High-salt diets (HSDs) are known to impact blood pressure and cardiovascular health, but their effects on glucose metabolism, liver function, and gut microbiota remain poorly understood. This study investigates how long-term HSD affects these physiological processes and evaluates the potential therapeutic effects of ACE inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs). Male Sprague-Dawley rats were fed a normal salt diet (0.3% NaCl), a moderate salt diet (2% NaCl), or a high-salt diet (8% NaCl) for 12 wk. Two subgroups in the HSD condition received telmisartan or enalapril. We assessed blood pressure, glucose homeostasis, liver inflammation, pancreatic function, and gut microbiota composition. HSD rats exhibited significantly higher blood pressure [130 ± 2 mmHg in normal diet (ND) vs. 144 ± 4 mmHg in HSD; P < 0.01], reduced fasting insulin (1.33 ± 0.14 ng/mL in ND vs. 0.60 ± 0.05 ng/mL in HSD; P < 0.01), and gut microbiota dysbiosis, with a 71% reduction in Ruminococcus species (P = 0.018). Liver inflammation, indicated by an increase in CD68+ macrophages, was also observed in the HSD group. Telmisartan treatment significantly reduced liver inflammation but did not fully restore metabolic homeostasis. HSD disrupts multiple physiological systems, including glucose metabolism and liver function, partly through gut microbiota alterations. ACEIs and ARBs provided partial protection, highlighting the need for multitargeted interventions to mitigate high-salt diet effects.NEW & NOTEWORTHY High-salt diet induces multisystem disruptions, including liver inflammation, reduced insulin levels, and gut microbiota imbalance. ACEIs and ARBs showed limited efficacy, highlighting the need for comprehensive therapeutic approaches.

• MeSH
• Angiotensin Receptor Antagonists * pharmacology   MeSH
• Enalapril pharmacology   MeSH
• Glucose * metabolism   MeSH
• Angiotensin-Converting Enzyme Inhibitors * pharmacology   MeSH
• Liver * drug effects   metabolism   MeSH
• Blood Glucose metabolism   drug effects   MeSH
• Blood Pressure drug effects   MeSH
• Rats MeSH
• Sodium Chloride, Dietary * adverse effects   MeSH
• Rats, Sprague-Dawley MeSH
• Gastrointestinal Microbiome * drug effects   MeSH
• Telmisartan pharmacology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH