CAREER: Microbial control of intestinal organoids development and function

Each day, Americans take over 200 million oral pills. A major question has been why the same drug does not work for everyone. Gut bacteria could play a significant role in the development of cellular models for drug development and improving their function, but are not currently utilized. Therefore, the goal of this CAREER project is to create microfluidic devices that can incorporate gut bacteria for the controlled generation of intestinal organoids. Through this, the project will also elucidate the role microbes play in modulating functions related to drug absorption. Coupled with these efforts, the research will provide opportunities to students in engineering by reaching them early in their curiosity. The educational objectives will leverage the project to create new coursework and a hands-on educational program “Engineering Biology using Microfluidics.” offered as annual workshops on different themes. The program will stimulate excitement in STEM education, in addition to equipping students with 21st-century scientific communication strategies. One long-standing challenge in medicine is the variability in the effectiveness of medicine, which in part is due to the lack of suitable cellular models that capture the variability in drug absorption that comes from diverse gut bacterial species. This is important because the intestine, home to gut bacteria, is the primary site for the absorption of small molecule drugs. Intestinal organoids have enormous potential to mimic organ function in drug development. However, the self-organizing processes underlying organoid development are poorly controlled, which has limited their adoption. A factor that has been largely overlooked is the gut bacteria, which can modulate intestinal function as well as drug absorption and metabolism. Yet, current stem cell derived organoids do not account for gut bacteria. Since gut bacteria are synergistic partners essential to organ development, they could be crucial in steering the controlled generation of organoids. Similarly, current pharmacokinetic models do not account for gut bacteria, which could be the reason for the observed variability in the effectiveness of drugs. These gaps exist because growing the largely anaerobic gut bacterial species with intestinal cells remains a technical challenge in the field. Resolving this challenge could transform the field. The goal of this CAREER project is to engineer a microfluidic device to discover how gut microbes steer the development of intestinal organoids. In parallel, the project will uncover how gut microbes shape the absorptive functions of the small intestine epithelium. The research is built upon previous work in creating a) a microfluidic device with biomimetic freestanding extracellular membrane that enabled the cells to remodel the microenvironment and b) a microfluidic device to simultaneously culture anaerobic bacterial species with intestinal cells. These scientific advances will serve as the foundation for the engineering of small intestine organoids and provide a platform to study microbe-intestinal signaling. The engineered microfluidic devices could also be leveraged to study other organ systems such as the lung, skin, ovary, and tumors where bacterial colonization is increasingly appreciated as a significant functional modulator. 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.