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Examining the effect of short-term oral ketone supplementation on markers of NLRP3 inflammasome activation in individuals with obesity

University of British Columbia

Background: The NLRP3 inflammasome, an innate immune sensor, has been implicated in the progression in a number of chronic inflammatory diseases and represents an important therapeutic target. The ketone body, beta-hydroxybutyrate (BHB) has been shown to attenuate NLRP3 activation in murine and in vitro models. However, these findings have not yet been replicated in humans. Methods: We conducted a randomized, double-blind, placebo-controlled, crossover study in humans with obesity (N = 14). We tested the hypothesis that elevation of blood BHB by ingestion of an exogenous ketone monoester drink (KME) 3x/day for 14 days would attenuate basal NLRP3 activation and would reduce NLRP3 sensitivity to activation in response to an inflammatory challenge. NLRP3 activation was quantified by magnitude of caspase-1 activation and secreted IL-1b. We also conducted an exploratory in vitro experiment in parallel to the in vivo study in which whole blood from each participant was cultured with lipopolysaccharide (LPS) and increasing concentrations of BHB. Results: KME supplementation elevated blood BHB concentration to ~2 mM. Monocyte caspase-1 activation was reduced in response to an inflammatory stimulus following 14-days of KME compared to placebo (time x condition interaction, χ²(1)=3.80, P = 0.05). Similarly, low-to-moderate, but not high, concentrations of BHB in culture appeared to attenuate IL-1b secretion in a dose-dependent manner. However, basal caspase-1 activation and plasma cytokines remained unchanged. Conclusions: Fourteen days of KME, which elevates BHB to low-to-moderate levels, appears to attenuate NLRP3 activation in human monocytes exposed to an inflammatory stimulus. This is the first study to replicate this concept in an in vivo/ex vivo human model. Future research should investigate the potential therapeutic effect of KME in human disease that exhibit excessive NLRP3 activation.

Text

2020-12-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/74735

Health and Exercise Sciences

University of British Columbia

UBCO

http://creativecommons.org/licenses/by-nc-nd/4.0/