NLRP3 inflammasome blockade treats intestinal inflammation associated with chronic granulomatous disease.

Chronic granulomatous disease (CGD) is an inborn error of immunity associated with a 50% prevalence of inflammatory bowel disease (IBD) for which current treatments are suboptimal due to increased risk of infections in this population. CGD results from defects in the nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) complex, leading to minimal or absent phagocyte-derived reactive oxygen species production. Patients with CGD present with recurrent infections and severe inflammatory complications, especially in the gut. These inflammatory complications have been associated with increased systemic activation of the nucleotide-binding domain and leucine-rich-repeat-containing protein 3 (NLRP3) inflammasome and dysregulation of the T-cell compartment. However, the role of the NLRP3 inflammasome at the intestinal barrier and whether it can be targeted to treat CGD-IBD remain unclear. Beta-hydroxybutyrate (βHB), a ketone body produced during fasting or adherence to a ketogenic diet, can inhibit the NLRP3 inflammasome and restore T-cell balance. In this preclinical study, we demonstrated that a ketogenic diet significantly improves colitis in CGD mice, to a greater extent than in wild-type mice, by reducing NLRP3 inflammasome activity, altering the microbiota and inducing tolerogenic immune populations at the intestinal mucosal barrier. We also showed that βHB supplementation can significantly improve colitis in CGD mice while decreasing systemic inflammation. We further confirmed in human CGD blood cells that βHB effectively reduces levels of cytokines associated with inflammasome activation. In conclusion, our study identified NLRP3 inflammasome blockade using a ketogenic diet or βHB supplementation as a potential novel and safer treatment for CGD-IBD.