OBJECTIVE: Numerous studies have established a link between hypertension (HTN) and a high-salt diet (HSD). However, the precise mechanisms are still being investigated, with increasing evidence suggesting that HSD can alter the gut microbiome balance, influence the production of microbiome metabolites and potentially lead to high blood pressure, presenting a promising avenue for targeting specific microbiota in HTN treatment. Short-chain fatty acids (SCFAs) are produced by gut bacteria and are associated with blood pressure regulation. Thus, the relationships among HSD, SCFAs, and blood pressure could provide valuable information on the pathophysiology of HTN. This study aimed to assess the impact of HSD on HTN by investigating its influence on the gut microbiota composition and SCFA levels in a rat model of HTN. METHODS: The HTN rat model was constructed by placing the rats on HSD (8% NaCl) for 8 weeks. On the 8th week, fecal samples were collected from the rats for DNA extraction. The profile of the gut microbiota was subsequently evaluated through 16S rRNA sequencing. The fecal SCFAs were subsequently measured and analyzed. RESULTS: Analysis of 16S rRNA sequencing data revealed that consumption of HSD was associated with an increase in pathogenic bacteria, including Turicibacter and Clostridia_UCG-014, and a decrease in beneficial bacteria, including Bifidobacterium and Lactobacillus. Metabolomic analysis of fecal samples suggested that HSD could increase the concentrations of most SCFAs, except caproic acid. Notably, a significant correlation was observed through Spearman correlation analysis between SCFAs and the changes in the gut microbiota caused by HSD, leading to a direct effect on SCFA levels. CONCLUSION: The alterations in the gut microbiota resulting from HSD impact the levels of SCFAs, potentially disrupting gut equilibrium and initiating HTN, thereby increasing susceptibility to cardiovascular disease and associated health complications.