Combined statin–probiotic treatment mitigates atherogenic dyslipidemia fueling NAFLD in high-cholesterol-diet fed rats

Background Chronic hypercholesterolemia accelerates metabolic dysregulation, systemic oxidative stress, and endothelial dysfunction, driving the initiation and progression of atherogenesis. Although statins like Atorvastatin (AS) represent the clinical cornerstone of lipid-lowering therapy, long-term high-dose use is often constrained by adverse side effects. Probiotic interventions targeting the gut–heart axis, such as Bifidobacterium longum (B), offer a promising therapeutic strategy to enhance lipid homeostasis and reduce vascular inflammation. Methods Male rats were fed a High-Cholesterol Diet (HCD) for 120 days to establish hypercholesterolemia, dyslipidemia, and systemic vascular pathology. Experimental groups were administered AS monotherapy, B. longum monotherapy, or their dual combination (AS + B) daily from day 90 to 120. Redox dynamics (GSH, MDA, GSH/MDA ratio), functional HDL-associated proteins (PON1, APOA1), circulating oxidized LDL (oxLDL), inflammatory cytokines (CRP, TNF-α, IL-6, IL-8), and all adhesion molecules (ICAM-1, VCAM-1) were quantified, alongside histopathological evaluation of hepatic and aortic tissue microarchitecture. Results High-cholesterol diet feeding induced severe dyslipidemia, vascular remodelling, lipid peroxidation, and endothelial inflammation in rats. Monotherapy with Atorvastatin (AS) or Bifidobacterium longum (B) significantly reversed metabolic impairment (p<0.001), while dual AS + B therapy achieved maximum efficacy (p<0.01 vs. AS alone) in restoring hepatic and aortic microarchitecture. Mechanistically, combination treatment blunted oxidative stress by minimizing malondialdehyde and upregulating Paraoxonase 1 and Apolipoprotein A1 (p<0.01), which markedly suppressed low-density lipoprotein oxidation (p<0.001). Furthermore, dual therapy yielded the maximum downregulation of pro-inflammatory cytokines (C-reactive protein, tumor necrosis factor-α, interleukin-6, interleukin-8) and adhesion molecules (ICAM1,VCAM1); p<0.001), demonstrating potent anti-inflammatory effect against diet-induced atherogenesis. Conclusion Co-administration of Atorvastatin and Bifidobacterium longum demonstrates multi-targeted therapeutic synergy by effectively restoring HDL functional capacity, attenuating vascular endothelial inflammation, and mitigating hypercholesterolemia simultaneously, this dual pharmacological–probiotic strategy provides a robust, novel intervention against diet-induced atherogenesis.