Grant: Project Grant

Drugs that suppress inflammation have improved the lives of people suffering from Inflammatory Bowel Disease (IBD). However, even the most potent therapies can fail, leading to dose escalation, surgical resections or higher risk of adverse effects. Thus, our mission is to continue discovering new and better therapies for IBD. These could be used in combination with current therapies to increase their efficacy and safety profiles. To this matter, "cocktails" of bacteriophages (phages), viruses that kill bacteria with great accuracy, are being tested in clinical trials with the aim to eliminate bacteria that can cause inflammation in patients with Crohn's disease (CD). Unfortunately, it is unclear how those cocktails have been chosen or how they could interact with other IBD medications. Our preliminary studies have identified a phage (called HER259) that targets a bacterium (E. coli NRG857c) previously associated with CD, and that has been shown to be proinflammatory. Mice that are colonized with this E. coli develop colitis, which is prevented if phage HER259 is administered orally. We also discovered that when combined with topical corticosteroid, "budesonide", used to treat localized flares in IBD, phage HER259 enables budesonide to be effective at lower doses. These results imply that phage HER259 curbs E. coli aggressive behaviour rather than killing it, reducing the dose of some IBD drugs needed to inhibit inflammation. In this proposal, using a combination of basic microbiological and mouse modelling techniques, as well as access to samples from patients with CD, we will characterize the relationship between phage and E. coli, and with other IBD drugs, and their effects on the immune system. Our long-term aim is to identify and test the best phage candidates that target CD-associated bacteria, to increase treatment response in patients with IBD in the future.