Microbial drivers of metabolically unhealthy obese phenotype

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PROJECT SUMMARY (from main K01 award) This application for the Mentored Research Scientist Development Award will facilitate the principal investigator (Pl)'s transition to independence dissecting host-microbe interactions in obesity-related metabolic diseases. Candidate: The Pl is an experimental biologist with a strong background in gut mucosa! immunology and infection biology. She did her postdoctoral training under the mentorship of Dr. Rodney Newberry, a mucosal immunology expert. Under Dr. Newberry's guidance, the Pl demonstrated the novel role of intestinal goblet cells in promoting immune tolerance to luminal antigens. Additionally, the Pl has also demonstrated how enteric bacteria interact with intestinal goblet cells to modulate their function. She will leverage the skills gained during her training to characterize the dialogue between obesity-associated gut microbes and intestinal immune cells. Career Development Plan: The Pl will execute this proposal under the co-mentorship of Dr. Newberry and Dr. Samuel Klein (a leader in the field of obesity research), advised by a team of scientific experts who also have experience in nurturing independent investigators. Washington University provides an outstanding environment, collaborators and cores that will foster the Pl's career development. This proposal builds on the Pl's prior experience and fills in the gaps in her training, providing her with the tools needed for independence. It includes the following objectives: (1) master techniques in macrophage biology (i.e., immune cell trafficking, phenotyping); (2) developing expertise in obesity and metabolic dysfunction; (3) training in microbial ecology; (4) immersion in bioinformatics; and (5) publishing manuscripts directly related to this proposal. Research Plan: The scientific premise of the proposal is that gut microbiota from individuals with metabolically unhealthy obesity (MUO) compared to metabolically healthy obesity (MHO) propel intestinal and adipose tissue inflammation. To investigate the role of microbial drivers on the onset of metabolic syndrome, the Pl has established a model of colonizing genetically identical wildtype mice consuming a normal chow diet with stool specimens collected from well-characterized obese or metabolically-healthy lean (MHL) human subjects with known degrees of adipose tissue inflammation, glucose intolerance and whole-body insulin sensitivity. Preliminary studies demonstrate that mice colonized with MUO, but not MHO or MHL donor microbiota have glucose intolerance, higher serum insulin concentration and significant expansion of macrophages in the intestine and adipose tissue. By completing the proposed aims, the Pl will address 1) whether gut microbes from people with MUO promote host inflammation and the onset of metabolic diseases, and 2) determine the contribution of monocuclear phagocytes in microbiota driven-metabolic dysfunction. In completing these aims, the Pl will complement her expertise in mucosa! immunology with rigorous training in macrophage biology, microbial ecology and metabolic dysfunction to becomes an independent investigator with the long-term goal of dissecting how microbes contribute to obesity-related metabolic disease, in alignment with the NIDDK mission.