Immune cell modulation by the ketogenic diet

What follows is a list of research that shows how a ketogenic diet can have effect on the immune system. A lot of this research is done in non-human bodies or circumstances so none of it has been proven to be similar in humans.

This is very important to know because mice and rats have a somewhat more different and stronger immune system than humans.

1. A first, most recent article is where it helps gamma-delta T-cells respond better to Influenza. How exactly the ketogenic diet caused an increase in these gd T-cells is not clear yet.

“Ketogenic diet activates protective γδ T cell responses against influenza virus infection”

2. The next one talks about improved functioning of CD8-T cells. However, this is caused by the enhanced PGC-1α expression. Beta-hydroxybutyrate (BHB) and butyrate itself increase PGC-1α expression through their HDAC inhibitory function. But butyrate may have the upper hand in this.

“Enforced PGC-1α expression promotes CD8-T cell fitness, memory formation and antitumor immunity”

“Prominent action of butyrate over β-hydroxybutyrate as histone deacetylase inhibitor, transcriptional modulator and anti-inflammatory molecule”

“Suppression of Oxidative Stress by β-Hydroxybutyrate, an Endogenous Histone Deacetylase Inhibitor”

3. Further on the CD8-T cells we find epigenetic modulation. The result is that these cells are able to divert energy towards glycogen, which is the stored form of glucose. What I suspect from this is that it gives these T-cells the ability to respond more quickly, proliferate more quickly when a pathogen is detected. Just like cancer cells, fast growing cells need a lot of glycolysis, not only to support the metabolic demand but also to synthesise fatty acids to form membranes for the new cells. I see a potential link here with the first paper on gd T-cells where the same mechanism could help in the fast proliferative response.

“Ketogenesis-generated β-hydroxybutyrate is an epigenetic regulator of CD8+ T-cell memory development.”

4. We continue a bit more on CD8-T cells. When they are challenged in an environment of low glucose and low oxygen, they switch over to fatty acid catabolism. In a tumor environment where cancer cells take up glucose 10x to 100x more than normal cells, glucose becomes scarce. Being able to switch fuel can help preserve efficacy. Hypoxia itself changes their metabolism towards fatty acids. If they are shown to take up BHB then it could be a very effective way to continue that efficiency against cancer. And the previous article seems to indicate this is the case.

“Enhancing CD8+ T cell fatty acid catabolism within a metabolically challenging tumor microenvironment increases the efficacy of melanoma immunotherapy”

5. The following study looked at BHB supplementation and noted increased INF gamma output from T1 helper cells.

“Acute hyperketonaemia alters T-cell-related cytokine gene expression within stimulated peripheral blood mononuclear cells following prolonged exercise.”

6. Not only CD8 T-cells but also CD4 T-cells seem to be affected positively. The next paper fed mice high fat and saturated fat, thinking it would result in a negative situation. However, what they found was a reduction of cholesterol in the membrane of these T-cells and an increase in proliferation response. Of note, mice with LDLr-/- have a higher metabolism (see second link).

“Prolonged Intake of Dietary Lipids Alters Membrane Structure and T Cell Responses in LDLr−/− Mice”

“The low density lipoprotein receptor modulates the effects of hypogonadism on diet-induced obesity and related metabolic perturbations”

7. A ketogenic diet contributes to a higher AMPK activity. AMPK helps the T-cells to survive longer and proliferate better. These memory T-cells are the ones that respond to a specific antigen which is valuable when a second infection arrives from the same virus.

“Long-term T cell fitness and proliferation is driven by AMPK-dependent regulation of reactive oxygen species.”

Overall it looks like a high fat, ketogenic diet seems supportive to the immune response helping in the proliferation capability and survival/efficacy in challenging environments.

There are also lots of anecdotes in various channels where people on a ketogenic diet report improvements in resistance to flu. Either they no longer get sick or the duration is shortened with less severe symptoms.

I would say, give the diet a try and take good care of yourself as we go through this COVID-19 episode.

Update 2021.06.22

Aged mCoV-A59-infected mice have increased mortality and higher systemic inflammation in the heart, adipose tissue and hypothalamus, including neutrophilia and loss of γδ T cells in lungs. Activation of ketogenesis in aged mice expands tissue protective γδ T cells, deactivates the NLRP3 inflammasome and decreases pathogenic monocytes in lungs of infected aged mice.

“Ketogenic diet restrains aging-induced exacerbation of coronavirus infection in mice”

So far these were all animal studies. The following is in vitro and in vivo human research.

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.

“Very-low-carbohydrate diet enhances human T-cell immunity through immunometabolic reprogramming”

Update 2022.01.22

10. Monocytes-turned-macrophages are part of our immune system and present throughout our body. Acetoacetate, another ketone body produced by our body in larger numbers when on a ketogenic diet, protects the cells from metabolic disturbance due to a reduction in cellular pH.

“Acetoacetate protects macrophages from lactic acidosis-induced mitochondrial dysfunction by metabolic reprograming”

11. The SARS-COV-2 spike protein anti-bodies are prolonged in the body because the ketone body beta-hydroxybutyrate attaches to its free lysine. The result is that it protects the anti-body from degradation so that it remains longer in circulation. It also makes it more resistant to heat so that it is less affected by fever for example.

“Lysine β-Hydroxybutyrylation Improves Stability of COVID-19 Antibody”


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