Grant: CIHR Fellowship

People with inflammatory bowel disease (IBD) are twice as likely to develop dementia, develop dementia earlier (on average 7 years sooner than those without IBD), and have a six-fold increased risk of developing Alzheimer's disease (AD). However, the mechanisms that link IBD and an increased risk of developing AD are still unknown. IBD causes disruption of the gut microbiome leading to dysregulation of short-chain fatty acid (SCFA) production and an increase in systemic inflammation, making them likely candidates for driving the increased risk of developing AD. Importantly, data from animal models support this hypothesis. Under the supervision of Dr. Annie Ciernia (expert in microglia and gut-brain axis), and with our collaborators Dr. Carolina Tropini (expert in IBD and microbiome signaling) and Dr. Cheryl Wellington (expert in AD), we will create a mouse model of IBD that will investigate that role SCFA and inflammatory signaling on the lifelong risk for AD. The studies outlined in this proposal will utilize 4 experimental groups of humanized GF mice. Mice will be humanized by inoculation with microbiota from human IBD patients or healthy controls: (1) healthy control wildtype mice (HC-WT), (2) healthy control 5XFAD mice (HC-5XFAD), (3) IBD wildtype mice (IBD-WT), and (4) IBD 5XFAD mice (IBD-5XFAD). I will characterize the microbiota of these mice, assess biomarkers during development that are implicated in the development of AD (inflammatory cytokines, SCFAs), assess them on behaviours associated with AD (anxiety and spatial memory), and examine brain pathology associated with AD (AB plaques). These studies will provide insight into a mechanistic link between IBD and Alzheimer's specifically. More broadly, these data will be informative for the gut-brain axis and the role of SCFA's and inflammation in brain aging and degeneration.