Dataset Information

Indol-3-Carbinol and Quercetin Ameliorate Chronic DSS-Induced Colitis in C57BL/6 Mice by AhR-Mediated Anti-Inflammatory Mechanisms.

ABSTRACT: Inflammatory bowel diseases (IBD), such as Crohn's disease and ulcerative colitis, are multifactorial inflammatory disorders of the gastrointestinal tract, characterised by abdominal cramps, bloody diarrhoea, and anaemia. Standard therapies, including corticosteroids or biologicals, often induce severe side effects, or patients may develop resistance to those therapies. Thus, new therapeutic options for IBD are urgently needed. This study investigates the therapeutic efficacy and safety of two plant-derived ligands of the aryl hydrocarbon receptor (AhR), quercetin (Q), and indol-3-carbinol (I3C), using a translationally relevant mouse model of IBD. Q and I3C are administered by gavage to C57BL/6 wild-type or C57BL/6 Ahr^-/- mice suffering from chronic colitis, induced by dextran sulphate sodium (DSS). The course of the disease, intestinal histopathological changes, and in-situ immunological phenotype are scored over 25 days. Our results show that both Q and I3C improved significantly clinical symptoms in moderate DSS colitis, which coincides with a significantly reduced histopathological score. Even in severe DSS colitis I3C, neither Q nor the therapy control 6-thioguanine (6-TG) can prevent a fatal outcome. Moreover, treatment with Q or I3C restored in part DSS-induced loss of epithelial integrity by induction of tight-junction proteins and reduced significantly gut inflammation, as demonstrated by colonoscopy, as well as by immunohistochemistry revealing lower numbers of neutrophils and macrophages. Moreover, the number of Th17 cells is significantly reduced, while the number of Treg cells is significantly increased by treatment with Q or I3C, as well as 6-TG. Q- or I3C-induced amelioration of colitis is not observed in Ahr^-/- mice suggesting the requirement of AhR ligation and signalling. Based on the results of this study, plant-derived non-toxic AhR agonists can be considered promising therapeutics in IBD therapy in humans. However, they may differ in terms of efficacy; therefore, it is indispensable to study the dose-response relationship of each individual AhR agonist also with regard to potential adverse effects, since they may also exert AhR-independent effects.

SUBMITTER: Riemschneider S

PROVIDER: S-EPMC7956562 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Indol-3-Carbinol and Quercetin Ameliorate Chronic DSS-Induced Colitis in C57BL/6 Mice by AhR-Mediated Anti-Inflammatory Mechanisms.

Riemschneider Sina S Hoffmann Maximilian M Slanina Ulla U Weber Klaus K Hauschildt Sunna S Lehmann Jörg J

International journal of environmental research and public health 20210225 5

Inflammatory bowel diseases (IBD), such as Crohn's disease and ulcerative colitis, are multifactorial inflammatory disorders of the gastrointestinal tract, characterised by abdominal cramps, bloody diarrhoea, and anaemia. Standard therapies, including corticosteroids or biologicals, often induce severe side effects, or patients may develop resistance to those therapies. Thus, new therapeutic options for IBD are urgently needed. This study investigates the therapeutic efficacy and safety of two p ...[more]

PMID: 33668818

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Project description:Dextran sodium sulfate (DSS)-induced colitis is widely used to study pathological mechanisms and potential treatments of inflammatory bowel disease. Because temporal changes in genome expression profiles remain unknown in this model, we performed whole genome expression profile analysis during the development of DSS colitis in comparison with ulcerative colitis (UC) specimens to identify novel and common responses during disease. Colon tissue from DSS-treated mice was collected at days 0, 2, 4, and 6. Half of each specimen was used for histopathological analysis and half for Affymetrix whole genome expression profiling and qRT-PCR validation. Genesifter and Ingenuity software analysis was used to identify differentially expressed genes and perform interactive network analysis. Identified DSS-associated genes in mice were also compared with UC patient data. We identified 1,609 genes that were significantly altered during DSS colitis; the majority were functionally related to inflammation, angiogenesis, metabolism, biological adhesion, cellular growth and proliferation, and cell-to-cell signaling responses. Five hundred and one genes were progressively upregulated, while one hundred seventy-three genes were progressively downregulated. Changes in gene expression were validated in a subset of 33 genes by qRT-PCR, with r(2) = 0.925. Ingenuity gene interaction network analysis revealed novel relationships among antigen presentation, cell morphology, and other biological functions in the DSS mouse. Finally, DSS colitis gene array data were compared with UC patient array data: 152 genes were similarly upregulated, and 22 genes were downregulated. Temporal genomewide expression profile analysis of DSS-induced colitis revealed novel associations with various immune responses and tissue remodeling events such as angiogenesis similar to those in UC patients. This study provides a comprehensive view of DSS colitis changes in colon gene expression and identifies common molecules with clinical specimens that are interesting targets for further investigation.

Project description:Methylthioadenosine (MTA) is a precursor of the methionine salvage pathway and has been shown to have anti-inflammatory properties in various models of acute and chronic inflammation. However, the anti-inflammatory properties of MTA in models of intestinal inflammation are not defined. We hypothesized that orally administered MTA would be bioavailable and reduce morbidity associated with experimental colitis. We examined clinical, histological, and molecular markers of disease in mice provided oral MTA before (preventative) or after (therapy) the induction of colitis with 3% dextran sulfate sodium (DSS). We found a reduction in disease activity, weight loss, myeloperoxidase activity, and histological damage in mice given preventative MTA compared with DSS alone. We also found that equivalent supplementation with methionine could not reproduce the anti-inflammatory effects of MTA, and that MTA had no detectable adverse effects in control or DSS mice. Expression microarray analysis of colonic tissue showed several dominant pathways related to inflammatory cytokines/chemokines and extracellular matrix remodeling were upregulation by DSS and suppressed in MTA-supplemented mice. MTA is rapidly absorbed in the gastrointestinal tract and disseminated throughout the body, based on a time course analysis of an oral bolus of MTA. This effect is transient, with MTA levels falling to near baseline within 90 min in most organs. Moreover, MTA did not lead to increased blood or tissue methionine levels, suggesting that its effects are specific. However, MTA provided limited therapeutic benefit when administered after the onset of colitis. Our results show that oral MTA supplementation is a safe and effective strategy to prevent inflammation and tissue injury associated with DSS colitis in mice. Additional studies in chronic inflammatory models are necessary to determine if MTA is a safe and beneficial option for the maintenance of remission in human inflammatory bowel disease.

Dataset Information

Indol-3-Carbinol and Quercetin Ameliorate Chronic DSS-Induced Colitis in C57BL/6 Mice by AhR-Mediated Anti-Inflammatory Mechanisms.

Publications

Indol-3-Carbinol and Quercetin Ameliorate Chronic DSS-Induced Colitis in C57BL/6 Mice by AhR-Mediated Anti-Inflammatory Mechanisms.

Similar Datasets

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