P147 IBD relevant pathways are upregulated in Paneth cells in a murine model of dietary induced intestinal inflammation

Abstract

Abstract Background Dietary constituents are believed to play a role in the development of Crohn’s disease (CD) (1). Recently we were able to demonstrate, that polyunsaturated fatty acids (PUFA), induce a CD like enteritis phenotype in genetically susceptible mice (2,3). Furthermore, we could show, that PUFA intake correlated negatively with disease course in CD patients (3). In this project we tried to untangle the role of Paneth cells (PC) in the development of PUFA induced enteritis. Methods scRNA sequencing was performed on cells isolated from mice lacking one allele of Gpx4 (GPX4+/-IEC) in their intestinal epithelial cells (IEC) after feeding them a PUFA enriched western style diet (PUFA-WD). Furthermore, mice lacking both alleles of Gpx4 in their PC (GPX4ΔPC) where fed a PUFA-WD for four weeks and enteritis was assessed based on a histological enteritis score and immunhistochemical stainings. Results scRNAseq of murine intestinal cells revealed an upregulation of IBD relevant pathways (such as JAK or TNFα) in Gpx4 deficient IECs and PC. GPX4ΔPC mice developed a CD like enteritis phenotype, characterized by a mucosal and submucosal infiltration of neutrophils, macrophages and other leucocytes, after only four weeks of PUFA enriched diet, indicating that GPX4 dependent intestinal inflammation is controlled by PC. Conclusion The upregulation of IBD relevant pathways in our model of dietary induced intestinal inflammation renders this model a valuable tool to investigate mechanistical understanding in the role of dietary components in IBD. Our results further link PC metabolism to the development of intestinal inflammation.