Investigating Ketone Bodies as Immunometabolic Countermeasures against Respiratory Viral Infections

Stubbs, Brianna J.; Koutnik, Andrew P.; Goldberg, Emily L.; Upadhyay, Vaibhav; Verdin, Eric; Newman, John C.

doi:10.1016/j.medj.2020.06.008

Cited by 52 publications

(61 citation statements)

References 245 publications

(362 reference statements)

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“…According to the conclusions of a recent review, ketone bodies are endogenous metabolites involved in cellular energy homeostasis, but they also have important signaling activities that affect immunological activity. Therefore, knowledge regarding the role of ketone bodies in the fight against respiratory viral infections and the development of intervention studies based on the administration of exogenous ketone bodies as new immunometabolic therapies for these diseases could offer potential resources to deal with the SARS-CoV-2 pandemic [165]. Finally, due to the continuous production of scientific evidence and the results of the first clinical trials, it cannot be ruled out that other compounds must also be considered as potential strengtheners of the immune system, and other elements beyond genetics must be taken into account as factors that require less bioavailability of these essential nutrients.…”

Section: Discussionmentioning

confidence: 99%

Current State of Evidence: Influence of Nutritional and Nutrigenetic Factors on Immunity in the COVID-19 Pandemic Framework

2020

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The pandemic caused by the new coronavirus has caused shock waves in many countries, producing a global health crisis worldwide. Lack of knowledge of the biological mechanisms of viruses, plus the absence of effective treatments against the disease (COVID-19) and/or vaccines have pulled factors that can compromise the proper functioning of the immune system to fight against infectious diseases into the spotlight. The optimal status of specific nutrients is considered crucial to keeping immune components within their normal activity, helping to avoid and overcome infections. Specifically, the European Food Safety Authority (EFSA) evaluated and deems six vitamins (D, A, C, Folate, B6, B12) and four minerals (zinc, iron, copper and selenium) to be essential for the normal functioning of the immune system, due to the scientific evidence collected so far. In this report, an update on the evidence of the contribution of nutritional factors as immune-enhancing aspects, factors that could reduce their bioavailability, and the role of the optimal status of these nutrients within the COVID-19 pandemic context was carried out. First, a non-systematic review of the current state of knowledge regarding the impact of an optimal nutritional status of these nutrients on the proper functioning of the immune system as well as their potential role in COVID-19 prevention/treatment was carried out by searching for available scientific evidence in PubMed and LitCovid databases. Second, a compilation from published sources and an analysis of nutritional data from 10 European countries was performed, and the relationship between country nutritional status and epidemiological COVID-19 data (available in the Worldometers database) was evaluated following an ecological study design. Furthermore, the potential effect of genetics was considered through the selection of genetic variants previously identified in Genome-Wide Association studies (GWAs) as influencing the nutritional status of these 10 considered nutrients. Therefore, access to genetic information in accessible databases (1000genomes, by Ensembl) of individuals from European populations enabled an approximation that countries might present a greater risk of suboptimal status of the nutrients studied. Results from the review approach show the importance of maintaining a correct nutritional status of these 10 nutrients analyzed for the health of the immune system, highlighting the importance of Vitamin D and iron in the context of COVID-19. Besides, the ecological study demonstrates that intake levels of relevant micronutrients—especially Vitamins D, C, B12, and iron—are inversely associated with higher COVID-19 incidence and/or mortality, particularly in populations genetically predisposed to show lower micronutrient status. In conclusion, nutrigenetic data provided by joint assessment of 10 essential nutrients for the functioning of the immune system and of the genetic factors that can limit their bioavailability can be a fundamental tool to help strengthen the immune system of individuals and prepare populations to fight against infectious diseases such as COVID-19.

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Section: Discussionmentioning

confidence: 99%

Current State of Evidence: Influence of Nutritional and Nutrigenetic Factors on Immunity in the COVID-19 Pandemic Framework

2020

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“…However, therapies that increase R-BHB levels, including the consumption of a ketogenic diet or different forms of exogenous ketones, will be the focus of this review. Others have also suggested that increasing systemic ketone levels may aid host defenses against respiratory viral infection, in part, by decreasing inflammation [ 1 , 2 ], including a recent comprehensive review [ 3 ], while a clinical trial of the effects of a ketogenic diet on intubated SARS-CoV-2 patients has recently been registered ( NCT04358835 ).…”

Section: Introductionmentioning

confidence: 99%

COVID-19: Proposing a Ketone-Based Metabolic Therapy as a Treatment to Blunt the Cytokine Storm

Bradshaw

Seeds²,

Miller

et al. 2020

Oxidative Medicine and Cellular Longevity

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Human SARS-CoV-2 infection is characterized by a high mortality rate due to some patients developing a large innate immune response associated with a cytokine storm and acute respiratory distress syndrome (ARDS). This is characterized at the molecular level by decreased energy metabolism, altered redox state, oxidative damage, and cell death. Therapies that increase levels of (R)-beta-hydroxybutyrate (R-BHB), such as the ketogenic diet or consuming exogenous ketones, should restore altered energy metabolism and redox state. R-BHB activates anti-inflammatory GPR109A signaling and inhibits the NLRP3 inflammasome and histone deacetylases, while a ketogenic diet has been shown to protect mice from influenza virus infection through a protective γδ T cell response and by increasing electron transport chain gene expression to restore energy metabolism. During a virus-induced cytokine storm, metabolic flexibility is compromised due to increased levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) that damage, downregulate, or inactivate many enzymes of central metabolism including the pyruvate dehydrogenase complex (PDC). This leads to an energy and redox crisis that decreases B and T cell proliferation and results in increased cytokine production and cell death. It is hypothesized that a moderately high-fat diet together with exogenous ketone supplementation at the first signs of respiratory distress will increase mitochondrial metabolism by bypassing the block at PDC. R-BHB-mediated restoration of nucleotide coenzyme ratios and redox state should decrease ROS and RNS to blunt the innate immune response and the associated cytokine storm, allowing the proliferation of cells responsible for adaptive immunity. Limitations of the proposed therapy include the following: it is unknown if human immune and lung cell functions are enhanced by ketosis, the risk of ketoacidosis must be assessed prior to initiating treatment, and permissive dietary fat and carbohydrate levels for exogenous ketones to boost immune function are not yet established. The third limitation could be addressed by studies with influenza-infected mice. A clinical study is warranted where COVID-19 patients consume a permissive diet combined with ketone ester to raise blood ketone levels to 1 to 2 mM with measured outcomes of symptom severity, length of infection, and case fatality rate.

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“…Studies have shown that a KD reduces circulating inflammatory markers in humans [26] . The KD, via hydroxybutyrate (HB), is capable of activating hydroxycarboxylic acid receptor 2 (HCA2), a G protein-coupled receptor, which inhibits NF-kB in macrophages, dendritic cells and microglia and reduces neuroinflammation [27] .…”

Section: Discussionmentioning

confidence: 99%

Clinical efficacy of eucaloric ketogenic nutrition in the COVID-19 cytokine storm: A retrospective analysis of mortality and intensive care unit admission

et al. 2021

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Objective : Primary objective is to explore the effect of eucaloric ketogenic diet (EKD) on mortality, admission to intensive care unit (ICU) and the need for non-invasive ventilation (NIV) in hospitalized patients affected by COVID-19 in comparison to eucaloric standard diet (ESD). Secondary objectives are: the verification of safety and feasibility of the diet and its impact on inflammatory parameters, in particular interleukin-6 (IL-6). Results : The preliminary multivariate analysis shows a statistical significance in survival (P=0,046) and need for ICU (P=0,049) with EKD compared with ESD. Considering EKD start day as a "time-dependent" variable, however, the results maintain a positive trend towards the application of the diet and it is not possible to reject the null hypothesis (p <0.05). IL-6 concentrations between t 0 and t 7 (seven days after the beginning of the diet) in the ketogenic nutrition group shows a trend almost significant (P = 0.062). EKD was safe and no adverse events were observed. Conclusions : These results show a possible therapeutic role of EKD in the clinical management of COVID-19. Currently, a prospective controlled randomized trial is running out in order to confirm these preliminary data.

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Investigating Ketone Bodies as Immunometabolic Countermeasures against Respiratory Viral Infections

Cited by 52 publications

References 245 publications

Current State of Evidence: Influence of Nutritional and Nutrigenetic Factors on Immunity in the COVID-19 Pandemic Framework

Current State of Evidence: Influence of Nutritional and Nutrigenetic Factors on Immunity in the COVID-19 Pandemic Framework

COVID-19: Proposing a Ketone-Based Metabolic Therapy as a Treatment to Blunt the Cytokine Storm

Clinical efficacy of eucaloric ketogenic nutrition in the COVID-19 cytokine storm: A retrospective analysis of mortality and intensive care unit admission

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