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.