RestorPro

Inflammatory bowel diseases (IBD) are a major health challenge due to their incidence and burdens, both financially and on patients’ wellbeing. Effective and well-tolerated therapeutic approaches are still direly needed for these multifactorial diseases. A promising diagnostic and therapeutic target are proteases. These enzymes are host- and microbiome-borne, and show an increased activity in the guts of IBD patients. Moreover the abundance of protease inhibitors is reduced in patients while we found that microbial antiproteases exert a protective effect against microbial protease-induced inflammation in rodents. To begin translating these discoveries in a human application, we measured the activity of protease families in 100 patients stratifying them into 4 groups, thereby allowing for a personalised approach to inhibiting deleterious protease activities. RestorPro will establish the proof of concept for a novel therapeutic pathway to restore protease homeostasis thanks to our unique library of new microbiota antiproteases. First, we will stratify 650 IBD patients by their protease activities, validate these novel biomarkers and design antiprotease combinations targeting patients' groups. Second, we will test the efficacy of these combinations in a human microbial co-culture gut-on-chip system integrating organoids from patients or healthy donors. Third, we will resolve the antiproteases modes-of-action using ex-vivo and in-vivo systems. RestorPro will fill important knowledge gaps on specific functions, modes-of-action, and inter-individual variability of human-microbiome interactions via protease/anti-protease activities in IBD condition and will provide proofs needed for further translation. For this goal, French and Luxembourgish experts joint their skills in protease-antiprotease activity in IBD, biomarker identification, gut-on-a-chip, organoids and murine models to better understand the interactions between the host and its microbiome in health and disease