On Tuesday, April 4, 2023 Diana Zajac successfully defended her dissertation and earned her doctoral degree in physiology. Congratulations Dr. Zajac!
ALZHEIMER’S DISEASE GENETICS AND SHORT-CHAIN FATTY ACID TREATMENT IN STUDIES OF THE MURINE GUT MICROBIOME
Elucidating the relationship of the gut microbiome in Alzheimer's Disease (AD) risk and pathogenesis is an area of intense interest. Since 60 to 80% of AD risk is related to genetics and APOE alleles represent the most impactful genetic risk factors for AD, their mechanism(s) of action are under intense scrutiny. APOE4 is robustly associated with increased AD risk compared to the neutral APOE3 and protective APOE2. APOE alleles have also been associated with differential inflammation and gastrointestinal recovery after insult in human and murine studies. Preliminary work in my lab led me to show an APOE allelic difference in murine gut microbiome profiles in an AD transgenic mouse model (5xFAD). In this study, I showed APOE-specific microbiome profiles where the AD-protective APOE2 mice had increased short-chain fatty acid- (SCFA) producing bacteria. SCFAs are major microbiota metabolites that have been implicated as a mediator of gut microbiome effects in the brain. Here, I studied the genetic impact of APOE alleles on the murine gut microbiome. The findings of that study led me to conduct another wherein I studied the effects of SCFA supplementation on the gut microbiome of AD mice, as well as cognitive impairment and AD pathology.
First, I conducted a study in which the housing conditions of the mice were designed to reduce environmental impact on the gut microbiome, ensuring that gut microbiome changes in the mice were mainly contributed by APOE allelic differences. This study validated and improved on our previous work studying APOE effect on the murine gut microbiome. The richness and evenness (alpha-diversity) and microbial community composition (beta-diversity) of the fecal microbiome was robustly associated with APOE status in male but not female mice. The relative abundance of bacteria from the class Clostridia, order Clostridiales, family Ruminococacceae and related genera increased with APOE2 status. The relative abundance of Erysipelotrichia increased with APOE4 status, a finding that extended to humans. Since Ruminococacceae have been associated with increased SCFA production, these findings suggest that SCFA-producing bacteria are increased in the AD-protective APOE2 positive mice. Hence, I hypothesized that SCFAs as a dietary supplement may act to reduce AD risk.
Next, I compared the effects of SCFA- water vs. saline-treated water on APPswe/PSEN1dE9 mice maintained under standard laboratory conditions. I found that SCFA treatment increased alpha-diversity and impacted the gut microbiome profile by increasing, in part, the relative abundance of several bacteria that typically produce SCFAs. Of the taxa that were significantly increased by SCFA treatment, the genera Bifidobacterium and Lactobacillus are known to produce SCFAs and SCFA precursors. I speculate that SCFA treatment is creating a feedforward mechanism by creating a gut environment that allows for SCFA-producing bacteria to thrive. Although gut microbiome changes in SCFA-treated mice were robust, SCFA treatment did not significantly affect behavior, cortical or hippocampal astrocyte activation, or soluble and insoluble amyloid levels.
In conclusion, there is robust evidence of an APOE allelic effect on the murine gut microbiome that implies an AD-relevant genetic impact on the gut microbiome. The gut microbiome can be modulated by SCFA supplementation, revealing a potential therapeutic for AD prevention. These pioneering studies represent the medical importance of gut health on disease prevention and treatment. Further studies will be needed to characterize the therapeutic potential of SCFAs for neuroprotection. Future studies on other AD risk-associated genes and their impact on the gut microbiome will greatly inform dietary therapeutic development for disease prevention.