Modified Bacteria for Mn-based anti-oxidants production and Delivery for gut Inflammation Control – MOBIDIC

The objective of the MOBIDIC project is to develop an innovative approach to the treatment of inflammatory bowel diseases (IBD) using new oral bio-medicines. To date, these diseases remain incurable. As one of the first triggers of inflammation is an overproduction of reactive oxygen species, we propose to target this step to control intestinal inflammation during IBD. To do this, we are currently designing manganese (Mn) metal-based antioxidants that mimic the activity of an oxidative stress protective enzyme: the superoxide dismutase (SOD). These SOD mimics (SODm) coordinated to Mn, offer therapeutic possibilities, and because they act in a catalytic way, allow considering efficiency at low doses. They are small diffusible molecules, either artificial synthetic (SODm-A) or peptidic (SODm-P). These molecules will be screened on cellular models, macrophages and cells of the intestinal epithelium, representing the first line cells of the intestinal mucosa, capable of initiating an inflammatory response in response to oxidative stress. This screening will allow determining the most efficient SODm, i.e. having the best anti-inflammatory activity after induction of an oxidative stress). These most effective SODm will then be tested on mice models of colitis by oral administration in order to prevent colitis. In the context of oral administration, and in order to avoid the degradation due to the acidic gastric and biliary environment, we will explore a novel delivery system using several bio-technologies. They will be the subject of a patent application and cannot be discussed in a 'non confidential' abstract. After their delivery in the digestive tract, we will analyze the ability of these SODm (A and P) to coordinate with Mn(II) in vivo by mass spectrometry approaches. We will be able to finely regulate this coordination by choosing a bio-technological pathway and/or an environment (intestinal lumen) naturally rich in Mn(II) or by supplementing our systems with Mn(II). We will evaluate the effect on the intestinal barrier (permeability tests) and on the inflammatory response (macro and microscopic colitis score, mucosal and systemic cytokine and chemokine assays) of these SODm vectored into the intestinal lumen. Finally, in IBD patients, using dedicated questionnaires and during a prospective study, we will assess the acceptability of these new types of bio-medicines.