Exploring Gut Microbial Metabolic Signatures Associated with the Gut-Lung Axis in Lung Adenocarcinoma

The gut-lung axis (GLA) is increasingly recognized as a biological communication pathway relevant to lung cancer. However, the potential molecular associations between gut microbial metabolites and lung adenocarcinoma (LUAD) remain incompletely understood.

By integrating public databases, including gutMGene, GeneCards, and TCGA, with computational tools such as WGCNA, STRING, and CIBERSORT, candidate genes and gut microbiota-derived metabolites potentially associated with LUAD were identified. A microbiota-metabolite-targets-pathway (MMTP) interaction network was constructed, followed by functional enrichment, immune infiltration analysis, miRNA-target prediction, and drug-likeness analyses.

Among the 12 key targets identified, JUN, IL6, and CXCL8 were prioritized as core genes. These targets mainly involved miRNA-related processes and immune pathways like IL-17 signaling, Toll-like receptor, and Th17 differentiation. Immune infiltration showed that core gene expression correlated with specific immune cell patterns, indicating inflammatory and immunosuppressive features of the tumor microenvironment (TME). The MMTP network further suggested that several gut microbial metabolites, including butyrate, propionate, acetate, succinate, 3-indolepropionic acid, and trimethylamine N-oxide, may be associated with core gene-related pathways. In silico drug-likeness and toxicity predictions indicated that these metabolites generally met basic Lipinski-based criteria; however, several predicted toxicity signals, particularly human hepatotoxicity, warrant cautious interpretation.

Key gut microbial metabolites may be linked to LUAD progression via inflammatory and immune pathways involving JUN, IL6, and CXCL8, along with miRNA regulatory processes. These findings offer a bioinformatics framework for understanding GLA-related molecular links in LUAD and may help find biomarkers or metabolites for further study.