P030. High fat diet aggravates Crohn's disease-like ileitis independently of obesity via alterations of epithelial barrier homeostasis
L. Gruber1, S. May1, J. Fiamoncini2, V. Müller2, M. Lichtenegger3, M. Rychlik3, H. Daniel2, D. Haller1, 1Technical University Munich, Biofunctionality, ZIEL – Research Center for Nutrition and Food Sciences, CDD – Research Center for Diet and Disease, Freising, Germany, 2Technical University Munich, Department of Biochemistry, ZIEL – Research Center for Nutrition and Food Sciences, Freising, Germany, 3Technical University Munich, Bioanalytics, ZIEL – Research Center for Nutrition and Food Sciences, Freising, Germany
The incidence of IBD has risen considerably over the last decades, coinciding with a high prevalence of obesity and associated metabolic disorders. Though IBD patients have historically been lean, recent studies report increasing rates of overweight patients and associate obesity with a more severe disease course. We therefore challenged a mouse model of Crohn's Disease-like ileitis, TNFΔARE/WT mice, by a high-fat diet to elucidate the connection between diet-induced obesity, intestinal barrier function and inflammatory processes in the intestine.
TNFΔARE/WT mice and wildtype littermates were fed high-fat diet (HFD; 48%kcal from fat) or control diet (CD; 12%kcal from fat) for different durations. We analysed intestinal pathology and metabolic parameters, and characterised intestinal barrier integrity using different approaches. Epithelial expression of barrier proteins and inflammatory markers in epithelial cells as well as infiltration of lymphocytes were assessed by immunofluorescence techniques, western blotting and PCR. Microbial composition was analysed by Illumina technology and caecal bile acids were quantified by LC-MS/MS.
HFD accelerated ileal inflammation in TNFΔARE/WT independently of significant overweight or typical parameters of metabolic syndrome. Expression of the tight junction protein Occludin was dramatically reduced in the ileal epithelium of HFD mice and endotoxin levels were increased in hepatic portal plasma, though translocation of polyethylene glycols of similar size was not altered by HFD. Epithelial cells showed enhanced expression of different markers of immune activation and recruitment mechanisms. Consistent with increased expression levels of the chemokine CCL20 in epithelial cells, recruitment of CD11c+ dendritic cells into the lamina propria was increased under HFD. In vitro modelling revealed higher chemotactic potential of epithelial cells towards bone-marrow-derived dendritic cells when stimulated with caecal lysates from HFD mice compared to CD. This indicates luminal triggers as responsible factors, which we characterised as caecal bile acid shifts and microbial composition changes due to HFD.
These results point out that diet rich in fat may aggravate small intestinal inflammation via modulation of barrier homeostasis, activation of epithelial cells and their possible interaction with antigen presenting cell populations present in the lamina propria, not necessarily associated with obesity.