# 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.

## Key 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.