Summary Diet and nutrition are central to the treatment and prevention of many diseases. Diet is also a convenient, non- invasive lever to manipulate the composition and physiology of the distal gut microbiome, a community of nearly 100 trillion microorganisms that live in the ileum and colon of all humans. Although precise mechanisms are still being unraveled, the microbiome is emerging as a contributor to many diseases, suggesting that diet- mediated microbiome intervention is a fruitful but underdeveloped path to control some diseases. Dietary fibers are mostly polysaccharides and are enriched in the edible plants (fruits, vegetables, nuts, etc.) that are common in our diet and are directly degraded by some bacterial members of the microbiome. Some members of the microbiome are also capable of consuming mucin glycoproteins, the largest component of secreted mucus, which forms a protective barrier overlying the colonic epithelium. We and others have shown that dietary fiber—the major nutrient category that escapes digestion in the upper intestine and therefore reaches the microbiome—offsets colonic mucus erosion when eaten in sufficient quantities. Part of our working model is that dietary fiber encourages growth of non-mucin-degrading bacteria by providing alternative nutrients. However, we have also discovered that dietary fiber or fiber-derived simple sugars actively repress expression of mucin utilization functions in the generalist bacterium, Bacteroides thetaiotaomicron (Bt). This repression leads to reduced mucus erosion and less severe symptoms in a model of post allogeneic bone marrow transplant graph versus host disease (GVHD). The central hypothesis of this proposal is that certain plant foods are capable of delivering nutrients to Bt and other mucin-degrading bacteria, which offset their ability to erode mucus and cause worse GVHD in transplant patients. Since Bt cannot directly access all of the fibers available via diet, we further hypothesize that some repressive effects are indirect and dependent on the presence and activity of other fiber degrading bacteria that release simple sugars consumed by Bt. We will test our hypothesis using a variety of in vitro and in vivo experiments. Our focus on foods that contribute beneficial fibers will be guided by direct measurements of the abilities of commonly consumed plant foods to repress Bt mucus degradation in vitro, followed by separate tests of how the most repressive food items translate to reduced mucus erosion in vivo in animal models and correlate with improved GVHD outcomes in patients. We will focus our investigations on the effects of fibers contained in actual fruits, vegetables and other plant items, providing an innovative approach that will better connect real foods with microbiome effects at a mechanistic level. Finally, we will perform molecular genetic experiments in Bt to define the regulatory mechanisms through which fiber-based nutrients cause suppression of mucin uti...