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Dissecting the respective role of microbiota and host genetics in the susceptibility of Card9-/- mice to colitis

ABSTRACT: Background: The etiology of Inflammatory Bowel Disease (IBD) is unclear but involves both genetics and environmental factors, including the gut microbiota. Indeed, exacerbated activation of the gastrointestinal immune system toward the gut microbiota occurs in genetically susceptible hosts and under the influence of the environment. For instance, a majority of IBD susceptibility loci lie within genes involved in immune responses, such as caspase recruitment domain member 9 (Card9). However, the relative impacts of genotype versus microbiota on colitis susceptibility in the context of CARD9 deficiency remain unknown. Results: Card9 gene directly contributes to recovery from dextran sodium sulfate (DSS)-induced colitis by inducing the colonic expression of the cytokine IL-22 and the antimicrobial peptides Reg3 and Reg3 independently of the microbiota. On the other hand, Card9 is required for regulating the microbiota capacity to produce AhR ligands, which leads to the production of IL-22 in the colon, promoting recovery after colitis. In addition, cross-fostering experiments showed that five weeks after weaning, the microbiota transmitted from the nursing mother before weaning had a stronger impact on the tryptophan metabolism of the pups than the pups' own genotype. Conclusions: These results show the role of CARD9 and its effector IL-22 in mediating recovery from DSS-induced colitis in both microbiota-independent and microbiota-dependent manners. Card9 genotype modulates the microbiota metabolic capacity to produce AhR ligands, but this effect can be overridden by the implantation of a WT or healthy microbiota before weaning. It highlights the importance of the weaning reaction occurring between the immune system and microbiota for the host metabolism and immune functions throughout life. A better understanding of the impact of genetics on microbiota metabolism is key to developing efficient therapeutic strategies for patients suffering from complex inflammatory disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE262585 | GEO | 2024/05/01

REPOSITORIES: GEO

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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.

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. Gene expression profiles were established for normal miR-21-/- mice and wild type c57BL/6 mice (WT). Total of 6 samples with replicates were included in this study.

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Dissecting the respective role of microbiota and host genetics in the susceptibility of Card9-/- mice to colitis

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