Research Review: Oral Ketone Supplements and Inflammation

Jun 11

Oral ketone supplements are becoming more widely available, but what do we know about their effects on the human body? Are they anti-inflammatory or potentially pro-inflammatory?

Two separate randomized, controlled human clinical trials in healthy, young adults (aged 18-35) found that oral ketone supplements activate the NLRP3 inflammasome, a pathway responsible for the regulation of inflammation. The researchers tested two different types of exogenous ketone supplements: 1) ketone salts; and 2) ketone monoesters. Biomarkers used to measure NLRP3 inflammasome activation included: 1) caspase-1; 2) IL-1β secretion; 3) IL-1β; and 4) NLRP3 mRNA. Metabolic markers, including glucose and insulin, where also measured. Both types of ketone supplements significantly raised measures of NLRP3 inflammasome activation and also raised insulin.

This was the first study to investigate whether exogenous ketones are inflammatory in a human model, and the researchers had expected the results to be in line with pre-clinical research. However, their results conflicted with both in vitro (cell culture) and in vivo (animal model) evidence, which has suggested that exogenous ketones may be anti-inflammatory. Further, these results conflicted with studies of the ketogenic diet in humans, which suggest that it also has anti-inflammatory effects.

So what’s my take on this research? First, both studies were very small (n=10; n=18) and larger studies are needed to confirm the results. That said, to me this indicates that healthy individuals should be cautious about using oral ketone supplements until the evidence further evolves. Ketosis is a metabolic state, best induced by fasting and/or a low carbohydrate, moderate protein, higher fat diet. The problem with oral ketone supplements is that the individual taking them may or may not be in this metabolic state, thus signaling a mismatch to the body. The oral ketone supplements used in this study also raised insulin levels in the subjects, which is the opposite of what happens during a ketogenic diet. Here’s a great excerpt from the paper that sums up these salient points:

“The coinciding increase in both insulin and β-OHB may be a key difference between ketone supplements and ketogenic diets, as restricting carbohydrates leads to increased β-OHB at a time when insulin is lowered…A sudden increase of fuel entry into the cell without the appropriate adaptations to process the fuel, regardless of the source, could have the potential to overload the mitochondria, potentially increasing activation and signaling through the NLRP3 inflammasome, a known sensor of nutrient overload.” (Neudorf et al., 2019, pp. 22-23).

These studies excluded individuals who had followed ketogenic diets in the past three months. The subjects may not have been metabolically flexible, and may not have been restricting sugar or carbohydrate intake during the study. While the researchers did collect food diaries from the study subjects, they did not report on the details of this or discuss it with respect to the results.

In some disease states (e.g., traumatic brain injury), it may still make sense to use oral ketone supplements therapeutically, however that decision should be made on a case-by-case basis. Further, steps should be taken to modulate the inflammatory response with compounds that promote SIRT2, including resveratrol, quercetin and berberine.

With oral ketone supplements becoming widely available, it’s important that more research is done in humans to understand the effects that these supplements may have in the body. What are your thoughts on this research? Have you used exogenous ketone supplements?

Reference:

Neudorf, H., Durrer, C., Myette‐Cote, E., Makins, C., O'Malley, T., & Little, J. P. (2019). Oral ketone supplementation acutely increases markers of NLRP3 inflammasome activation in human monocytes. Molecular nutrition & food research, 63(11), 1801171.