Intermittent Fasting Restores Cardiac Lipid Homeostasis in Diabetic Cardiomyopathy in Association With Akkermansia Muciniphila and 1‐methyl‐L‐histidine

ABSTRACT Diabetic cardiomyopathy (DCM) is a major cardiovascular complication of diabetes with limited effective interventions. Using a streptozotocin‐induced insulin‐deficient, type 1 diabetes‐like DCM mouse model, we show that intermittent fasting (IF) improves cardiac function and attenuates myocardial remodeling. Antibiotic‐mediated microbiota depletion largely abolished these benefits, whereas fecal microbiota transplantation from IF‐treated donors recapitulated cardioprotection, supporting a causal role of the gut microbiota. Metagenomic profiling identified Akkermansia muciniphila ( A. muciniphila ) as a prominent IF‐responsive taxon, and A. muciniphila supplementation alleviated cardiac injury without obvious improvement in glycaemia. Integrated serum and heart metabolomics identified 1‐methyl‐L‐histidine as a microbiota‐associated metabolite reduced in diabetes but restored by IF and A. muciniphila . In vitro and ex vivo assays further supported an L‐anserine‐linked microbial route for 1‐methyl‐L‐histidine generation. Importantly, oral 1‐methyl‐L‐histidine supplementation recapitulated key cardioprotective effects, remodeled cardiac lipid homeostasis, and reduced lipid peroxidation and oxidative injury. Together, these findings support a gut microbiota–metabolite–lipid axis associated with IF‐related cardioprotection in DCM and highlight microbial metabolites as tractable targets to complement dietary intervention.