Intermittent Fasting Amplifies Gut-Endocrine Axis Responses to Senna alexandrina Supplementation in Obese Rats

Obesity induced by high‑fat, high‑sucrose diets (HFSD) remains a major global health challenge, disrupting lipid metabolism, glucose homeostasis, and gut microbial balance. These disturbances underscore the need for safe interventions capable of restoring metabolic regulation. Senna alexandrina (SA), traditionally used for weight reduction, has recently been shown to modulate the gut microbiota beyond its laxative effects. To enhance efficacy while minimizing adverse outcomes, this study investigated the effects of a low and safe dose of SA combined with intermittent fasting (IF), a strategy that reshapes nutrient availability and microbial dynamics. HFSD‑induced obese rats were treated for four weeks with SA leaf powder (300 mg/kg/day), IF, or both. Bioactive constituents of SA were characterized using LC‑HRMS, alongside systematic evaluation of physiological and metabolic parameters-including adiposity, morphometry, lipid profiles, insulin sensitivity markers, and gut-endocrine axis indicators. SA supplementation showed improvements across all parameters, surpassing those achieved with IF alone. Importantly, the combined intervention (SA+IF) yielded complementary benefits, notably enhancing GLUT4 expression, short‑chain fatty acid (SCFA) production, peptide YY (PYY) secretion, and reducing the Firmicutes/Bacteroidetes ratio. These findings highlight the complementary roles of SA and IF in metabolic regulation, providing experimental evidence for a potential dietary approach to mitigate obesity‑related dysfunction.