Deconstructing interactions between diet, microbiome, and immunity to gain mechanistic insight into health and disease - Project Summary/Abstract Intestinal immune responses are linked to the trillions of microorganisms that colonize the gastrointestinal tract. Thus, inter-individual variations in the gut microbiome could contribute to altered immune responses that impact immune driven diseases such as autoimmunity. Activation of T helper 17 (Th17) cells by members of the gut microbiota can contribute to autoimmunity. Further, evidence is emerging that the diet influences both the immune system and the microbiome. While the pairwise interactions between dietary factors, the microbiota, and immunity have been broadly characterized, the field is just beginning to investigate the mechanistic interplay between diet, microbiome, and immunity and the downstream consequences on autoimmunity. The goals of this work are to investigate microbial mechanisms of Th17 cell activation, their diet-responsiveness, and the functional consequences of these interactions on autoimmune diseases such as inflammatory bowel disease (IBD) and multiple sclerosis (MS). Our preliminary studies reveal mechanistic insights into specific diet- dependent factors that counteract specific pro-inflammatory gut bacterial species. Two prevalent human gut species associated with human autoimmune diseases, Eggerthella lenta and Bifidobacterium adolescentis, induce Th17 cells in the intestine in a diet-dependent manner. Dietary arginine and ketogenic diets (KDs) prevent Th17 induction by E. lenta and B. adolescentis respectively. Further, a specific bacterial gene in E. lenta, cgr2, is sufficient to activate Th17 cells. We aim to determine diet-dependent mechanisms of Th17 activation by E. lenta metabolites and functional consequences IBD and MS mouse models. By combining immunological and microbiome techniques with metabolomics and translational research expertise of our collaborators we aim to identify a small molecule metabolized by E. lenta responsible for Th17 activation and assess the disease relevance of dietary modulation of this metabolism. Secondly, we aim to examine the mechanism and disease relevance of ketone bodies for limiting gut bacterial Th17 induction. A KD-associated gut microbiota reduces intestinal Th17 cells via selective inhibition of bifidobacterial growth by the ketone body β-hydroxybutyrate (βHB). Therefore, we hypothesize that the ketone body βHB selectively inhibits B. adolescentis-mediated Th17 induction resulting in functional consequences for MS disease models. To address this hypothesis and elucidate the mechanism by which βHB impacts the Th17 induction capacity of B. adolescentis, we will use bacterial genetic manipulation and disease models. The proposed aims will leverage the candidate’s expertise in immunology and microbiome studies with new training in metabolomics, bacterial genetics, and translational research studies. UCSF’s institutional focus on the microbiome, metabolomics, immunology and translational research and close collaboration with experts in these areas will provide an ideal environment for the proposed scientific and professional development leading to the creation of an independent research program.
