Trigonelline Improves Metabolism and Cardiac Function of HFpEF Mice Via Gut Microbiome Alterations‐Mediated AMPK Activation

Abstract Heart failure with preserved ejection fraction (HFpEF) is a prevalent end‐manifestation of cardiovascular diseases currently lacking effective treatment. Using a high‐fat diet and L‐NAME‐induced mouse model, untargeted metabolomic profiling is performed and trigonelline is identified as a markedly reduced metabolite in HFpEF hearts. Oral trigonelline supplementation alleviates metabolic syndromes, including obesity, insulin resistance, and hepatic injury, leading to improved cardiac function in HFpEF mice. AMPK inhibition blunts the protective effects of trigonelline despite trigonelline per se not activating AMPK directly. Gut microbiota is required in AMPK activation and consequent beneficial effects on HFpEF mice by trigonelline. Further investigations demonstrate that trigonelline significantly restores HFpEF mouse gut microbiome dysbiosis by decreasing Firmicutes and increasing Bacteroidetes. In conclusion, the studies demonstrate that trigonelline supplementation mitigates HFpEF‐associated metabolic disorders and improves cardiac function via gut microbiome alterations‐mediated AMPK activation. These findings suggest that trigonelline has therapeutic potential for HFpEF.