Cardioprotective effects of Ganoderma atrum polysaccharide in a type 2 diabetes mellitus involvement with gut-derived metabolites and NLRP3 inflammasome

[Display omitted] •Ganoderma atrum polysaccharide (PSG) could reduce diabetic cardiomyopathy damage.•PSG demonstrated antioxidant properties and effectively reduced inflammation.•PSG played a beneficial role in modifying metabolites derived from gut microbiota.•Microbiota-derived metabolites might act as mediators of gut-heart communication. The study aimed to explore the effects of Ganoderma atrum polysaccharide (PSG) on diabetic cardiomyopathy in type 2 diabetic rats. Results suggested that PSG significantly attenuated diabetic cardiomyopathy, as evidenced by alleviating heart histopathological changes and LDH release, mitigating weight loss, and improving fasting blood glucose and serum insulin levels. PSG could also reduce ROS generation and malondialdehyde contents, while significantly enhancing antioxidant enzyme activities and Nrf2 expression. Furthermore, PSG reduced inflammation by suppressing NLRP3 inflammasome, caspase-1, TLR4, NF-κB p65 expression, IL-1β and IL-6 secretion. Moreover, PSG treatment significantly manipulated intestinal microbiota metabolites, including short-chain fatty acids, plasma lipopolysaccharide, and trimethylamine N-oxide. These metabolites might mediate gut-heart communication through interaction with NLRP3 inflammasome. Collectively, PSG attenuated diabetic cardiomyopathy by activating the Nrf2 antioxidant pathway, controlling inflammation via NLRP3/Caspase-1/IL-1β signaling, and using gut microbial metabolites as alternative biomarkers for predicting the mechanisms of diabetic cardiomyopathy and assessing PSG interventions.