Harnessing Genetic Tools and Metabolic Pathways of Gut Microbes to Enhance Host Resilience Against Pathogens, Inflammation, and Metabolic Disease

The intestinal microbiota profoundly shapes host physiology, influencing metabolic, immune, and barrier functions. However, the mechanistic dissection of these effects has been limited by the inaccessibility of many commensal species to genetic manipulation. My dissertation addresses this challenge through the development and application of genetic tools to engineer gut-resident. These efforts enabled the construction of programmable commensals capable of delivering therapeutic effectors and probing microbe–host interactions in vivo. First, this work expands the molecular toolkit for previously intractable anaerobes to achieve stable gene expression across multiple species. Using genetic tools, multiple species were engineered to produce defined metabolites and cytokines, including recombinant IL-22 and tryptophan-derived aryl hydrocarbon receptor (AhR) ligands, thereby enabling targeted modulation of hepatic and intestinal pathways in diet-induced metabolic disease models. Complementary multi-omics and histological analyses, including metagenomics, transcriptomics, metabolomics, and high-resolution image segmentation, revealed how microbial gene function shapes host metabolic outcomes such as steatosis and inflammatory signaling. Together, these studies bridge microbial engineering, host physiology, and mechanistic microbiome research.