Grant: CIHR Fellowship

A healthy mammalian gastrointestinal tract is shaped by a co-evolution between the immune system and molecules derived from our resident gut microbes, the gut microbiome. Despite the wide array of mechanisms working to promote intestinal homeostasis, breakdowns in this relationship can result in chronic inflammation and Inflammatory bowel disease (IBD). IBD is likely due to abnormal host immune responses to the gut microbiome in genetically susceptible individuals. While we know there is an alteration in the intestinal microbiome of IBD patients correlating with disease status, many specific mechanisms as to how our gut microbiome can influence IBD remain unresolved. Here, we aim to fill this gap in knowledge by analyzing which microbial products can interact with the host to initiate inflammatory disease. Specifically, we are interested in specialized membrane lipids called sphingolipids which are abundant in human cells, and altered in abundance during IBD. Recently, we discovered that certain bacterial species in the intestine can also produce sphingolipid metabolites, of which many have unknown functions and could feed into inflammatory pathways triggering IBD. We hypothesize these microbial sphingolipid metabolites can impact the initiation and progression of IBD. To study this, we have developed a protocol to isolate sphingolipids from clinically relevant strains of bacteria and screened these lipids in immune cells for their impact on IBD associated pathways using RNA sequencing. This screen will aim to identify novel bacterial sphingolipids that can activate pro-inflammatory signalling events in immune cells. Further, using gene-knockdown strategies, we will determine which receptor any novel sphingolipid can interact with on immune cells to trigger inflammation. We plan to further investigate these observations in animal models and human biopsies to determine the relative impact microbial sphingolipids have on IBD.