Integrative analysis reveals gut microbiota-associated host regulatory networks in liver fibrosis

Abstract

Gut microbiota-derived metabolites may contribute to liver fibrosis by affecting host inflammatory, metabolic, and epigenetic pathways. We aimed to identify microbiota-associated host genes shared across liver fibrosis of different etiologies. Microbiota- and metabolite-associated host genes were obtained from gutMGene v2.0 and integrated with differentially expressed genes from two human liver transcriptomic datasets: GSE84044 for HBV-related fibrosis and GSE49541 for NAFLD-related fibrosis. Shared genes were analyzed using protein–protein interaction and functional enrichment analyses. Selected metabolite–protein interactions were assessed by molecular docking and molecular dynamics simulations. Two-sample Mendelian randomization was used to examine potential associations between candidate gene expression and liver fibrosis risk. Fourteen microbiota-associated genes were differentially expressed in both fibrosis cohorts, including CCL2, CCL20, CXCL6, PTGS2, HDAC2, HDAC3, ADRA2A, SOD1, PEMT, and GNMT. These genes were mainly associated with chemokine activity, histone deacetylation, and IL-17 and TNF signaling. Molecular docking suggested structural compatibility between phenylacetylglutamine and ADRA2A, while butyrate showed weaker predicted interactions with HDAC2 and HDAC3.Molecular dynamics analysis supported the stability of the ADRA2A–phenylacetylglutamine complex under the simulated conditions. Mendelian randomization identified nominal associations of HDAC3, CCL2, PTGS2, and VCL expression with liver fibrosis risk. This study identified shared microbiota-associated host regulatory candidates in HBV- and NAFLD-related liver fibrosis.HDAC3 and ADRA2A may represent potential links between microbial metabolic signals and fibrotic responses, although further experimental validation is required.