Ketone Therapy Reduces Systemic and Organ Inflammation in Sepsis

Introduction Sepsis is the body's reaction to an infection that often causes lasting 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 inflammation‐mediated damage and thus, sepsis accounts for approximately 20% of all global causes of death. In addition, many patients who recover from sepsis have permanent damage to many organ systems which makes them more susceptible to future injury that likely affects them more severely. Thus, therapeutic strategies to reduce the inflammatory response in sepsis are needed to save lives and improve the outcomes and quality of life of those who survive sepsis. Herein, we tested the efficacy of a ketone therapy that increases circulating ketones via ketone ester supplementation. Ketones are small molecules that are normally produced by the liver and are elevated during carbohydrate‐deprived states, such as fasting or exercise. While ketones are classically known to be a metabolic source of energy, they also have non‐metabolic effects, such as inhibiting inflammation, which can be of therapeutic importance. We hypothesized that ketones have potent anti‐inflammatory effects in a mouse model of lipopolysaccharide (LPS)‐induced sepsis and that ketones can be used to mitigate the inflammation‐mediated organ damage. Objective To determine if ketone supplementation can effectively reduce inflammation and organ dysfunction/damage in a model of LPS‐induced sepsis. Methods 8‐week‐old mice orally received either vehicle or a clinically tested ketone ester (KE) for 3 days. On day 3, mice were injected with saline or LPS to induce systemic inflammation and organ damage. 24 hours post‐injection, cardiac function was assessed and then mice were euthanized to assess systemic and organ inflammation from the 3 groups (control, LPS, LPS+KE). Results LPS‐treated mice had higher blood ketones compared to controls, suggesting that ketones may be important as an innate defense mechanism, and this response was further augmented in KE‐treated septic mice. While LPS‐treated mice had an induction of systemic pro‐inflammatory cytokines (e.g., IL‐1β, IL‐6, interferon‐γ) these cytokines were significantly lower in KE‐treated septic mice. Similarly, LPS induced numerous inflammatory markers in the heart, kidney, and liver, a large majority of which were reduced in the KE‐treated septic mice. LPS‐induced cardiac dysfunction and renal fibrosis was also significantly lower in KE‐treated septic mice. Finally, there was either no change or a reduction of ketolytic enzymes in various organs, suggesting that these protective and anti‐inflammatory effects do not depend on ketone metabolism for energy production. Conclusion Together, these data are the first to show that ketone therapy may be a novel approach to reducing systemic and organ inflammation and dysfunction, and subsequent organ damage in a model of LPS‐induced sepsis.

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