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Multi-omics profiling reveals the interactions of host defense and hyper-keratinization in psoriasis

ABSTRACT: Objectives: To understand the crosstalk between the immune system and keratinization in psoriatic skin, using a systems biology approach based on transcriptomics, proteomics and microbiome profiling. Methods: We collected the skin tissue biopsies and swabs in both lesion and non-lesion skin of 13 patients with psoriasis (PsO), 15 patients with psoriatic arthritis (PsA), and healthy skin from 12 patients with ankylosing spondylitis (AS). We performed transcriptome sequencing and metagenomics profiling on the local skin sites to study the similarities and differences in the molecular profiles between the three conditions. To assess the systemic nature of the disease, we performed a high-throughput proteome profiling to study the profiles of proteins circulating in the serum of the same donors. Results: We found that lesion and non-lesional samples were remarkably different in terms of their transcriptome profiles. Functional annotation of differentially expressed genes (DEGs) showed a major enrichment in neutrophil activation. By using co-expression gene networks, we identified a gene module that was associated with local psoriasis severity at the site of biopsy. From this module, we extracted a “core” set of genes that were functionally involved in neutrophil activation, epidermal cell differentiation and response to bacteria. Skin microbiome analysis revealed that the abundance of Enhydrobacter, Micrococcus and Leptotrichia were significantly correlated with the “core network” of genes. We further identified 39 circulating proteins from the serum that were significantly correlated with the corresponding local skin gene expression, highlighting systemic aberrations due to skin disease. Integration of “core” genes identified from skin with circulating protein profiles revealed PI3 as a key biomarker for psoriasis. Conclusions: We identified a core network that regulates inflammation and hyper-keratinization in psoriatic skin, and is associated with local disease severity and microbiome composition. Multi-omics analysis identified PI3 as a psoriasis-specific biomarker for disease severity and potential target for treatment strategies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE186063 | GEO | 2022/12/28

REPOSITORIES: GEO

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Project description:<p>Psoriasis, a highly prevalent disease of humans of unknown cause, is a chronic inflammatory disorder primarily involving skin, with distinctive clinical characteristics. With the newly developed tools that facilitate microbiome research, it now is possible to assess whether the cutaneous microbiome plays a role in the pathogenesis of this disorder. Preliminary data from our studies suggest that the cutaneous microbiome in psoriasis is complex and possibly different from normal. To deal with this complexity, we propose to examine the cutaneous microbiome in relation to psoriasis with explorations at several taxonomic and informatic levels. Our overall objective is to examine how changes in the normal cutaneous microbiome contribute to the pathogenesis of psoriasis. Since causality is complex and often difficult to prove, and beyond the scope of this RFP, our overall hypothesis is that there are alterations in the cutaneous microbiome in areas of skin affected by psoriasis in comparison with the range observed in clinically unaffected areas, or in healthy persons. We also hypothesize that the characteristics of the microbiome may affect clinical responses to the immunomodulatory agents used to treat psoriasis. An alternative hypothesis is that effective treatment of psoriasis with systemic immunomodulatory agents will not substantially affect the disordered microbial ecosystem. Such observations would provide evidence for the roles of the microbiota in this disorder. Since an important consideration in microbiome research is the optimal level (e.g. phylum, genus, species, strain, gene) at which to examine a scientific question, and we are not yet certain what are the optimal levels for psoriasis, this also will be examined. Our studies of psoriasis should allow development of both approaches and tools that will have general utility for Microbiome research. To test our hypothesis, we propose the following specific aims: 1) To understand the cutaneous microbiome species composition overlaying psoriatic lesions; 2)To investigate differences in metagenome content for psoriatic lesions compared to normal skin; 3) To identify differences in the transcriptional profiles of the microbiome and the host between normal skin and psoriatic lesions using high-throughput sequencing; and 4) To estimate the effects of systemic immunomodulatory therapy for psoriasis on microbiome composition. In total, these studies should help us understand the role of the microbiome in psoriasis pathogenesis.</p> <p>We sought to characterize and compare the cutaneous microbiota of psoriatic lesions (lesion), unaffected contralateral skin from psoriatic patients (normal), and similar skin loci in matched healthy controls (control) in order to discern patterns that govern skin colonization and their relationship to clinical diagnosis. Using high-throughput 16S rRNA sequencing, we assayed the cutaneous bacterial communities of 51 matched triplets and characterized these samples using community data analysis techniques.</p>

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Multi-omics profiling reveals the interactions of host defense and hyper-keratinization in psoriasis

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