Gut Microbiota Dysbiosis Remodels the Multi-Tissue Transcriptional Landscape of the Host

The gut microbiota exerts a profound influence on host physiology, but its systemic impact on gene expression across diverse tissues remains poorly characterized. This study investigated the transcriptional effects of gut microbiota depletion and restoration in mice across six tissues (colon, jejunum, liver, heart, lung, and kidney) using whole-transcriptome sequencing. We found that the presence of gut microbiota significantly altered the transcriptome, with the most pronounced effects in the colon. Using a linear mixed-effects model, we identified 7,365 effector genes. Tissue-specific analysis revealed that these genes were associated with distinct functional pathways, such as immunity in the gut and lung, and metabolism in the liver. Further refinement with LASSO regression pinpointed gut microbiota-mediated key effector genes, whose expression levels were significantly associated with patient survival in corresponding human cancers (e.g., LIHC, LUAD, KIRC). Furthermore, we observed a widespread remodeling of competing endogenous RNA (ceRNA) networks by the gut microbiota. Single-cell data analysis highlighted a potential gut-liver axis interaction, primarily mediated by colonic enterocytes and hepatic cholangiocytes, meanwhile gut microbiota repressed the transcription initiation of Noct in colonic enterocytes, whose expression level was significantly negatively correlated to gut-liver axis interaction. Our findings provide a comprehensive map of the multi-tissue transcriptional landscape shaped by the gut microbiota, revealing tissue-specific regulatory mechanisms and identifying key genes with potential clinical relevance in cancer.