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

Abstract

Recent cell culture studies indicate that the ketone body β‐hydroxybutyrate (β‐OHB) directly inhibits the NLRP3 inflammasome, which plays an important role in regulating inflammation. However, there is limited direct evidence demonstrating this effect in humans.ObjectivesTo determine the effects of acutely raising blood β‐OHB on NLRP3 inflammasome activation in healthy humans.MethodsWe conducted two randomized double‐blind placebo‐controlled experiments wherein participants' blood β‐OHB levels were directly elevated by ingesting supplements containing ketone salts (0.3 g β‐OHB/kg; Study 1, N = 10 males) or ketone monoesters (0.482 g β‐OHB/kg; Study 2, N = 20, 50% females). Blood samples were obtained in the fasted state and 30‐minutes following ingestion of ketones or placebo. Markers of NLRP3 inflammasome activation included monocyte caspase‐1 (flow cytometry) and interleukin (IL)‐1β secretion (ELISA) in LPS‐stimulated whole blood cultures, and IL1B and NLRP3 mRNA expression (qPCR) from whole blood.ResultsBlood β‐OHB was significantly raised from baseline following both ketone salt (0.2 ± 0.1 mM to 0.9 ± 0.2 mM; P < 0.001) and ketone monoester (0.2 ± 0.1 mM to 3.2 ± 0.6 mM; P < 0.001) ingestion with no change in placebo. Caspase‐1 activation increased 30 minutes after consuming both ketone salt (condition X time interaction, P = 0.012) and ketone monoester (condition X time interaction, P = 0.016) supplements but not placebo. IL‐1β secretion from stimulated whole blood cultures was increased following ketone monoester consumption (9.1 ± 7.6 pg/mL to 10.9 ± 6.5 pg/mL; main effect of condition, P = 0.024) with no change in placebo. There were no significant effects of ketone supplementation on IL1B and NLRP3 mRNA expression.ConclusionsMeasures of NLRP3 activation increased when blood β‐OHB was acutely elevated using ketone supplements, suggesting that artificially increasing β‐OHB may have unintended metabolic effects that augment activation of circulating immune cells.Support or Funding InformationThis study was funded by a Natural Sciences and Engineering Research Council (NSERC) of Canada Discovery Grant (Grant number 435807). JPL is supported by a Canadian Institutes of Health Research (CIHR) New Investigator Salary Award (MSH‐141980) and a Michael Smith Foundation for Health Research (MSFHR) Scholar Award (16890). H.N. was supported by a NSERC Undergraduate Student Research Award.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.