Multi-omics analysis reveals altered lipid metabolism in the skin of high fat diet-fed mice of atopic dermatitis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE227042 | GEO | 2024/05/01
REPOSITORIES: GEO
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Project description:BackgroundIn order to study the relations of hepatocellular functions, weight gain and metabolic imbalance caused by low-dose antibiotics (LDA) via epigenetic regulation of gene transcription, 32 weaned piglets were employed as animal models and randomly allocated into two groups with diets supplemented with 0 or LDA (chlorotetracycline and virginiamycin).ResultsDuring the 4 weeks of the experiment, LDA showed a clear growth-promoting effect, which was exemplified by the significantly elevated body weight and average daily gain. Promoter methylome profiling using liquid hybridization capture-based bisulfite sequencing (LHC-BS) indicated that most of the 745 differential methylation regions (DMRs) were hypermethylated in the LDA group. Several DMRs were significantly enriched in genes related with fatty acids metabolic pathways, such as FABP1 and PCK1. In addition, 71 differentially expressed genes (DEGs) were obtained by strand-specific transcriptome analysis of liver tissues, including ALOX15, CXCL10 and NNMT, which are three key DEGs that function in lipid metabolism and immunity and which had highly elevated expression in the LDA group. In accordance with these molecular changes, the lipidome analyses of serum by LC-MS identified 38 significantly differential lipids, most of which were downregulated in the LDA group.ConclusionsOur results indicate that LDA could induce epigenetic and transcriptional changes of key genes and lead to enhanced efficiency of lipid metabolism in the liver.
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Project description:Atopic dermatitis (AD), or atopic eczema, is one of the most common inflammatory skin diseases with up to 10% prevalence in adults, and approximately 15-20% in children in industrialized countries. As a result, there is an unmet need for faster, safer, and effective treatments for AD. AD pathogenesis represents a complex interplay between multiple factors, such as environmental factors or stimuli, genetic factors, immune dysfunctions. However, although multi-omics label studies have been very useful in understanding the pathophysiological mechanisms of AD and its clinical manifestations, there have been very few studies that integrate different labels of omics data. Here, we attempted to integrate gene expression and metabolomics datasets from multiple different publicly available AD cohort datasets and conduct an integrated systems-level AD analysis. We used four different GEO transcriptome data sets and, by applying an elastic net machine learning algorithm, identified robust hub genes that can be used as signatures, for example, H2AFX, MCM7, ESR1 and SF3A2. Moreover, we investigated potential associations of those genes by applying a pathway-based approach over metabolomics and miRNA datasets. Our results revealed potential novel associations between fatty acids and peroxisomal lipid metabolism pathways, as well as with several microRNAs.
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Project description:Atopic dermatitis (AD) is characterized by dysregulated T cell immunity and skin microbiome dysbiosis with predominance of Staphylococcus aureus (S. aureus). Emerging evidence suggests a role for S. aureus in exacerbating AD skin inflammation. Interestingly, specific glycosylation of S. aureus cell wall structures amplifies skin inflammation through interaction with Langerhans cells (LCs). However, the role of LCs in AD remains poorly characterized. Here, we performed single cell RNA-sequencing of primary epidermal LCs and dermal T cells isolated from skin biopsies of AD patients and healthy controls, alongside specific glycoanalysis of S. aureus strains isolated from the AD lesions. Our findings reveal four LC subpopulations, including two steady-state clusters (LC1 and LC1H) and two pro-inflammatory/matured subsets (LC2 and migratory LCs). The latter two subsets were enriched in AD skin. AD LCs showed enhanced expression of C-type lectin receptors, the high-affinity IgE receptor (FcεR1), and activation of prostaglandin and leukotrienes biosynthesis pathways, as well as upregulated transcriptional signatures related to T cell activation pathways and increased expression of CCL17 (specifically LC2) compared to healthy LCs. Correspondingly, T helper 2 and regulatory T cell populations were increased in AD lesions. Our study provides proof-of-concept for an active role of LCs in connecting the S. aureus-T cell axis in the AD inflammatory cycle.
2024-05-03 | GSE266239 | GEO
Project description:Atopic dermatitis can result from loss of structural proteins in the outermost epidermal layers, leading to a defective epidermal barrier. To test whether this influences tumour formation, we chemically induced tumours in EPI-/- mice, which lack three barrier proteins-Envoplakin, Periplakin, and Involucrin. EPI-/- mice were highly resistant to developing benign tumours when treated with 7,12-dimethylbenz(a)anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). The DMBA response was normal, but EPI-/- skin exhibited an exaggerated atopic response to TPA, characterised by abnormal epidermal differentiation, a complex immune infiltrate and elevated serum thymic stromal lymphopoietin (TSLP). The exacerbated TPA response could be normalised by blocking TSLP or the immunoreceptor NKG2D but not CD4+ T cells. We conclude that atopy is protective against skin cancer in our experimental model and that the mechanism involves keratinocytes communicating with cells of the immune system via signalling elements that normally protect against environmental assaults.DOI: http://dx.doi.org/10.7554/eLife.01888.001.
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Project description:Atopic dermatitis (AD) is an important chronic or relapsing inflammatory skin disease that often precedes asthma and allergic disorders. New insights into the genetics and pathophysiology of AD point to an important role of structural abnormalities in the epidermis as well as immune dysregulation not only for this skin disease but also for the development of asthma and allergies. Patients with AD have a unique predisposition to colonization or infection by microbial organisms, most notably Staphylococcus aureus and herpes simplex virus. Measures directed at healing and protecting the skin barrier and addressing the immune dysregulation are essential in the treatment of patients with AD, and early intervention may improve outcomes for both the skin disease as well as other target organs.
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Project description:Atopic dermatitis (AD) is a chronic and relapsing disease affecting an increasing number of patients. Usually starting in early childhood, AD can be the initial step of the so-called atopic march, i.e. followed by allergic rhinitis and allergic asthma. AD is a paradigmatic genetically complex disease involving gene-gene and gene-environment interactions. Genetic linkage analysis as well as association studies have identified several candidate genes linked to either the epidermal barrier function or to the immune system. Stress, bacterial or viral infections, the exposure to aero- or food-allergens as well as hygienic factors are discussed to aggravate symptoms of AD. Athough generalized Th2-deviated immune response is closely linked to the condition of AD, the skin disease itself is a biphasic inflammation with an initial Th2 phase and while chronic lesions harbour Th0/Th1 cells. Regulatory T cells have been shown to be altered in AD as well as the innate immune system in the skin. The main treatment-goals include the elimination of inflammation and infection, preserving and restoring the barrier function and controlling exacerbating factors. The overall future strategy in AD will be aimed to control skin inflammation by a more proactive management in order to potentially prevent the emergence of sensitization as well as to design customized management based on genetic and pathophysiologic information.
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Project description:Atopic dermatitis (AD) is a chronic inflammatory skin disease with a complex pathogenesis. Although regulatory T cells (Tregs) have previously been studied in AD, their role remains controversial, likely owing to patient heterogeneity. Thus, we recruited adult AD patients and age-matched healthy controls, and assessed their filaggrin (FLG) genotype, serum IgE level, and eczema area and severity index (EASI). We found increased proportions of all circulating Treg subpopulations in AD patients. Moreover, we show positive correlations between circulating Tregs and serum IgE FLG null mutations limited the expansion of both memory and effector Tregs and enhanced that of recently thymus-emigrated Tregs. Furthermore, proportions of circulating Th2- or Th17-Tregs but not Th1-Tregs were increased in AD patients, and accentuated by FLG null mutations, thereby mimicking the immune deviation observed in Th cell populations. Moreover, ICOS+ Tregs showed reduced production of interleukin-10, suggesting impaired immunosuppression in AD. The level of demethylation of FOXP3i1, which reflects the stability of FOXP3 expression, was similar in the blood and skin of AD patients and healthy controls. Overall, these results show that Tregs may participate into AD pathogenesis and that FLG null mutations exert further modifications on specific subpopulations of circulating Tregs.
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Project description:Based on the gut-liver axis theory, to survey the effect of low-dose antibiotic (LDA) to hepatocellular functions of weight gain and metabolic imbalance by epigenetic transcription regulation, 32 weaned piglets were employed as the animal models and half were treated with Chlorotetracycline and Virginiamycin for four weeks. During the experiment, LDA showed an obviously growth-promoting effect, which was exemplified by the significantly elevated body weight and average daily gain. The DNA methylome profiling of promoter using liquid hybridization capture-based bisulfite sequencing (LHC-BS) indicated most of 745 differential methylation regions (DMRs) were hypermethylated in the LDA group, and some other DMRs were significantly enriched in genes related with fatty acids metabolic pathways, such as FABP1 and PCK1. Meanwhile, three key DEGs with the function of lipid metabolism and immunity were obtained by the liver strand-specific transcriptome analysis, including ALOX15, CXCL10 and NNMT, which were highly elevated for expressions in the LDA group. Correspondingly, the lipidome analyses of serum by LC-MS identified 38 significantly differential lipids, most of which were down-regulated in the LDA group. All these results suggest antibiotics could induce epigenetic and transcriptional changes of key genes related lipid metabolism pathway, and contributed to a more efficient metabolism of lipids.
2019-10-31 | GSE122027 | GEO
Project description:Background: DOCK8 deficiency is an autosomal recessive form of hyperimmunoglobulinemia E syndrome (HIES). Severe atopic dermatitis (AD) shares with DOCK8 deficiency some clinical symptoms, including eczema, eosinophilia, and increased serum IgE levels. The deficiency of DOCK8 protein is potentially a life-threatening autosomal recessive HIES and only curable with bone marrow transplantation. Despite identified metabolomics and cytokine biomarkers, novel proteomics biomarkers need to be identified, as the connecting networks are critical to our understanding of this disease. Hence we performed serum proteomics profiling using LC-MSE SynaptG2. Method: Label-free untargeted proteomics analysis was used to identify potentially reliable, sensitive, and specific protein biomarkers in serum collected from DOCK8 (n=10), AD (n=9) patients, which were compared to ctrls (n=5). Results: From a total of 275 quantifiable proteins, binary comparisons between AD vs. Ctrl, DOCK8 vs. Ctrl, and DOCK8 vs. AD revealed 109, 105 and 85 dysregulated proteins, respectively. 24 among 85 proteins were specific potential biomarkers among the DOCK8 and AD groups. The sensitivity and specificity of few proteins like Claspin, Immunoglobulin kappa and heavy, complement components as potential biomarkers to distinguish between DOCK8 and AD patients were evaluated using the receiver operating characteristic curve. DOCK8 deficiency and AD groups' profiling revealed a shared role of ERK1/2 among the commonly dysregulated proteins. Conclusion: In this study, we have identified potential proteomics biomarkers and profile to distinguish between DOCK8 and AD, with possible diagnostic and therapeutic applications to help create effective interventions for managing these diseases. Further studies to confirm these associations in prospective cohorts are warranted.
2022-05-17 | PXD029052 | Pride
Project description:Various factors have been reported to influence lipid metabolism and cause metabolic syndrome. However, the influence of allergy on the liver that plays important role of lipid metabolism has not been clarified. The aim of this study was to examine the influence of allergy on lipid metabolism of liver. A model of atopic dermatitis was developed in the NC/Nga mouse using picryl chloride to induce allergy. Lipid metabolism parameters were measured and the mechanism of changes in these parameters was examined using DNA microarray analysis and quantitative reverse transcriptase PCR. Triacylglycerol accumulation was promoted in the liver in the mouse atopic dermatitis model despite reductions in food intake, body weight gain, and serum glucose. As this mechanism, it was thought that atopic dermatitis caused the suppression of fatty acid β-oxidation. These results suggest that atopic dermatitis causes lipid accumulation in the liver.
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