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Principal Investigator: Ashley Loeven
Organization: FLORIDA STATE UNIVERSITY
Fiscal Year: 2023
Award: $42,193
Funding agency: National Institute on Deafness and Other Communication Disorders
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.
Terms: <Anatomic Sites><Anatomic structures><Anatomy><Anosmia><Automobile Driving><Bacteroidetes><Behavior><Behavioral><Binding><Body Tissues><Brain><Brain Nervous System><CD14 Antigen><CD14 Monocyte Differentiation Antigen><CD14 molecule><CD14 receptor><Calories><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><ChIP assay><Chromatin><Chronic><Clinical><Clinical Treatment><Cognitive Discrimination><Cognitive deficits><Consumption><DNA-Protein Interaction><Degenerative Neurologic Diseases><Degenerative Neurologic Disorders><Diet><Dietary Fats><Discrimination><Encephalon><Event><Exhibits><Fats><Fatty acid glycerol esters><Firmicutes><Functional Metagenomics><GI microbiome><GI microbiota><Gastrointestinal microbiota><Genes><Goals><Gram-Negative Bacteria><Harvest><Health><Heart><High Fat Diet><Homolog of Drosophila TOLL><Immune><Immune Precipitation><Immunes><Immunoprecipitation><Inflammation><Inflammatory><Injections><Intestinal><Intestines><Intracellular Communication and Signaling><Knowledge><LPS Receptor><Ligands><Link><Lipoglycan Receptor><Lipopolysaccharide Receptors><Lipopolysaccharides><Measures><Membrane><Metagenomics><Mice><Mice Mammals><Molecular Interaction><Murine><Mus><Myeloid Cell-Specific Leucine-Rich Glycoprotein><Nerve Cells><Nerve Degeneration><Nerve Unit><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neuron Degeneration><Neurons><Nuclear><Obesity><Occluding Junctions><Odors><Olfactory Pathways><Olfactory system><Organ System><Pathway interactions><Performance><Physiologic><Physiological><Physiology><Prescribed exercise><Proteobacteria><Purple Bacteria><Reducing diet><Role><Sampling><Series><Signal Transduction><Signal Transduction Systems><Signaling><Structure><TLR4><TLR4 gene><Testing><Tight Junctions><Tissues><Toll Homologue><Transplantation><Unhealthy Diet><Zonula Occludens><adiposity><anosphrasia><bacteria in the gut><behavior change><biological signal transduction><body system><bowel><bowel inflammation><brain health><chromatin immunoprecipitation><cognitive defects><corpulence><cytokine><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><diet-associated obesity><diet-induced obesity><diet-related obesity><dietary><dietary lipid><diets><digestive tract microbiome><driving><dysbacteriosis><dysbiosis><dysbiotic><enteric microbial community><enteric microbiome><enteric microbiota><exercise prescription><experiment><experimental research><experimental study><experiments><fecal microbial transplantation><fecal microbiome transplantation><fecal microbiota transplant><fecal microbiota transplantation><fecal transplant><fecal transplantation><feeding><gastrointestinal microbial flora><gastrointestinal microbiome><gut bacteria><gut commensal><gut community><gut flora><gut health><gut inflammation><gut microbe community><gut microbial community><gut microbial composition><gut microbial consortia><gut microbiome><gut microbiota><gut microbiotic><gut microflora><gut to brain axis><gut-associated microbiome><gut-brain axis><gut-brain communication><gut-brain interactions><gut-brain relationship><gut-brain signaling><inflamed bowel><inflamed gut><inflamed intestine><intestinal barrier><intestinal biome><intestinal epithelium><intestinal flora><intestinal inflammation><intestinal microbes><intestinal microbiome><intestinal microbiota><intestinal microflora><intestinal mucosal barrier><intestinal tract microflora><loss of smell><membrane structure><metabolic endotoxemia><microbial imbalance><microbiome community composition><microbiome composition><microbiome species composition><nerve cell death><nerve cell loss><neural degeneration><neural inflammation><neurodegeneration><neurodegenerative><neurodegenerative illness><neuroinflammation><neuroinflammatory><neurological degeneration><neuron cell death><neuron cell loss><neuron death><neuron loss><neuronal><neuronal cell death><neuronal cell loss><neuronal death><neuronal degeneration><neuronal loss><obesity prevention><olfactory circuitry><olfactory circuits><olfactory loss><olfactory sensory neurons><pathway><poor diet><prevent><prevent obesity><preventing><sensory system><social role><systemic inflammation><systemic inflammatory response><toll-like receptor 4><transplant><treatment strategy><trial regimen><trial treatment>