Abstract 10861: Administration of Non-Absorbable Antibiotics Attenuate High-Fat High-Cholesterol Diet Induced Atherosclerosis in LDLR-/- Mice

Consumption of diets enriched in fat and cholesterol not only leads to obesity but is associated with chronic low grade inflammation. Diet induced changes in intestinal barrier function leading to bacterial translocation and/or release of lipopolysaccharide (LPS) to plasma contributes to increased inflammation. We hypothesized that administration of non-absorbable antibiotics such as Neomycin and Polymyxin-B should selectively decontaminate the gut, decrease high-fat high-cholesterol diet (HFHC) induced chronic inflammation and attenuate atherosclerosis, an inflammation linked disease. LDLR-/- mice at 8-weeks of age were fed HFHC diet with or without supplementation with Neomycin (100 mg/ml) and Polymyxin-B (10 mg/ml) in drinking water. After 16 weeks, mice were sacrificed. Plasma LPS levels were determined as a measure of diet-induced change in intestinal barrier function as well as inflammation. Antibiotic treatment significantly decreased plasma LPS concentration (2.18±0.89 vs 3.61±0.90 units/ml, P=0.013). Consistently, there was attenuation in the circulating levels of pro-inflammatory cytokines. Development of diet-induced atherosclerosis was assessed by en face analyses. Consistent with this model, there was significant lesion development in the aortic arch compared to thoracic and abdominal aorta (see Figure) which was dramatically reduced with antibiotic supplementation. Treatment with antibiotics significantly attenuated diet-induced atherosclerosis with a 43.9% decrease (3.00±1.16 vs 6.82±1.72, P=3.01E-06) in total lesion area and 45.6% decrease (11.34±4.38 vs 24.82±4.81, P=5.95E-07) in area occupied by lesions in the aortic arch. These data demonstrate that selective decontamination of the gut can significantly reduce the release of LPS into the plasma and systemic inflammation leading to attenuation of HFHC diet-induced atherosclerosis, thus establishing gut decontamination as a novel anti-atherogenic target.