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.

2nd Medical Faculty Charles University Prague Prague Czech Republic

5th Department of Medicine University Medical Center Mannheim University of Heidelberg Mannheim Germany

Academy of Scientific Research and Technology Cairo Egypt

Center for Development and Regeneration Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences Guangzhou People's Republic of China

Clinical Research Center for Reproduction and Genetics in Hunan Province Reproductive and Genetic Hospital of CITIC Xiangya Changsha People's Republic of China

Department of Nephrology and Endocrinology Klinikum Ernst von Bergmann Potsdam Germany

Department of Veterinary Medicines Federal Office of Consumer Protection and Food Safety Berlin Germany

Faculty of Veterinary Medicine Benha University Toukh Egypt

Guangzhou Linghang Digital Technology Co Ltd Guangzhou People's Republic of China

Hunan International Scientific and Technological Cooperation Base of Development and Carcinogenesis Changsha People's Republic of China

Institute for Clinical Research and Systems Medicine Health and Medical University Potsdam Germany

Institute of Medical Diagnostics Berlin Germany

Institute of Pharmacy Freie Universität Berlin Berlin Germany

Key Laboratory of Reproductive and Stem Cell Engineering Central South University Changsha People's Republic of China

Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province School of Medicine Hunan Normal University Changsha People's Republic of China

Medical Faculty of Charité Universitätsmedizin Berlin Berlin Germany

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