The inflammatory bowel disease (IBD) subtype, Crohn?s disease (CD) is a chronic, commonly disabling inflammatory disorder of the gastrointestinal tract that results from a dysregulated immune response to enteric bacteria in a genetically susceptible host. [1-5] In fact, recent advances in technology have allowed insight into the specific differences that exist between CD patients and healthy controls in their intestinal microbiota composition. In addition, shifts in microbial community structure and products of bacterial activity (i.e. metabolites) are reported to have regulatory effects on the inflammatory process in CD. [2,5] Diet is considered the main driving force in shaping gut microbiota composition and, in turn, [6,7] the metabolites they produce. [8- 12] Today, gut microbiota modulation by dietary intervention is a well-advocated strategy in the therapeutic management of CD. [13,14] However, no specific recommendations exist for CD patients, and little is known regarding the microbiota mediated effects of diet on host immune systems, particularly in relation to the optimal time for manipulation of microbial composition. [15] Addressing these issues through human studies is challenging because of numerous uncontrolled variables, both genetic and environmental. [7, 15-17] Therefore, animal models are an invaluable first line approach in advancing our understanding between intestinal microbiota and diet in an IBD susceptible host. [18-19] Transplantation of human fecal microbiota can enhance translation of results to clinical research. [20] The central hypothesis of this present application is that one or more individual bacterial species (or groups of species), and their associated metabolites, may successively contribute to altering immune pathways, and that extent of contribution reflects specific ?immune windows? of disease course, but that this, can be mediated by host diet. To test this hypothesis we will characterize the effects of a ?pro-inflammatory? Western-based (high-fat/high-sugar) diet and an ?anti-inflammatory? Plant-based diet (low- fat/high-polysaccharide) administered to gnotobiotic SAMP1/YitFc (SAMP1) mice with characterized human fecal microbiota. These studies will test the hypothesis that diet has the ability to modulate the pro- or anti- inflammatory effect of a human donor microbiota on the development of CD-like ileitis after FMT in SAMP1 germ- free (GF) mice. This research takes advantage of the well-defined disease time course and 100% disease penetrance uniquely portrayed by SAMP1 mice, and of their impressive disease similarities to the human CD condition. [21] Using this design, our study will precisely determine: (1) the impact of diet on host immune response(s) in the early phase of ileitis, and (2) diet-induced alterations to the functional composition of gut microbiota. The overall objective of this proposal is to understand how different diet patterns can either enhance or suppress bacterial species identified for their potent anti- or pro-inflammatory capacity with the ultimate goal of developing diet intervention strategies that are of biological relevance to human IBD.
Crohn?s disease (CD) is a chronic, commonly disabling disorder of the gastrointestinal tract that is associated with imbalances in the composition of gut bacteria (?dysbiosis?), and affects more than 600,000 individuals in the US. Dietary intervention is a well-advocated strategy for the therapeutic alteration of gut bacteria in patients with CD, however no specific recommendations exist for these patients, and little is known about the complex interaction between diet, gut bacteria and host immune responses. Understanding these interactions, particularly how specific dietary patterns can cause or prevent CD, through their effect on gut bacteria composition, will allow us to develop novel therapeutic approaches to treat, prevent, and ultimately cure the disease.
