Dietary Nitrate and Corresponding Gut Microbiota Prevent Cardiac Dysfunction in Obese Mice

Abstract

Impaired heart function can develop in diabetic individuals in the absence of coronary artery disease or hypertension, suggesting mechanisms beyond hypertension/increased afterload contribute to diabetic cardiomyopathy. Identifying therapeutic approaches that improve glycemia and prevent cardiovascular disease are clearly required for clinical management of diabetes-related comorbidities. Since intestinal bacteria are important for metabolism of nitrate, we examined if dietary nitrate and fecal microbial transplantation (FMT) from nitrate-fed mice could prevent high-fat diet (HFD)-induced cardiac abnormalities. Male C57Bl/6N mice were fed an 8-week low-fat diet (LFD), HFD, or HFD+Nitrate (4mM sodium nitrate). HFD-fed mice presented with pathological left ventricular (LV) hypertrophy, reduced stroke volume and increased end diastolic pressure, in association with increased myocardial fibrosis, glucose intolerance, adipose inflammation, serum lipids, LV mitochondrial reactive oxygen species (ROS), and gut dysbiosis. In contrast, dietary nitrate attenuated these detriments. In HFD-fed mice, FMT from HFD+Nitrate donors did not influence serum nitrate, blood pressure, adipose inflammation, or myocardial fibrosis. However, microbiota from HFD+Nitrate mice decreased serum lipids, LV ROS, and similar to FMT from LFD donors, prevented glucose intolerance and cardiac morphology changes. Therefore, the cardioprotective effects of nitrate are not dependent on reducing blood pressure, but rather mitigating gut dysbiosis, highlighting a nitrate-gut-heart axis.

Lipotoxicity as a therapeutic target in obesity and diabetic cardiomyopathy

“…In addition to pharmaceutical interventions, the intake of dietary nitrate (NO 3 − ) through beetroot juice has been shown to enhance exercise capacity in patients with HFpEF [239] and increase the maximum rate of oxygen consumption during exercise in patients with diabetes [240]. Rodent studies demonstrated the beneficial effect of dietary nitrate on HFD-induced liver steatosis through the modulation of microbiota [241] and cardiomyopathy [242] in mice. These findings suggest that dietary nitrate could be a therapeutic option for diabetic cardiomyopathy through the modulation of gut microbiota.…”