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Rapid advances in DNA sequencing technologies have enabled population-scale genomic initiatives worldwide, including in Taiwan, generating vast biomedical datasets and uncovering numerous genetic associations with human disease. However, for many of these associations, the underlying molecular mechanisms remain poorly understood, limiting the translation of genetic discoveries into effective therapeutic strategies. In parallel, growing evidence links imbalances in the gut microbiota to a wide range of conditions, including metabolic disorders, neurological diseases, and cancer. Although correlations have been established between chronic disease development and microbiota-driven modulation of host gene regulation, metabolism, and inflammatory responses, it remains unclear whether microbial dysbiosis is a cause or a consequence of disease. In this seminar, I will present new functional genomics approaches and their applications in dissecting these relationships, with a focus on elucidating how gut microbiota and microbiota-derived metabolites influence gene regulation during the development of liver disease and colorectal cancer.