2535-P: Gut Microbiota Potentially Mediates the Metabolic Benefits of Cardiac Mitochondrial Akt Activation in Diet-Induced Diabetic Cardiomyopathy

Introduction and Objective: Cardiac mitochondrial Akt1 activation modulates metabolic homeostasis by attenuating fatty liver and reducing whole body adiposity, though the underlying mechanism remains incompletely understood. Since gut microbiota plays a critical role in cardiovascular diseases pathogenesis, we investigated whether gut microbiota also mediates the whole-body metabolic benefits of cardiac mitochondrial Akt signaling. Methods: We used an inducible myocardium-specific transgenic mouse model harboring a mitochondria-targeting constitutively active Akt1 (CAMCAKT). To assess the role of gut microbiota, CAMCAKT mice were treated with broad-spectrum antibiotics (Ampicillin and Enrofloxacin) during high fat-high fructose diet (HFFD) feeding. Non-induced vehicle injected CAMCAKT mice were used as controls. Results: After 2 months on HFFD, antibiotic treated CAMCAKT mice had 7% higher body fat mass compared to controls. In contrast, on HFFD, body fat mass of untreated CAMCAKT was 8% lower compared to controls. Notably, antibiotics did not change the body composition of control mice on HFFD. Serum free fatty acid levels decreased in untreated HFFD-CAMCAKT mice but remained unchanged with antibiotic treatment. Furthermore, on HFFD, pronounced liver steatosis was comparable in control and antibiotic treated CAMCAKT mice, whereas untreated CAMCAKT mice exhibited significantly reduced hepatic steatosis by lipid area and droplet size. Conclusion: Microbiota depletion negates the metabolic and hepatoprotective benefits of cardiac mitochondrial Akt1 activation, reversing improvements in fatty liver and body composition. These results provide the first evidence that gut microbiota might be essential for mediating the metabolic effects of cardiac mitochondrial Akt1 activation, warranting further investigation into the specific microbial species and metabolites underlying this cardio-microbiome axis. A. Pathak: None. A. Ta: None. R. Jenq: Other - patent royalties; Current; Seres Therapeutics. Consultant; Current; MaaT Pharma. Advisory Panel; Current; Postbiotics Plus. Consultant; Current; Nestlé. P.H. Wang: None.