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Background Dietary constituents impact the development and course of IBD (1). Especially a Western style diet is associated with an increased incidence and prevalence of IBD (2). The role of polyunsaturated fatty acids (PUFA) in the development of IBD is broadly discussed. Recently we could show that PUFAs elicit a pro-inflammatory response in intestinal epithelial cells (IEC) in a Glutathione peroxidase 4 (GPX4) deficient setting, which resembled phenotypic hallmarks of human CD (3). GPX4, an anti-oxidative enzyme, was described to be a risk gene for the development of CD (4) and is deficient in IECs derived from inflamed areas of the small intestine of CD patients (3). Stress responses in Paneth cells (PC) trigger small intestinal gut inflammation (5). In this study, we describe PC as originators of GPX4-restricted and PUFA-induced intestinal inflammation. Methods We analyzed PC morphology in mice lacking one allele of GPX4 specifically in IECs (GPX4+/-IEC) by electron microscopy. We generated mice lacking both alleles of Gpx4 specifically in PC (GPX4ΔPC) and exposed these mice (and wildtype controls) to a Western diet enriched with PUFAs for 12 weeks. Intestinal inflammation was assessed by histology and immunohistochemistry. Further we analyzed small intestinal whole tissue cultures and evaluated cytokine production by ELISA. Results Paneth cells of mice lacking one allele of Gpx4 showed morphological signs of ER-stress at baseline and after exposure to a PUFA-WD for 12 weeks when compared to WT mice (Fig 1a). Based on these results, we dissected a role for PC in GPX4-restricted gut inflammation. When fed a PUFA WD for 12 weeks GPX4ΔPC mice developed a CD like enteritis while WT controls did not (Fig 1b). A WD did not induce this inflammatory response in GPX4ΔPC or WT mice. The infiltrating leukocytes contained mainly neutrophils and macrophages (indicated by positive F4/80 staining, Fib 1c). Whole tissue cultures derived from GPX4ΔPC mice fed a PUFA WD produced more Interleukin-6 and CXCL-1, the murine homologue of the human Interleukin-8, compared to whole tissue cultures derived from WT mice fed the same diet (Fig 2). Figure legend 1a) % of PC showing massive, medium or no ER dilatation 1b&amp;c) enteritis score and representative H&amp;E and F4/80 staining 2) IL-6 and CXCL-1 in supernatant of whole tissue jejunal samples Conclusion The presented data identify Paneth cells to be crucially involved in the development of PUFA induced enteritis in genetically susceptible hosts. References 1. Roda G, NG S, et al Nat Rev Dis Primers 2020 2. Khalili H, Chan SSM, et al Nat Rev Gastroenterol Hepatol 2018 3. Mayr L, Grabherr F, et al Nat Com 2020 4. Jostins L, Ripke S, et al Nature 2012 5. Adolph TE, Tomczak M, Nature 2013

P085 Paneth cells translate dietary lipid exposure into gut inflammation