Multi-Omics Framework Integrating Genetics, Microbiome, Metabolism, and Immunity for Deciphering Ulcerative Colitis...

Area of Science:

• Gastroenterology
• Immunology
• Genetics
• Metabolomics
• Microbiomics

Background:

• Ulcerative colitis (UC) pathogenesis involves complex interactions between host genetics, gut microbiota, metabolism, and immune responses.
• Identifying reliable biomarkers for UC susceptibility and diagnosis remains a challenge.

Purpose of the Study:

• To systematically evaluate multi-omics factors associated with UC susceptibility.
• To identify robust diagnostic biomarkers for UC.
• To explore the functional roles of key genes in the UC tissue microenvironment.

Main Methods:

• Two-sample Mendelian randomization (MR) framework to assess causal associations.
• Integration of MR findings with transcriptomic datasets for gene identification.
• Machine learning modeling for diagnostic performance evaluation.
• Single-cell and spatial transcriptomics for gene localization and functional exploration.
• qRT-PCR validation and gene knockdown experiments.

Main Results:

• MR analysis revealed potential causal links between specific gut microbes, sphingomyelin metabolites, immune cell phenotypes, and UC.
• A four-gene signature (SAG, WDR48, IFITM2, SIRPA) was identified with high diagnostic accuracy (AUC=0.964).
• IFITM2 was primarily upregulated in myeloid cells (Neutrophil_IFITM2), suggesting a role in immune cell function.
• IFITM2 knockdown reduced pro-inflammatory cytokine expression (TNF-α, IL-6, IL-1β).

Conclusions:

• A multi-omics approach highlights the roles of microbiota, sphingolipid metabolism, and immune phenotypes in UC.
• The identified four-gene signature and IFITM2 characterization offer a promising framework for UC precision diagnosis.
• Further mechanistic studies are warranted to elucidate the precise functions of identified genes and pathways in UC pathogenesis.