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

SCOPE: Cell culture studies indicate that the ketone β‐hydroxybutyrate (β‐OHB) directly inhibits the NLRP3 inflammasome, a key regulator of inflammation. However, direct evidence demonstrating this effect in humans is lacking. METHODS AND RESULTS: To determine the effects of acutely raising blood β‐OHB in healthy humans, two separate randomized double‐blind placebo‐controlled experiments are conducted using similar methods but each employed different exogenous ketone supplements. Participants' blood β‐OHB is directly elevated by ketone salts (0.3 g β‐OHB per kg; Study 1, N = 10 males) or ketone monoester (0.482 g β‐OHB per kg; Study 2, N = 18, equal males/females). Markers of NLRP3 inflammasome activation include caspase‐1, IL‐1β secretion, and IL1B and NLRP3 mRNA in LPS‐stimulated whole blood collected at the baseline and 30 minutes following supplementation. Caspase‐1 activation increases after ketone salt (Study 1: condition × time interaction, p = 0.012) and monoester supplementation (Study 2: condition × time interaction, p = 0.016) compared to placebo. IL‐1β secretion increases (main effect of condition, p = 0.024; Study 2) while IL1B and NLRP3 mRNA remain unchanged. CONCLUSION: Measures of NLRP3 activation increases when blood β‐OHB is elevated using ketone supplements, suggesting that increasing β‐OHB exogenously may have unintended effects that augment inflammatory activation.