CAREER: Developing Synthetic Microbiome Mimics to Study Microbe-Host Interactions

The human gut houses trillions of bacteria important for health. Bacteria help maintain the gut lining and balance the immune system by sending signals to the host. These signals can come from the bacterial outer membrane and from small molecules such as fatty acids produced by bacteria. Many of these signals are generated in the lower intestine, and it is often difficult to study what each signal does. Using live bacteria (or probiotics) to study these effects can also be challenging, because outcomes depend strongly on bacterial viability and on whether a strain can survive and grow in the gastrointestinal tract. This CAREER project will build synthetic microbiome mimics, which are nanoparticles that enable controlled delivery and unambiguous cause-and-effect studies in the gut. The mimics are tunable. They can be designed to release different bacterial products and be coated with membrane vesicles from different strains. The project will integrate computational models to predict where the mimics go and how they act. Results will show how different signals influence the gut lining, the immune system, and bacteria composition in the gut. The project will provide new course modules in microbiome and immune engineering and interdisciplinary workshops. K-12 outreach with the University of Washington (UW) Engineering Academy and the UW Microbiome Interactions and Microbiome Center will provide mentored summer research experiences for students. This CAREER project addresses a central question in microbiome science and engineering: deconvoluting the distinct versus synergistic contributions of commensal-derived structural cues and microbial metabolites to gut barrier integrity and immune regulation at physiologically relevant distal gut sites. The project will: (i) engineer synthetic microbiome mimics (outer membrane vesicles-coated, metabolite-releasing polymer nanoparticles) with modular control of core chemistry and shell composition to systematically interrogate microbiome-host interactions; (ii) evaluate these mimics across clinically relevant in vitro/ex vivo and in vivo models to quantify effects on gut epithelial barrier function, immune modulation, and microbiome dynamics under healthy and dysbiotic conditions; (iii) develop an integrated physiologically based pharmacokinetic–pharmacodynamic (PBPK-PD) modeling framework to predict intestinal transit, local exposure, and concentration-response relationships. The isolation, synthesis and characterization, testing, and optimization of the synthetic microbiome mimics are integral to biomanufacturing. The project will enable efficient formulation iteration, inform translational design for studying microbiome-derived signals, and guide next-generation oral therapeutics for microbiome and immune modulation. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria. NSF Award ID: 2540512 | Program: 01002627DB NSF RESEARCH & RELATED ACTIVIT | Principal Investigator: Shijie Cao | Institution: University of Washington, SEATTLE, WA | Award Amount: $574,462 View on NSF Award Search: https://www.nsf.gov/awardsearch/show-award/?AWD_ID=2540512 View on Research.gov: https://www.research.gov/awardapi-service/v1/awards/2540512.html