Integrative bioinformatics analysis identifies gut microbiota-derived metabolite-associated immune candidate targets...

This study aimed to identify and prioritize gut microbiota-derived metabolite-associated host candidate targets in high-risk primary biliary cholangitis (PBC) through integrative multi-omics analysis and external validation.

Differentially expressed genes between high-risk and low-risk PBC liver samples were identified using GSE79850. Gut microbiota-derived metabolite-host gene associations and PBC-related targets were obtained from gutMGene and the Open Targets Platform, respectively. Candidate genes were identified through integrative intersection analysis and ranked using an exploratory priority score. Human Liver Cell Atlas-based reference localization, immune signature analysis, and external validation using GSE119600 were performed to further characterize the candidate genes.

A total of 163 differentially expressed genes were identified in GSE79850. Integrative analysis with gutMGene and the Open Targets Platform identified six core candidate genes: CCL2, CDKN1A, BCL2, CD44, FOS, and MAPK3. CCL2 showed the highest priority score, was associated with multiple gut microbiota-related metabolites, including acetate, butyrate, propionate, and succinate, and was significantly upregulated in high-risk PBC liver samples. Human Liver Cell Atlas-based reference localization showed that CCL2 was mainly distributed in immune-related cell populations, including macrophages and monocyte-derived cells. High-risk PBC samples exhibited increased chemokine signaling signature scores, and CCL2 expression was positively correlated with this signature. In the GSE119600 cohort, CD44, FOS, and CDKN1A were significantly upregulated in PBC samples compared with controls.

This integrative analysis identified six candidate host targets associated with high-risk PBC. CCL2 showed the most convergent evidence within the discovery framework and may represent a chemokine-related hepatic microenvironment-associated candidate target. In contrast, CD44, FOS, and CDKN1A showed supportive expression patterns in the GSE119600 blood cohort. These findings represent exploratory candidate prioritization, and further validation in independent liver tissue cohorts and experimental studies is warranted.