COVID-19: ketogenic diets and beta-hydroxybutyrate boost immune cells helping recovery

A new study led by researchers from the University Hospital Bonn, University of Bonn-Germany has found that ketogenic diets and β-hydroxybutyrate (BHB) can help in COVID-19 especially in boosting immune cells.

The study findings were published in the peer reviewed journal: Nature
https://www.nature.com/articles/s41586-022-05128-8

Sickness behaviors are an evolutionary preserved coordinated set of adaptive behavioral changes including lethargy, fever, social withdrawal, and loss of appetite, that have evolved to support host survival in response to infections1-3.

Human and animal data show that infection- induced anorexia and the induction of ketogenesis, a well-described host metabolic adaptation in response to fasting4, are promoted in the context of respiratory viral infections5,6.

This indicates that infectious diseases and host metabolism are intimately intertwined7.

However, in contrast to fasting, the physiological role of ketogenesis during an infection remains elusive2. Although host metabolic adaptations shaped by evolutionary pressure in response to endemic viruses are conserved, they may be dysfunctional in the context of newly emerging zoonotic infections.

This notion is of particular interest in light of the current pandemic outbreak of Coronavirus Disease 2019 (COVID-19), caused by the zoonotic virus Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2)8,9.

In the majority of infected people, the host immune response is sufficient to resolve the infection. In some cases, however, dysfunctional immune responses may result in severe lung and systemic pathology10,11.

Two of the main cellular immune populations involved in the clearance of the viral infections are CD4+ type 1 helper T (Th1) cells and CD8+ cytotoxic T cells, acting through the production of cytokines such as IFN-(GAMMA)  or killing of infected cells, respectively.

Cellular metabolism and mitochondrial function are major determinants of T cell activation and function12, raising the question of a potential link between infection-induced ketogenesis and T cell immunity.

Discussion
Here, we uncover that SARS-CoV-2-induced immune dysregulation correlated with an attenuated increase in BHB in the circulation, indicating impaired infection-induced ketogenesis in COVID-19 but not influenza ARDS. Although the underlying reasons for this disparity remain to be revealed, we show that BHB substantially boosts the antiviral immune response by promoting IFN-(GAMMA) production and survival of human and murine CD4+ T cells.

In COVID-19 ARDS, T cells are exhausted and skewed towards glycolysis, probably as a result of reduced oxygenation of the pulmonary tissue46.

BHB not only rewires T cells to OXPHOS by fueling the TCA cycle, but also promotes AA synthesis, nutrients found to be depleted in COVID-19 ARDS36.

Consequently, impaired ketogenesis and BHB production in COVID-19 ARDS may be at the root of the metabolic dysregulation and defective effector function of T cells, predisposing patients to pulmonary pathology, including fibrosis. Indeed, lower serum concentrations of IFN-(GAMMA) in COVID-19 patients have been linked to increased risk to develop pulmonary fibrosis47.

Hence, our results point towards an additional mechanism beyond immune overactivation underlying severe COVID-19 pathology46. We reveal ketogenesis as a metabolic program promoting type 1 immunity and preventing the pathogenic remodeling of the airway epithelial tissue.

Although, therapeutic (as opposed to prophylactic) relevance has yet to been assessed, our discovery highlights the potential of BHB and KD as a broadly applicable treatment to enhance functional T cell responses in nutrient deprived environments,

commonly observed in the context of infections but also tumor growth. In summary, our study establishes a better understanding of how dysregulated host metabolic adaptations to infections may contribute to deleterious outcomes in COVID-19.