Helminth secretome as novel antifibrotic therapy for inflammatory bowel disease

Background and aims Given the lack of potent anti-fibrotic therapies in inflammatory bowel disease (IBD) there is an urgent need for novel therapeutic interventions. Helminths are multicellular parasitic worms that infect nearly one-third of the global population. Intestinal helminths modulate the host immune system to promote their own survival. Interestingly, although these helminths damage the intestinal wall, this does not lead to clinically relevant fibrosis. We hypothesize that the identification of anti-fibrotic agents secreted by helminths could lead to innovative drugs for IBD. At the same time, crucial information will be obtained on the effects of helminths on fibroblast subsets and extracellular matrix organization in the intestine. Methods 1. Identifying intestinal fibroblast subsets, their spatial location, and extracellular matrix (ECM) components in patients with chronic helminth infections and IBD in the global South. Intestinal biopsies from patients with and without chronic helminth infections will be stained with our 40-marker fibroblast-specific imaging mass cytometry panel. Furthermore, abundance of distinct fibroblast subsets will be compared between biopsies from Crohn’s disease patients from both the global North and South. 2. Assessing the effects of components of the helminth secretome on primary fibroblasts and 3-dimensional models for intestinal fibrosis. Intestinal fibroblasts (IBD/healthy) will be exposed to components of the helminth secretome and fibrotic responses analysed using a) RNA-sequencing, b) fibroblast-derived ECM deposition and c) 3D ECM-remodelling assays. 3. Studying the most potent anti-fibrotic component of the helminth secretome in vivo. Two anti-fibrotic components identified in aim-2 will be tested in vivo for their anti-fibrotic effects using a murine intestinal fibrosis model. Anticipated impact This project could lead to innovative anti-fibrotic drugs for IBD. While also unravelling essential knowledge on fibroblasts/ ECM remodelling in both intestinal helminth infections and IBD in the global South. Furthermore, this project will promote North-South sharing of advanced research technologies and knowledge.