Chronic stress is a key risk factor for depression and metabolic dysfunction, widely mediated through oxidative stress and inflammatory pathways. Natural products such as honey are increasingly investigated for their potential to attenuate stress-induced pathophysiological changes. This study evaluated the protective effects of Malaysian Acacia honey (AH) on glucose regulation, oxidative damage, histopathological alterations, and pro-inflammatory cytokine expression in stress-induced rats. Male Sprague–Dawley rats (n = 42) were subjected to chronic unpredictable mild stress and supplemented with AH, amitriptyline (AMT), or their combination for 28 days. Blood glucose levels, erythrocyte hemolysis, histological changes in liver and kidney, and expression of IL-1β and TGF-β1 in ileum, caecum, and hypothalamus were assessed. Data were reported as mean and standard error of mean (SEM) after three or more independent experiments had been conducted. The data were analyzed using a paired-t-test or a one-way or two-way analysis of variance (ANOVA) and considered significant if p < 0.05. Stress markedly elevated glucose levels (7.97 ± 0.20 mmol/L), increased hemolysis (14.30% ± 2.96), and induced hepatic (cytoplasmic vacuolation, 1.40 ± 0.25; cell lining absent, 1.20 ± 0.37) and renal lesions (dilated intertubular capillaries, 1.40 ± 0.51; inflammation, 2.20 ± 0.20), accompanied by upregulation of IL-1β (1.27-fold ± 0.20) and TGF-β1 (1.00-fold ± 0.08). Supplementation with AH significantly reduced hyperglycemia, inhibited hemolysis, ameliorated tissue damage, and downregulated pro-inflammatory cytokines. Combination therapy with AH and AMT produced the most significant improvements near to normal level, suggesting synergistic benefits. These findings highlight the therapeutic potential of AH as a natural adjunct in managing stress-related metabolic and inflammatory disturbances.

Bile acids (BA) are classically known as an agent important in lipid absorption and cholesterol metabolism. Nowadays, BAs have been found to be involved in various cellular signaling pathways such as protein kinase cascades, cyclic AMP (cAMP) synthesis and calcium mobilization. In addition, they have also been shown to regulate glucose and energy homeostasis. Bile acids are ligands for several nuclear hormone receptors, including FXR. Recently, muscarinic receptor and TGR5, G-protein-coupled receptor (GPCR), have been suggested to play a role in bile acid activity which is independent of nuclear hormone receptors. Moreover, BAs have also been studied in other GPCR associated pathways, namely sphingosine-1-posphate and glucagon receptor. Hydrophobic bile acids have been proven to affect heart rate and its contraction. Elevated bile acids are associated with arrhythmias in adults and fetal heart. Altered ratios of primary and secondary bile acid are reported in chronic heart failure patients. Meanwhile in patients with liver cirrhosis, cardiac dysfunction has been strongly linked to the increase of serum bile acid concentrations. In contrast, the most hydrophilic BA known as ursodeoxycholic acid has been found beneficial in improving peripheral blood flow in chronic heart failure patients and protecting heart against reperfusion injury.