When a new study researched the effects ketones have on inflammation, the results were opposite to what everyone expected...including the researchers themselves.

The paper was published in the Journal of Molecular Nutrition and Food Research, and the research group that carried out the work were led by Dr Jonathan Little at the University of British Columbia.

Rather than inhibiting the inflammatory response through BHB’s (a ketone body) actions on the NLRP3 inflammasome, the researchers found that activity of several immune markers was higher when people had consumed ketones.

It can be easy to jump to conclusions and state that "Exogenous Ketones = Increased Inflammation"...as the title of the paper acutely suggests.

Dr. Brianna Stubbs tackles this study and provides further, necessary nuance on how the experiment was conducted, why the results may actually be more positive than negative, and why this development warrants future research.

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Transcription

Overview & Background

The paper we will dive into today was looking at the effects of ketones on inflammation. We went into the ketones and inflammation topic in quite a bit of detail in a recent Research Roundup...if you are interested you should go back and listen.

A quick summary if you don’t have time: There are a number of research studies in cells and animals that have shown that ketones, especially the ketone body beta hydroxybutyrate (or BHB) could reduce inflammation by inhibiting part of our innate immune system called the NLRP3 inflammasome.

The NLRP3 inflammasome is part of a complex set of proteins that are a part of our innate immune system. The inflammasome drives the inflammatory response in several disorders including autoimmune diseases, type 2 diabetes, Alzheimer’s disease, atherosclerosis, and autoinflammatory disorders as well as in response to some bacterial infection.

BHB can lessen the activation of the NLRP3 inflammasome, which improves outcomes in models of inflammatory diseases. Also, studies looking at ketogenic diets in both healthy individuals and in disease have indicated that the diet can also lower some markers of inflammation. So it was looking like BHB could be at the center of this anti-inflammatory effect. However, no one had ever looked specifically at raising BHB in isolation using exogenous ketones and how it affected inflammation in humans.

Oral Ketone Supplementation Acutely Increases Markers of NLRP3 Inflammasome Activation in Human Monocytes

The authors of this paper set out with the hypothesis that raising BHB through exogenous ketone supplementation would lower immune cell activation and decrease the secretion of chemicals linked to inflammation.

The paper was published in the Journal of Molecular Nutrition and Food Research, and the research group that carried out the work were led by Dr Jonathan Little at the University of British Columbia. Dr Little is no stranger to the field of exogenous ketones, having published papers on the effects of ketone salts on exercise metabolism and also more recently publishing a paper that showed that ketone esters could decrease blood glucose response to an oral glucose tolerance test and improve insulin sensitivity.

First up, lets give you an overview of what the researchers in the Little paper did. There were two parts in the experiment.

In the first part, 10 people drank ketone salt drinks and then placebo drinks. In the second part, 20 people drank ketone ester drinks and control drinks. Just before the drink, the researchers collected a blood sample, and then at 30 minutes, just as ketone levels were peaking, a second sample was collected.

The researchers then split the blood samples in half- one half was kept aside, and the second half had a bacterial toxin added into it. The bacterial toxin would stimulate the immune cells to become active and release chemicals that trigger inflammation, to combat the bacteria. Both the stimulated and unstimulated samples were then used to measure the levels of immune cell activation.

So...what were the results?

The first thing to note is that the samples that weren’t stimulated with the bacterial toxin did not have any immune response, and it didn’t make a difference if people had consumed ketones or not.

Only the blood samples where bacterial toxin was added saw an uptick in inflammatory markers. This is pretty much what you would want- you only get inflammation in response to a potentially harmful stimulus.

But wait! Key takeaway number one is that ketone drinks didn’t trigger inflammation just by themselves.

If it was me writing the paper, I would have reflected this nuance in the title and changed it to "Oral Ketone Supplementation Acutely Increases Markers of NLRP3 Inflammasome Activation in Bacterial Toxin Stimulated Human Monocytes" - as there was no increase in inflammatory response in the blood cells when people consumed ketones but no bacteria was added.

What about the stimulated samples?

This is where the results were unexpected- the opposite of what everyone had predicted in fact! Rather than inhibiting the inflammatory response through BHB’s actions on NLRP3, the researchers found that activity of several immune markers was higher when people had consumed ketones before their blood was stimulated by bacteria.

Now, whilst unexpected, this paper isn’t actually the first time a immune boosting effect of ketones such as this has been described. A research paper published late last year did quite an invasive human experiment, where they infused ketones and bacterial toxin directly into the blood of healthy young adults - they must have had good doctors on hand and a very trusting ethics board! These researchers also saw a relative increase in the same inflammatory markers when people were infused with ketones and exposed to bacterial toxin, so the finding presented here the Little paper is nicely in line with that.

There are a few other things that I think are interesting to consider about this study.

Firstly, the control arm was a calorie free drink, whereas the ketone drinks contain calories in the form of BHB. It is reasonable to suspect that the availability of substrate, such as BHB, might have affected the activity and responsiveness of the immune cells.

What is more, the ketone drinks triggered a small increase in insulin. There was no rise in insulin with the calorie free control drink. The researchers point out that this rise in insulin can boost release of inflammatory markers, so this might play a role in the results. So, the unanswered questions from this study are firstly if having calories from a substrate (i.e a glucose drink) or altering insulin levels might have also increased immune activation after bacterial stimulation compared remaining in the fasted state; without that comparison it isn't clear if this inflammation boosting effect is ketone specific.

Secondly, how would this effect play out if the sampling window was extended past thirty minutes? A single time point gives us quite limited information on which to base conclusions. What about if multiple ketone drinks were used over several days?

Thirdly, it isn't clear if this immune boosting effect would be present in people with pre-existing inflammatory conditions. There have been enough people using ketone ester (and salt) drinks and reporting improvement in inflammatory conditions that I'm not totally discounting that there could be a beneficial effect on the basis of this paper. There have been plenty of researchers, such as Dr Dom D'Agostino, who have been using ketone supplements personally, or looking at blood work of people who do for some time now, and so if there was a negative effect there would have likely been more reports of these people having increased immune activation in their blood work.

Finally, I think an interesting point to finish on is that, you have to take a step back and look at what is happening here. You drink ketones and nothing seems to happen in the immune system. But then you add in a bacterial danger signal after drinking ketones and then you get boosted immune response manifested as more markers of inflammation. One can certainly argue that boosting the immune response to bacteria may actually be beneficial..!

Conclusion

You want your immune system to be able to effectively fight off infection in order to survive. Its very much a case of context- in the right setting inflammation is protective and in other settings it can be harmful. I like the metaphor that inflammation is something of a “Goldilocks” effect- not too much, not too little, it has to be just right.

These results support the idea that BHB and ketones are more than just a fuel- they are a signal that can modulate the activity of many systems of our body, including the immune system. But they also highlight the importance of more human work in the future. Studies like this will help to understand the basic science mechanism, but we also need more applied clinical studies.

It is exciting to see human work start to tease out the differences between exogenous ketones and the ketogenic diet - perhaps in the future we could repeat this study and include a cohort of people on the ketogenic diet too. Hopefully, this intriguing paper is the first of many more similar studies to come!