Dietary regulation of type 2 immunity and inflammation in the gut

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PROJECT SUMMARY Understanding the role of environmental factors including signals derived from the diet and microbiota is key to improving therapeutic and intervention strategies for gastrointestinal disorders including inflammatory bowel diseases (IBD) and inflammation-associated colorectal cancer (CRC). Dietary fiber can exert immunoregulatory effects through microbial fermentation products including short chain fatty acids (SCFAs). However, the influence of dietary fiber on most microbiota-derived metabolites and their role in immunoregulation remain unclear. In new preliminary studies, I identified that an inulin-rich high fiber diet triggers colonic eosinophilia in a microbiota- dependent manner which exacerbates disease outcomes in murine models of intestinal damage and inflammation-associated CRC. These diet-induced type 2 inflammatory responses are associated with upregulation of microbiota-derived bile acids and activation of mesenchymal stromal cells (MSCs) and group 2 innate lymphoid cells (ILC2s). However, the cellular and molecular components in the host and the metabolic pathways in the microbiota that mediate the dietary effects on intestinal inflammation remain unclear. In Aim 1, I will determine how bile acids regulate type 2 cytokines and eosinophilia during high fiber diet-induced intestinal inflammation. In Aim 2, I will investigate how dietary fiber-induced eosinophils contribute to intestinal damage. In Aim 3, I will employ bacterial genetics and gnotobiotic approaches to identify the microbial metabolic pathways required for high fiber diet-induced intestinal inflammation. Upon successful completion of the proposed aims, I expect to contribute to a fundamentally new understanding of the biology of dietary fiber, microbiota-derived metabolites, and stromal cells in regulating type 2 inflammation which could contribute to rational design of diet- and microbiota-based therapeutic approaches. My overarching career goals are to become an independent investigator and an inspirational mentor at a leading academic institution and to study the mechanisms by which environmental factors regulate intestinal inflammation and gastrointestinal diseases. Completion of my research aims in this proposal will allow me to develop various scientific, professional, and personal skills critical to become a successful independent investigator. These will include acquiring expertise in various fields including metabolomic analyses and genetic engineering with help of my collaborators, as well as developing skills in writing, mentoring, communicating and laboratory management. I will perform the K99 phase in the laboratory of Dr. David Artis, a world leader in the fields of mucosal immunology and host-microbiota interactions. The laboratory has access to all instruments and facilities necessary to complete the proposed aims including a gnotobiotic animal facility and provides an outstanding environment and training program to support postdoctoral researchers. In addition to my mentor and co-mentor, I have support from several distinguished investigators with extensive expertise as advisors and collaborators that will greatly facilitate the completion of my experiments during the K99 phase as I progress to become an independent investigator.