Sa1797 Altered Immunometabolism As a Result of Colonic Inflammation and Westernized Diet in Experimental Models of Colitis and Colitis-Associated Colorectal Cancer

Abstract

Background: Environmental factors, e.g. diet, immune dysregulation and genetic predisposition are thought to trigger inflammatory bowel diseases (IBD). Westernized diets have a negative impact on immunometabolism resulting in obesity, diabetes. The impact of IBD and westernized diet on immunometabolism are not fully explored. Aims: To examine the immunometabolic responses in experimental Colitis and Colitis-Association Cancer (CAC) and upon westernized diet feeding. Methods: Male C57BL/6 mice were fed low fat (LF, 10%Kcal) or high fat (HF, 45%Kcal) diet for 5 weeks. Colitis was induced by Dextran Sodium Sulphate (acute: 2%DSS-5d & water-4d; chronic: 1.5%DSS-5d & water-14d). CAC was induced by injection of the carcinogen azoxymethane accompanied by 3xDSS cycles. Plasma, visceral adipose tissue (VAT), liver and colons were harvested and assayed for inflammatory and metabolic markers. VAT stromal vascular cells (SVCs) were isolated and characterized by flow cytometry. Gas-liquid chromatography was employed to profile liver and VAT fatty acids (FA). Results: Mice with colitis and CAC presented significantly higher signs of disease (colon pro-inflammatory cytokines and tumor incidence), which were significantly reduced by HF-feeding (p<0.05). Plasma levels of metabolic markers were significantly increased by HF-diet in controls and were significantly reduced by colitis or CAC-challenges regardless of diet treatment (p<0.05). Colitis or CAC reduced levels of liver linolenic acid, arachidonic acid (AA), eicosapentaenoic acid and docosahexaenoic acid and increased oleic acid when compared to controls. HF diet reduced levels of palmitoleic acid and increased linolenic acid, stearic acid and AA in animals with Colitis and CAC compared to HF-controls. Colitis or CAC increased the levels of VAT myristic and palmitoleic acid, while oleic acid, linoleic acid and γ-linolenic acid were lower compared to controls. HF-feeding did not significantly alter VAT FA profile in diseased mice. Colitis or CAC lead to an alteration in SVCs macrophage profile due to an induction in M1/M2 phenotype (iNOS, Irf5, MGL1, Irf4, Fizz1, Ym1, Arg-1 and Mrc1). HF-feeding to diseased mice reduced the expression of alternative M2 phenotype genes (Ym1, Arg-1, Irf4), while sustaining M1 and IL-4 responsive genes (Stat6, Fizz1 and Mrc1) in VAT. Inflamed and tumor bearing colons presented a similar M1/M2 profile with HF-diet reducing mainly iNOS mRNA expression. Conclusions: Colitis and CAC induced a M1/M2 phenotype in colon and VAT, reduced liver n-3 FA and plasma metabolic markers. High fat diet ameliorated colitis and tumor progression accompanied by sustained presence of M1 and IL-4-dependent M2 macrophages. Overall, the data reveals both detrimental and beneficial alterations in immunometabolism as a result of mucosal inflammation alone or in combination with westernized diet.