Inhibition of Inflammasome Activation through the Modulation of b‐hydroxybutyrate Levels In vivo Decreases Alzheimer’s Disease Pathology

Using gnotobiotic models, our research group has demonstrated that specific changes in the gut microbiome modulate serum and brain b‐hydroxybutyrate (BHB) levels. BHB levels measured in blood also differ in Alzheimer’s disease (AD), and BHB has been linked with immune function. Recently, microglial activation of the nod‐like receptor family pyrin domain containing protein 3 (Nlrp3) inflammasome—a multi‐protein complex that when activated results in apoptosis specks‐like protein containing a caspase recruitment domain (Asc)‐speck accumulation—has been recognized as feature of AD (extracellular Asc‐specks can nucleate Ab plaques and enhance AD pathology). Given that gut microbiome modulates immune function and may impact inflammasome activation, here we tested the extent to which BHB differs in AD brain, impacts the Nlrp3 inflammasome and impacts AD pathology.