ABSTRACT Previous experiments in our lab have shown that a fatty diet reduces olfactory sensory neuronal abundance. Isocaloric feeding in which a fat-fed mouse consumed the same number of calories as a control-fed mouse, but of fatty chow, prevented obesity but did not prevent the neuronal loss. It appears that the consumption of fat in the diet induces the observed olfactory changes, not excess adiposity or overconsumption. The physiological connections between fat consumption and olfactory anatomical and functional changes have not been explored. The overall objective of this proposal is to uncover the mechanistic link between fatty diet consumption and olfactory changes. A fatty diet is known to modify gut microbiome composition, often increasing Firmicutes and Proteobacteria, and decreasing Bacteroidetes. The gut microbiome influences intestinal epithelial structure, and a high-fat diet compromises intestinal barrier function by reducing tight junction integrity. This allows for molecules to leak out of the gut and can result in an elevation of circulating lipopolysaccharides (LPS). This condition is called metabolic endotoxemia and is observed in fat-fed mice. LPS is a component of the outer membrane of Gram-negative bacteria. LPS is a ligand for the Toll-like receptor 4, and activates immune cells, induces inflammatory cytokine release, and is used experimentally to induce systemic inflammation. LPS has been shown to induce neurodegeneration, neuroinflammatory NF-κB signaling, and behavioral changes. This proposal seeks to probe the connections between a fatty diet, gut microbiome changes, circulating LPS, neuroinflammation, and olfactory changes through a series of experiments. I hypothesize that the fatty diet induces changes in the gut microbiome that compromise intestinal integrity, leading to elevated levels of circulating LPS, which causes chronic neuroinflammation and the subsequent anatomical and behavioral changes of the olfactory system. First, circulating levels of LPS will be measured in ad libitum fat- and isocalorically fat-fed mice to determine if they exhibit metabolic endotoxemia. Next, neuroinflammation will be induced via LPS injection to uncover if this is sufficient to induce olfactory changes. Fecal samples collected from control-fed, fat-fed ad libitum, and iscalorically fat-fed mice will be sequenced to measure changes in gut microbiota. Fecal samples from these mice will also be transplanted to control-fed mice to determine if this can induce olfactory changes. Finally, olfactory tissue will be harvested from control-fed, fat-fed ad libitum, and isocalorically fat-fed mice to measure neuroinflammation using chromatin immunoprecipitation. Overall, these experiments will investigate the role of neuroinflammation and the gut microbiome on olfactory sensory neuronal abundance and odor discrimination to uncover the physiological events linking a fatty diet and olfactory changes.