Grant: Discovery Grants Program - Individual

The intestinal tract of mammals is heavily colonized by large numbers of resident bacteria. These bacteria help digest food and promote the proper functioning of the intestine, so it is critical that the relationship between the intestine and the bacteria it contains is a healthy one. To ensure a mutually beneficial relationship, the gut bacteria are separated from the host's immune system by a single layer of cells (called epithelial cells) that lines the inner surface of the intestine. Moreover, the immune system within the intestine is somehow suppressed, so it does not attack the resident bacteria. At present it is unclear what factors suppress the intestinal immune system, and maintain healthy interactions with the gut microbes, however we and others have recently found that vitamin D might be involved. Vitamin D is an important fat-soluble vitamin that can be obtained through exposure to sunlight, or in the diet. When mice are missing vitamin D in their diets, or genetically lacking the vitamin D receptor, their intestines show greater inflammation than those of mice that are fed sufficient levels of vitamin D. Moreover lack of vitamin D is associated with a leaky intestinal epithelium that is also more responsive to immune signals. To define how vitamin D affects the interface between the intestine and the populations of microbes it contains, we will see if vitamin D levels (and its effects on the host) alters the makeup of the intestinal microbes. We will also explore what parts of the immune system are driving these changes, by removing specific parts of the immune system from vitamin D receptor mice, or by exposing different types of immunodeficient mice to vitamin D deficient diets. Lastly, we will define the cell types in the intestine that require vitamin D signaling to control immunity and intestinal epithelial responses, as an additional way to define how vitamin D exerts its effects. Taken together, these studies will help clarify how factors in the diet, such as vitamin D help control the functions of our intestines, and promote beneficial interactions with our microbiota.