Inhibition of the NLRP3 Inflammasome With MCC950 Improves Gut Health in Huntington's Disease Mice

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder featuring abnormal cognition, psychiatric symptoms, movement, and gastrointestinal function. It is caused by a tandem-repeat gene mutation encoding an expanded polyglutamine tract in the huntingtin protein. Our group was the first to demonstrate gut microbial disruption in both clinical HD cohorts and validated preclinical models, supporting a role for microbiota-gut-brain axis dysfunction in HD. The NLRP3 inflammasome, a key innate immune sensor that integrates microbial, metabolic, and host-derived danger signals, has been implicated in HD pathology. However, its contribution to gut health and microbiota-linked cognitive deficits in HD remains unknown. This study addressed this critical gap by investigating whether targeting NLRP3 can restore gut and brain health in HD through modulation of the microbiota-gut-brain axis. We aimed to investigate the role of the NLRP3 inflammasome in microbiota-gut-brain axis dysfunction by targeting its inhibition. Here, we assessed whether inhibiting NLRP3 can ameliorate cognitive deficits, gut abnormalities, gut microbial alteration, and associated molecular and behavioural disturbances in HD. NLRP3 inflammasome inhibitor MCC950 was administered to R6/1 transgenic HD mice and their wild-type (WT) littermate controls from 6 to 20 weeks of age. Cognitive and behavioural performance was evaluated using validated tests, alongside assessments of general health and gut function. HD mice exhibited reduced body and brain weight, increased fluid consumption, memory impairments, motor deficits, exacerbated gastrointestinal phenotype, and altered gut microbiota. Treatment with MCC950 did not affect body or brain weight, cognitive and motor performance, and it also did not affect the gut microbial profile of HD mice. However, MCC950 significantly rescued gut health, as evidenced by increased faecal output (in females) and water content (in both males and females), improved stool consistency (in both sexes), and ameliorated macroscopic gut abnormalities. Our findings highlight a promising therapeutic avenue for addressing the significant gastrointestinal anomalies observed in HD. By targeting the NLRP3 inflammasome in R6/1 HD mice, we have identified a novel strategy to improve gut health. These results support further investigation of inflammasome inhibition as a means to alleviate central and peripheral symptoms in HD and improve overall disease management.