2025 Theses Doctoral

Technologies to elucidate host-microbe interactions towards next generation probiotics and prebiotics

Sun, Yiwei

This thesis establishes an integrated framework to non-invasively profile human intestinal epithelial biology and systematically discover microbiome-derived therapeutics.

I first introduced fecal exfoliome sequencing, a method to capture and quantify host RNA shed into stool, enabling longitudinal measurement of intestinal transcriptional dynamics. Applied to murine models of gut inflammation and clinical inflammatory bowel disease cohorts, exfoliome profiling revealed temporal immune, barrier, and stress responses, resolves epithelial cell-state transitions associated with IBD, and identifies transcriptional signatures predictive of treatment response and relapse.

In parallel, I applied high-throughput screening approaches to identify probiotics and prebiotics that modulate host metabolism and immunity. Systematic characterization of bile-acid-metabolizing gut bacteria uncovered distinct metabolic pathways and strain- specific capacities to degrade pro-inflammatory secondary bile acids. Screening of polyphenol- metabolizing gut microbes further resolved microbe-diet interactions at strain-level resolution, revealing mechanistic links between microbial metabolism, dietary polyphenols, and host inflammatory responses.

Finally, functional screening of commensal microbiota identified gut bacteria capable of suppressing colonization by vancomycin-resistant Enterococcus (VRE), a multidrug-resistant nosocomial pathogen. This work reveals Bifidobacterium adolescentis strains that inhibit VRE through short-chain fatty acid production and demonstrates therapeutic efficacy in a preclinical infection model, highlighting a commensal-based strategy for combating antibiotic-resistant infections. Together, these studies provide a unified experimental and analytical framework that couples non-invasive intestinal transcriptomics with mechanistic microbiome discovery. This work advances fundamental understanding of host-microbe interactions and establishes translational paths toward precision microbiome therapeutics for inflammatory, metabolic, and infectious diseases.