Very‐low‐carbohydrate diet enhances human T‐cell immunity through immunometabolic reprogramming

Abstract

Very‐low‐carbohydrate diet triggers the endogenous production of ketone bodies as alternative energy substrates. There are as yet unproven assumptions that ketone bodies positively affect human immunity. We have investigated this topic in an in vitro model using primary human T cells and in an immuno‐nutritional intervention study enrolling healthy volunteers. We show that ketone bodies profoundly impact human T‐cell responses. CD4+, CD8+, and regulatory T‐cell capacity were markedly enhanced, and T memory cell formation was augmented. RNAseq and functional metabolic analyses revealed a fundamental immunometabolic reprogramming in response to ketones favoring mitochondrial oxidative metabolism. This confers superior respiratory reserve, cellular energy supply, and reactive oxygen species signaling. Our data suggest a very‐low‐carbohydrate diet as a clinical tool to improve human T‐cell immunity. Rethinking the value of nutrition and dietary interventions in modern medicine is required.

Ketone Bodies Improve Human CD8+ Cytotoxic T-Cell Immune Response During COVID-19 Infection

“…Patient characteristics are depicted in Table 1 . Lymphocytes were subjected to an established cell culture model ( 8 ) and cultivated with D/L-BHB (BHB + ) under T-cell specific stimulation (CD3/CD28 dynabeads, Supplementary Figures 1A–D ). These cells will be referred to as BHB + CD8 + T cells.…”

“…We demonstrated that BHB boosters CD8 + T-cell function by inducing significantly higher expression of central immune cytokines and enhanced cytotoxicity. These changes were based on a substantial rewiring of T-cell immunometabolism toward mitochondrial oxidative energy production ( 8 ).…”

Peculiarities of the T Cell Immune Response in COVID-19

“…Thus, Hirschberger et al ( 2021) studied the effect of a very low-carbohydrate diet on T cell immunity in an in vitro model on human T cells and in a study in healthy volunteers. According to the results of the study, the authors demonstrated that ketone bodies formed during a very low-carbohydrate diet enhance the response of CD4+ and CD8+ cells [73]. A review by Cadler (2021) provides information suggesting that both obesity and malnutrition hurt the immune response to COVID-19 and may be factors contributing to the severe course of the disease [74].…”

Your Regulatory T Cells Are What You Eat: How Diet and Gut Microbiota Affect Regulatory T Cell Development

“…Conversely, isocaloric ketogenic diets consisting of high fat (70–80%) and low carbohydrate (5–10%) content increase naïve T cell fatty acid oxidation, promoting Treg differentiation and IL-10 production ( 64 ). To our knowledge, only one study has investigated the impact of a ketogenic diet over 3 weeks on Treg induction in humans ( 64 ). Data in mice are inconsistent depending on the model with either an increase in Tregs in a carcinomatous peritonitis model ( 65 ) or a decrease in a diabetic obese mouse ( 66 ).…”

“…Conversely, isocaloric ketogenic diets consisting of high fat (70–80%) and low carbohydrate (5–10%) content increase naïve T cell fatty acid oxidation, promoting Treg differentiation and IL-10 production ( 64 ). To our knowledge, only one study has investigated the impact of a ketogenic diet over 3 weeks on Treg induction in humans ( 64 ).…”