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Liver diseases are profoundly influenced by the gut–liver axis, where microbial signals modulate liver function through epigenomic interactions. Dysbiosis—an imbalance in gut microbiota—has been associated with disease progression, yet critical questions remain: Is dysbiosis a cause or consequence of liver pathology? Which microbial species and metabolites are involved, and how do they impact liver physiology? To address these challenges, we have developed new tools to functional dissect host–microbiome interactions under physiological conditions. In this seminar, I will present our recent work leveraging these tools to explore microbiota-driven gene regulation and discuss how these insights may inform novel therapeutic strategies for liver disease.