Grant: Doctoral Research Award: Canada Graduate Scholarships

Hemophilia A (HA), an inherited bleeding disorder that is characterized by a deficiency or dysfunction in the coagulation protein Factor VIII (FVIII), can result in major bleeding events that can lead to serious health complications if not properly managed. The most effective treatment for these patients is intravenous injections of the FVIII protein. However, up to 30% of patients develop an adverse immune response towards the therapeutic FVIII that results in inhibitors, antibodies that bind to and neutralize the FVIII protein. FVIII inhibitors render treatment ineffective and complicates the management of bleeding in people with HA. Although several risk factors have been identified, no significant progress has been made to prevent inhibitors from forming. Interestingly, bacteria throughout our gastrointestinal tract are critical for the healthy functioning of our immune system. Evidence suggests that a loss of certain healthy bacteria, termed dysbiosis, can predispose you to immune-related disease. Thus, gut dysbiosis may be a potential risk factor for FVIII inhibitor development. Research published by us shows that dysbiosis in HA mice results in enhanced FVIII inhibitor production but how this occurs is not understood. We hypothesize that a specific class of metabolite healthy bacteria produce, short-chain fatty acids, are responsible. This study aims to elucidate the way gut bacteria and their metabolites regulate FVIII inhibitor production and will give insight into what an ideal gut composition may look like to prevent inhibitor occurrence. Results generated here may also provide rationale for clinical translation, whereby bacteria in the gut of people with HA is screened prior to their first FVIII injection. Ultimately, knowledge contributed to the field by this study may benefit research in rheumatoid arthritis, whereby anti-drug antibodies can also develop, and other diseases characterized by autoimmunity to self-proteins.