Lack of Structural Change in Olfactory Circuitry Following Fecal Microbiome Transplant From Donors Subjected to Diet-induced Obesity

Obesity and fatty diets are known to damage the structure and function of chemosensory systems. Consumption of a moderately high-fat diet (MHF) induces loss of olfactory sensory neurons (OSNs) and reduces the density of associated axonal projections to the olfactory bulb that are central in the coding of odor information. Previous work has demonstrated reduced alpha diversity, as well as signature changes in microbiome composition when mice are challenged with a MHF diet that precipitates diet-induced obesity. Herein, we tested the hypothesis that a dysbiotic gut microbiome is sufficient to induce olfactory damage. Male and female donor mice were randomly assigned to a control-fat (CF) or MHF diet for 5 months duration, followed by baseline measurements of body weight, body composition (EchoMRI), glucose tolerance, and metabolic phenotyping via indirect calorimetry. We next performed fecal microbiome transplantation (FMT) from these donors to CF-maintained recipient mice. After 8 weeks post FMT, we observed no difference in body weight, glucose clearance, body composition, or fat pad weights as a consequence of transfer from MHF-maintained donors. Following FMT, recipient male mice exhibited increased Erysipelotrichaceae abundance and decreased Lactobacillaceae abundance, similar to MHF-fed donors. Recipient brains were processed for tissue clearing using immunolabeling-enabled three-dimensional imaging of solvent-cleared organs (iDISCO) and then imaged using high resolution light sheet microscopy. The volume of olfactory glomeruli expressing Olfr160 odor receptors could be visualized using genetic reporters; the FMT from MHF-maintained donors failed to evoke structural changes to these defined olfactory synapses. We conclude that diet-induced obesity, associated adiposity, and metabolic dysfunctions drive functional loss and structural changes to the olfactory system, but that gut microbiome dysbiosis alone is not sufficient to yield olfactory circuitry deficits.