Hesperidin modulates gut–adipose axis and calcium signaling via microbiota-derived metabolites: multi-omics evidence

Emerging evidence highlights the pivotal role of gut microbiota in mediating the health effects of dietary flavonoids. In this study, we uncover a novel mechanism through which hesperidin, a citrus-derived flavonoid glycoside, ameliorates high-fat diet-induced metabolic dysregulation by modulating the gut-adipose axis and activating UCP1 independent thermogenesis. The twelve-week hesperidin intervention significantly reduced weight gain, hepatic steatosis, adipose hypertrophy, dyslipidemia, and systemic inflammation in high-fat diet-fed mice. Multi-omics analyses revealed that hesperidin selectively enriched beneficial bacteria ( Lactobacillus , Bifidobacterium , Akkermansia ) and elevated microbial metabolites (e.g., cinnamic acid, hippuric acid). Transcriptomic profiling of inguinal white adipose tissue indicated upregulation of calcium cycling-associated thermogenic genes (ATP2A1, RYR1, RYR3, ITPR3) without affecting UCP1, suggesting an alternative thermogenic route. Notably, antibiotic-induced microbiota depletion abolished the metabolic benefits and impaired hesperidin bioactivation. These findings propose a previously underexplored microbiota–metabolite–calcium signaling axis, supporting hesperidin's potential as a microbiota-responsive dietary agent for obesity management.