Sepsis is the body's reaction to an infection that often causes lasting cardiac damage and multi-organ injury due to a dysregulated inflammatory response. Currently, there are no effective treatments to reduce inflammation during sepsis and assist in preventing the lasting cardiovascular damage. Not only are sepsis outcomes worse for cardiovascular disease patients, but the permanent organ damage to sepsis survivors also makes them more susceptible to diseases such as heart failure. Thus, therapeutic strategies to reduce the inflammatory response in sepsis are needed to mitigate the development of cardiovascular disease and improve the outcomes and quality of life for cardiovascular patients who survive sepsis. Herein, we tested the efficacy of a therapy that increases circulating ketones via ketone ester supplementation. Ketones are small molecules that are normally produced by the liver and are elevated during low-carbohydrate states, such as fasting. While ketones are classically known to be metabolic substrates that produce ATP, they also have non-metabolic effects, such as inhibiting inflammation. Thus, we hypothesized that ketones have anti-inflammatory effects which will protect against sepsis-induced cardiac dysfunction in a mouse model of sepsis.
Methods and Results
To determine the effects of ketone therapy in sepsis, 8-week-old mice orally received vehicle or a clinically tested ketone ester (KE) for 3 days. On day 3, mice were injected with saline or lipopolysaccharide (LPS), and cardiac function, cardiac inflammation, as well as systemic inflammation and multi-organ injury were assessed 24 hours post-injection. Vehicle-treated LPS mice had higher blood ketones compared to non-septic controls, suggesting that ketones may be important as an innate defense mechanism. This response was further increased in KE-treated LPS mice. While vehicle-treated LPS mice had an induction of cardiac and systemic inflammation (e.g., IL-1β, IL-6), most inflammatory markers were significantly lower in KE-treated LPS mice. Similarly, KE-treated septic mice had lesser cardiac dysfunction than vehicle-treated septic mice. These anti-inflammatory effects were also observed in other vital organs such as the kidney and liver thereby demonstrating that KE therapy had global protective effects. Lastly, ketolytic enzymes were reduced or unchanged in vehicle- and KE-treated septic mice, potentially ruling out a normalization of ketone metabolism as a mechanism by which KE treatment may improve function.
Together, these data show that ketone therapy may be a novel translational approach to reducing cardiac and systemic inflammation, as well as cardiac dysfunction in a model of sepsis.
Canadian Institutes of Health Research - Doctoral Research Award, Canadian Institutes of Health Research (CIHR), Heart and Stroke Foundation of Canada
© 2022 Published by Elsevier Inc.