The Role of Mucin-type O-glycosylation in Fitness and Transmission of Intestinal Symbiotic Bacteria In Vivo

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BACKGROUND AND RATIONALE. The human gut is home to trillions of bacteria of many different types. We know now this vast microbial community plays many roles in host physiology, including digestion, energy acquisition, and vitamin production. However, we are not clear how the host provides an environment that allows such beneficial bacteria to thrive in the gut. One emerging factor is intestinal mucus, which is secreted by cells of the gut lining and intermixes with the microbiota. This mucus is mostly comprised of structures called "O-glycans", which are made up of sugar molecules of different types joined together in unique conformations that are presented to the microbiota. Despite this knowledge, we still are unclear how important these O-glycans are in promoting a thriving microbial population, largely due to the lack of effective tools to study them in a living system. We also do not know whether differences in males and females exist in regards to how O-glycans impact the microbiota. This leaves a serious gap in our understanding of mammalian colon ecosystems and maintenance of beneficial bacteria in a population. Fortunately, we now have access to novel genetic and bacterial tools that allow us to manipulate the O-glycosylation system, as well as visualize and track specific bacterial responses, in a model mammalian gut (mouse). OBJECTIVES AND METHODS. My long-term objective is to determine how the host glycosylation program of the secreted mucus influences the mammalian colon ecosystem to promote mutually beneficial interactions with our microbiota. I have three short-term objectives for this five-year Discovery Grant, which focus on how host O-glycans contribute to microbial survival in the gut. My hypothesis is that the O-glycans on mucus are essential for promoting stability of the microbiota in the face of a changing luminal environment due to dietary and other interventions. Using my expertise with genetic tools to create various O-glycan deficiencies in the mammalian (mouse) colon, in combination with my "reporter" bacteria, I will use techniques in microbiology, microscopy, and computational approaches to test how different glycosylation programs impact the ability of my reporter to colonize, find their niche, and thrive in male and female intestines. IMPACT AND HQP. These studies will boost Canada's international research impact in the natural sciences by addressing a fundamental question in microbiology and microbiota research. Specifically, it will generate findings relevant to microbiologists interested in the mammalian microbiota; glycobiologists seeking to understand how O-glycans impact microbiota communities; researchers studying sex- and gender-based biology, and the general public who wish to understand how their intestines help support their microbial populations. This research program will additionally provide an ideal training ground for Canadian HQP who will be competitive for positions in academia and industry.