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

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.