Sex-dependent effects of carbohydrate source and quantity on caspase-1 activity in the mouse central nervous system

Mounting evidence links metabolic dysregulation, particularly glucose intolerance and diabetes, to an increased risk of developing dementia. Inflammation and particularly the inflammasome has emerged as a potential link between these disparate pathologies. Diet is a key factor in development and progression of metabolic disorders and prior research suggests dietary factors can influence cognitive health, in part by modulating inflammasome activity.5-week-old male and female transgenic mice expressing a caspase-1 bioluminescent reporter underwent cranial window surgeries and were fed control (65% complex carbohydrates, 15% fat), high glycemic index (65% carbohydrates from sucrose, 15% fat), or ketogenic (1% complex carbohydrates, 79% fat) diet from 6 to 26 weeks of age. Glucose regulation was assessed with a glucose tolerance test following a 4-hour morning fast. Bioluminescence in the brain was quantified using IVIS in vivo imaging. Blood cytokine levels were measured using cytokine bead array. 16S ribosomal RNA gene amplicon sequencing of mouse feces was performed to assess alterations in the gut microbiome. Behavior associated with these dietary changes was also evaluated.The ketogenic diet caused weight gain and glucose intolerance in both male and female mice. In male mice, the high glycemic diet led to increased caspase-1 biosensor activation over the course of the study, while in females the ketogenic diet drove an increase in biosensor activation compared to their respective controls. These changes correlated with changes in inflammatory cytokines present in the serum of these mice and anxiety-like behavior. In terms of mouse fecal microbiome composition, there was no significant link between diet and glucose tolerance, or between diet and caspase-1 signal. However, microbiome composition differed significantly between diets.Our findings suggest that diet composition, specifically the source and quantity of carbohydrates, has sex-specific effects on inflammasome activation in the central nervous system and behavior. This phenotype manifested as increased anxiety in male mice, which could be due to alterations in microbiome composition.