Ontology highlight
ABSTRACT:
PROVIDER: PRJEB33052 | ENA |
REPOSITORIES: ENA
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Project description:Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries. There is growing evidence that dysbiosis of the intestinal microbiota and disruption of microbiota-host interactions contribute to the pathology of NAFLD. We previously demonstrated that gut microbiota derived tryptophan metabolite indole-3-acetate (I3A) was decreased in both cecum and liver of high-fat diet-fed mice and attenuated the expression of inflammatory cytokines in macrophages and TNF-a and fatty acid induced inflammatory responses in an aryl-hydrocarbon receptor (AhR) dependent manner in hepatocytes. In this study, we investigated the effect of orally administered I3A in a mouse model of diet induced NAFLD. Western diet (WD)-fed mice given sugar water (SW) with I3A showed dramatically decreased serum ALT, hepatic TG, liver steatosis, hepatocyte ballooning, lobular inflammation, and hepatic production of inflammatory cytokines, compared to WD-fed mice given only SW. Metagenomic analysis show that I3A administration did not significantly modify the intestinal microbiome, suggesting that I3A’s beneficial effects likely reflect the metabolite’s direct actions on the liver. Administration of I3A partially reversed WD induced alterations of liver metabolome and proteome, notably, decreasing expression of several enzymes in hepatic lipogenesis and β- oxidation. Mechanistically, we also show that AMP-activated protein kinase (AMPK) mediates the anti-inflammatory effects of I3A in macrophages. The potency of I3A in alleviating liver steatosis and inflammation clearly demonstrates its potential as a therapeutic modality for preventing the progression of steatosis to NASH.
2024-02-23 | PXD046255 | Pride
Project description:Zebrafish larvae aryl hydrocarbon receptor ligands and inhibitor
| PRJNA495640 | ENA
Project description:Mitochondrial dysfunction is associated with inflammatory bowel diseases (IBD). To understand how microbial-metabolic circuits contribute to intestinal tissue injury, we disrupt mitochondrial function in the intestinal epithelium by deleting heat shock protein 60 (Hsp60Δ/ΔIEC). While metabolic perturbation causes self-resolving tissue injury, regeneration is disrupted in the absence of aryl hydrocarbon receptor (Hsp60Δ/ΔIEC;AhR-/-) or IL-10 (Hsp60Δ/ΔIEC;Il10-/-) leading to IBD-like pathology. Tissue pathology is absent in the distal colon of germfree (GF) Hsp60Δ/ΔIEC mice, highlighting bacterial control of metabolic injury. Selective colonization of GF Hsp60Δ/ΔIEC mice with the synthetic community OMM12 confirms expansion of metabolically-flexible Bacteroides ssp., which generates metabolic injury in mono-colonized mice. Transcriptional profiling of metabolically-impaired epithelium identifies gene signatures, such as Ido1, Nos2, and Duox2, differentiating active from inactive tissue inflammation in 343 tissue sections from Crohn’s disease patients. In conclusion, mitochondrial perturbation of the epithelium causes microbiota-dependent tissue injury and discriminative inflammatory gene profiles with relevance for IBD.
2024-07-15 | PXD052829 | Pride
Project description:The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in adaptive cell functions, and highly active in the epidermis. AhR-ligands can accelerate keratinocyte differentiation, but a precise role for AhR in the skin barrier is unknown. We here show that transepidermal water loss (TEWL), a parameter of skin barrier integrity, is high in AhR-deficient (AhR-KO) mice. Experiments with conditionally AhR-deficient mouse lines identified keratinocytes as the major responsible cell population for high TEWL. Electron microscopy showed weaker inter-cellular connectivity in the epidermis of keratinocytes in AhR-KO mice, and gene expression analysis identified many barrier-associated genes as AhR targets. Moreover, AhR-deficient mice had higher inter-individual differences in their microbiome. Interestingly, removing AhR-ligands from the diet of wild-type mice mimicked AhR-deficiency regarding the impaired barrier. Vice versa, re-addition of the plant-derived ligand indole-3-carbinol (I3C) rescued the barrier deficiency even in aged mice. Our results suggest that functional AhR expression is critical for skin barrier integrity and that AhR represents a molecular target for the development of novel therapeutic approaches for skin barrier diseases, including dietary intervention.
2016-08-31 | GSE80273 | GEO
Project description:Effect of the over activation of the aryl hydrocarbon receptor on gene expression of spleen derived dendritic cells. 8-12 week old, female C57BL6 mice were injected 10 µg/kg TCDD i.p. or solvent control. After 24 h mice were sacrificed and splenic dendritic cells purified by MACS sorting.
2008-11-25 | E-GEOD-13719 | biostudies-arrayexpress
Project description:Effect of the over activation of the aryl hydrocarbon receptor on gene expression of spleen derived dendritic cells.
2008-11-25 | GSE13719 | GEO
Project description:Environmental stimuli are known to contribute to psoriasis pathogenesis and that of other autoimmune diseases, but the mechanism is unknown. Here we show that the aryl hydrocarbon receptor (AhR), a transcription factor that senses environmental stimuli, modulates pathology in psoriasis. AhR-activating ligands reduced inflammation in the lesional skin of psoriasis patients, whereas AhR antagonists upregulated inflammation. Similarly, AhR signaling via the endogenous FICZ ligand reduced the inflammatory response in the imiquimod-induced model of psoriasis and AhR deficient mice exhibited a substantial exacerbation of the disease, compared to AhR sufficient controls. Non-haematopoietic cells, in particular keratinocytes, were responsible for this hyper-inflammatory response, which involved increased reactivity to IL-1beta and upregulation of AP-1 family members of transcription factors. Thus, our data suggest a critical role for AhR in the regulation of inflammatory responses and open the possibility for novel therapeutic strategies in chronic inflammatory disorders. Total RNA obtained from skin explants taken from AhR heterozygous or knock-out mice treated pericutaneously with imiquimod for 0 and 2d.
2014-06-11 | E-GEOD-47607 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE15857: The Aryl Hydrocarbon Receptor Regulates Tissue-Specific Dioxin-Dependent and Dioxin-Independent Gene Batteries: Kidney GSE15858: The Aryl Hydrocarbon Receptor Regulates Tissue-Specific Dioxin-Dependent and Dioxin-Independent Gene Batteries: Liver Refer to individual Series
2010-05-05 | E-GEOD-15859 | biostudies-arrayexpress