(P10-009-23) Prebiotic Fiber Improves Gut Microbial Metabolism and Anti-Inflammation in Apolipoprotein E Mice With Sex-Specific Responses

Objectives: Beta-amyloid plaques, tau tangles, and neurodegeneration characterize Alzheimer's disease (AD). Evidence suggests that dysbiosis may contribute to AD-like neuropathology, and mitigating dysbiosis may be crucial for preventing AD development, particularly in those with the APOE4 genotype and females. Previous research shows that inulin supplementation can improve gut microbiome composition, boost short-chain fatty acids (SCFAs) production, enhance mitochondrial function, and reduce neuroinflammation in young APOE4 mice. This study aims to investigate the effects of inulin on the gut microbiome and metabolic and inflammatory pathways in middle-aged asymptomatic mice with different APOE genotypes and sex.

Methods: We used a C57BL/6 mouse model with human-targeted replacement APOE. We fed mice prebiotic inulin or control at four months of age for 16 weeks. The mice were grouped based on genotype x diet and genotype x diet x sex (N = 19 per group, Male: Female = 11: 8). We collected the fecal samples and applied shotgun metagenomic sequencing. We performed the differential analyses for the gut β-diversity and 2-way and 3-way ANOVA and differential analyses for the microbial taxa and the kinase and pathway functional analyses. Statistical significance was set at a P-value < 0.05 or Q-value (false discovery rate corrected P value) ≤ 0.05.

Results: Inulin restored α-diversity, suppressed E. coli, and downregulated inflammation-related pathways in APOE4 female (E4-F) mice, suggesting its anti-inflammatory effect. It also increased the presence of SCFA-producing bacteria and lactic acid bacteria, mostly in APOE4 males (E4-M). Moreover, inulin increased the gene expression in the TCA cycle in E4-M and APOE3 male (E3-M) mice and reduced the mTOR pathway in E3-M mice, suggesting that inulin may positively impact mitochondrial function in male mice and negatively impact aging-related diseases in E3-M mice.

Conclusions: These findings highlight the importance of considering sex and APOE genotypes when exploring the link between diet, gut microbiome, and AD prevention. Further research into clinical trials using cost-effective inulin as a supplement could help develop effective strategies in precision nutrition for preventing metabolic disorders like AD.

Funding Sources: This research was supported by NIH grants RF1AG062480 (funded by NIA and ODS) to A-LL.