A Triple-Hit Multi-Omics Framework for Psoriasis: Microbial Metabolic Remodeling and Immune Cell Methylome Signature Associated with an AMP-Dominant Lesional Program

TL;DR

This study explores how gut microbes, immune cell changes, and skin inflammation are linked in psoriasis using a multi-omics approach.

Contribution

The novel 'Triple-Hit' framework integrates gut microbiome, immune cell methylomes, and skin transcriptomics to reveal psoriasis mechanisms.

Findings

Gut microbial lipid catabolic potential is selectively reduced in psoriasis.

Systemic immune cell methylomes show regional remodeling linked to lipid metabolism.

Skin miRNA and mRNA signatures align with an AMP-dominant inflammatory program.

Abstract

The gut–skin axis is increasingly implicated in psoriasis pathogenesis, yet the cross-compartment convergence of molecular programs remains incompletely defined. We constructed a conceptual “Triple-Hit” multi-omics framework by integrating five independent public datasets spanning gut microbial functional remodeling (shotgun metagenomics), systemic immune cell methylomes (PBMC and CD8+ T-cell EPIC 850K), and lesional skin regulatory layers (miRNA and bulk RNA-seq). In the gut compartment, functional profiles exhibited a selective reduction in microbial lipid catabolic potential, including decreased fatty acid degradation and a lowered composite lipid degradation score, alongside heterogeneous shifts across SCFA-associated metabolic pathways. Systemically, PBMC methylomes revealed widespread regional remodeling (45,396 DMRs) enriched for membrane-proximal signaling and cytoskeletal programs, while CD8+ T cells showed specific epigenetic alterations in lipid- and glycosphingolipid-associated loci, suggesting a systemic metabolic–epigenetic alignment. In the skin, we identified a compact miRNA signature (168 DE-miRNAs) and a mechanistically interpretable, directionality-constrained miRNA–mRNA bridge that aligns with an AMP-dominant inflammatory transcriptome, consistent with reduced post-transcriptional restraint. Collectively, these findings support a convergent multi-omics framework linking putative microbial metabolic remodeling, systemic immune priming, and cutaneous effector programs. This study provides a systems-level perspective on psoriasis pathogenesis, highlighting the metabolic–epigenetic–transcriptional convergence as a potential avenue for therapeutic intervention.

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