulating immune system, which exhibits an activation of pro-inflammatory innate immunity during colitis, as the vessel between gut and brain. Our unbiased approach provides supporting evidence for immune activation in the brain during colitis, suggests that myelination may be a vulnerable system with intestinal permeability, and identifies a possible role for oxidative stress and brain oxygenation. Overall, we provide a comprehensive evaluation of multiple systems in a prevalent experimental model of intestinal permeability, which will inform future studies using this model and others, assist in the identification of druggable targets, and contribute to our understanding of the concomitance of intestinal and neuropsychiatric dysfunction.

ORGANISM(S): Mus musculus

PROVIDER: GSE239820 | GEO | 2023/08/01

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Aim: RNA binding proteins (RBPs) are emerging as critical regulators of gut homeostasis via post-transcriptional control of key growth and repair pathways. IMP1 (IGF2 mRNA Binding Protein 1) is ubiquitously expressed during embryonic development and Imp1 hypomorphic mice exhibit severe gut growth defects. In the present study, we investigated the mechanistic contribution of intestinal epithelial IMP1 to gut homeostasis and response to injury. Method: We evaluated IMP1 expression in patients with Crohn’s disease followed by unbiased ribosome profiling in IMP1 knockout cells. Concurrently, we measured differences in histology and cytokine expression in mice with intestinal epithelial-specific Imp1 deletion (Imp1ΔIEC) following dextran sodium sulfate (DSS)- colitis. Based on ribosome profiling analysis, we evaluated changes in autophagy in Imp1ΔIEC mice as well as in silico and in vitro approaches to evaluate direct protein:RNA interactions. Finally, we analyzed the consequence of genetic deletion of Atg7 in Imp1ΔIEC mice using colitis and irradiation models. Results: IMP1 was robustly upregulated in Crohn’s disease patients and Imp1 loss lessened DSS-colitis severity. Unbiased ribosome-profiling revealed that IMP1 may coordinate translation of multiple pathways important for intestinal homeostasis, including cell cycle and autophagy, which we verified by Western blotting. Mechanistically, we observed evidence for increased autophagy flux in Imp1ΔIEC mice, reinforced through in silico and biochemical analyses revealing direct binding of IMP1 to autophagy transcripts. Finally, we found genetic deletion of Atg7 reversed the phenotype observed in DSS- or irradiation-challenged Imp1ΔIEC mice. Conclusions: IMP1 acts as a post-transcriptional regulator of gut epithelial repair, in part through modulation of autophagy. This study highlights the need for examining post-transcriptional regulation as a critical mechanism in inflammatory bowel disease.

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).

Project description:Background: MicroRNAs (miRNAs) acting as negative regulators of gene expression are differentially expressed in intestinal tissues of patients with inflammatory bowel disease (IBD). Assessing the functional role of miRNAs in murine models of colitis facilitates elucidating the role of specific miRNAs in human IBD. The aim of this study was to determine the miRNA signature of murine models of colitis and to assess the influence of miR-21 on intestinal inflammation. Methods: miRNAs expression was accessed by microarray for acute and chronic murine model of colitis induced by DSS or TNBS. miR-21-deficient mouse and littermates controls were assessed in the standard DSS, TNBS and CD4+ T cell transfer models of colitis. RNAs of mouse colon and CD4+CD45RBHigh cells were analyzed by miRNA and mRNA microarray, and quantitative RT-PCR. Th1 polarization was accessed by flow-cytometry and ELISA. Results: Alterations of in miRNAs expression were identified for acute and chronic DSS colitis and TNBS colitis, receptively. The Expression of miRs-21, -142-3p and -223 was were distinct between DSS and TNBS models while overlap of numerous miRNAs was seen. Importantly, miRs-19b, -192 and -215, that are decreased in IBD, were significantly decreased in all 4 models of colitis. miR-21, which is increased in IBD, was increased in TNBS colitis but not the DSS colitis models. Further assessment of the miR-21-deficient 1-/- mice revealed that the deletion of miR-21 results in the exacerbation of both the TNBS and T cell-transfer models of colitis. Conclusions: miRNAs are differentially expressed in both human IBD and murine colitis, with overlap of several IBD-associated miRNAs. The demonstration that miR-21 deletion exacerbated CD4+ T cell-mediated models of colitis provides further evidence that miRNAs play significant roles in the pathogenesis of IBD. miRNAs expression was accesed for acute and chronic murine model of colitis induced by DSS or TNBS.Total of 20 samples with duplicates were analyed in this study.

Dataset Information

Examining the brain's response to intestinal permeability and inflammation in the dextran sulfate sodium-induced colitis model.

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets