Abstract 4338161: Sqstm1/p62 Deficiency Remodels the Gut Microbiota Reducing Atherosclerosis and Improving Metabolic Outcomes in ApoE ^-/- Mice

Background: Atherosclerosis is a major cause of cardiovascular disease, and recent studies suggest the gut microbiome may modulate metabolic outcomes and vascular health. However, interactions between microbiota and host metabolism remain poorly understood, particularly in genetically modified mouse models predisposed to obesity and atherosclerosis. Our data show that the obese ApoE -/- Sqstm1 -/- mouse exhibits a cardioprotective phenotype with reduced plaque and improved lipid profiles. Hypothesis: We hypothesized that gut microbiota from ApoE -/- Sqstm1 -/- mice attenuates atherosclerosis and improves metabolic outcomes in ApoE -/- recipients. Methods: Age-matched 3-4-month-old male ApoE -/- mice were treated with antibiotics to deplete native gut microbiota and received either 1) their own feces (autologous FMT) or 2) feces from ApoE -/- Sqstm1 -/- male donor mice. Donor and recipient feces were collected before FMT and stored at -80°C. Fresh fecal suspensions were prepared for daily gavage (200 µL/mouse) for 5 consecutive days. Following FMT, mice were maintained on a control chow diet for 10 weeks. Outcome measures included atherosclerotic plaque area, gut microbiome composition, and metabolic function. Results: FMT from ApoE -/- Sqstm1 -/- donors reduced atherosclerotic plaque area, total cholesterol, LDL, and triglycerides in recipient mice compared to controls. ALT levels remained low in recipients despite elevated levels in donors. Notably, recipient mice did not acquire the obesity phenotype of donors; instead, they exhibited lower body weight, reduced fat mass, and increased muscle mass. Oral glucose tolerance tests revealed improved glucose sensitivity. Microbiome analysis showed that recipient mice developed a distinct microbial profile that overlapped with donor microbiota, indicating successful colonization and a potential role of the transferred microbiota in mediating these protective effects. Conclusions: Gut microbiota from ApoE -/- Sqstm1 -/- mice can modulate atherosclerosis and metabolic outcomes in recipient ApoE -/- mice, even in the absence of an obesity phenotype. The transfer of plaque reduction, cholesterol normalization, and improved glucose sensitivity suggests that specific microbiota may contribute to cardiometabolic protection, providing new insights into microbiome-targeted interventions for atherosclerosis and metabolic diseases. Funding: The Florida Department of Health (24K08), College of Education, Health and Human Sciences (Catalyst grant)