Exploratory metabolomic profiling reveals metabolic alterations potentially associated with pain and blood pressure regulation in a high-sugar diet rat model

A high-sugar diet (HSD) is associated with various health issues, including metabolic dysfunction, inflammation, hypertension, and increased pain sensitivity. However, the metabolic pathways potentially involved in these processes remain incompletely understood. This exploratory metabolomic profiling study aimed to investigate HSD-related alterations in serum and salivary metabolites and to identify metabolic pathways potentially relevant to pain and blood pressure regulation. Rats were randomly divided into two groups: a control group receiving standard chow and regular water, and an HSD group fed a cariogenic diet supplemented with 5% sucrose water for 28 days. Serum and saliva samples were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based untargeted metabolomics. Metabolomic profiling and pathway analysis assessed metabolic changes regarding pain and blood pressure regulation. Significant differences were observed in the serum metabolite profiles between HSD and control groups. The HSD group showed alterations with 330 down-regulated and 72 up-regulated metabolites. Notably, metabolites associated with blood pressure regulation were impacted; up-regulated metabolites like lysophosphatidylcholine and midodrine were linked to increased blood pressure, while down-regulated metabolites like taurochenodeoxycholic acid and hypotaurine have been associated with antihypertensive effects. Additionally, metabolites linked to pain sensitivity, including N-arachidonoyl dopamine and acetaminophen glucuronide, were down-regulated. Pathway analysis identified 12 up-regulated pathways in HSD-fed rats, including starch and sucrose metabolism, associated with vascular dysfunction, and 14 down-regulated pathways, such as vitamin B6 and taurine metabolism, linked to cardiovascular protection. Salivary analysis showed 186 altered metabolites, particularly the down-regulation of the anti-inflammatory metabolite N-acetylanthranilic acid and the up-regulation of the antihypertensive agent bethanidine. Cross-biofluid analysis highlighted consistent changes in nucleotide and arginine/proline metabolism. This exploratory metabolomic profiling study demonstrated that HSD exposure was associated with broad metabolic alterations in serum and saliva. Several identified metabolites and pathways may be potentially relevant to biological processes involved in pain sensitivity and blood pressure regulation. These findings are hypothesis-generating and provide a foundation for future mechanistic and longitudinal studies investigating the metabolic effects of high-sugar diets.