273 High Fat Feeding Alters Gut Microbiota and Protects Mice From Colitis and Colitis-Associated Colorectal Cancer

Abstract

Background: Environmental factors, such as diet and gut microbial composition, together with immune dysregulation are thought to trigger inflammatory bowel diseases (IBD) in genetically susceptible individuals. Long term chronic inflammation in IBD patients increases the risk of developing colitis-associated colorectal cancer (CAC). To date, studies exploring the cross-interaction among diet, immunity and microbiota are limited. One recent study reported that feeding of a diet based on milk derived fat to IL-10 deficient mice resulted in worsening colitis and promoted the expansion of a specific pathobiont. Aim(s): Here, we have examined the temporal relationship between diet, the gut microbiota and systemic and intestinal immune responses in an experimental model of colitis and colitis-associated cancer. Method(s): Male C57BL/6 mice (n=8-12 per group) were fed lard-based high fat (HF-45% Kcal) diet or low fat (LF-10% Kcal) diet, followed by injection with the carcinogen azoxymethane (AOM) accompanied by 3xDSS cycles [(1.5%DSS-5days & water-14days) - CAC-model] or 3xDSS cycles alone (Colitis model). Plasma and colonic tissue was collected at the end of the study and assayed for plasma cytokines, colonic and tumour cytokine mRNA expression and protein and histology evaluation. Faecal samples were collected at 3 different time points, DNA extracted and compositional analysis of the microbiota was performed by 16S rDNA amplicon pyrosequencing. Result(s): High fat feeding protected mice from developing colitis and CAC on the basis of significantly increasing body weight (p<0.001), and significantly reducing plasma IL-1beta, IFN-gamma, IL-12 and IL-4 levels (p<0.05) and colonic IFNgamma, iNOS, CXCL10, TNF-alpha (p<0.05) expression, tumour numbers and incidence (p<0.01), colon length and weight (p<0.05) and histological inflammation and tumour malignancy scorings (p<0.05) compared to LF-fed counterparts. Analysis of the murine gut microbiota showed a reduction in gut microbial diversity in mice with LF-Colitis and LF-CAC relative to their HF-fed counterparts. These changes were associated with a significant reduction in Proteobacteria (p<0.05) and a significant increase in Firmicutes and Verrucomicrobia (p<0.05) at the phylum level in mice with HF-Colitis and HF-CAC compared to their LFfed counterparts. Conclusion(s): Collectively, contrary to the previous report using a milk fat based diet, our data reveal that a lard-based HF-diet provides protection against colitis and a reduction in CAC risk, associated with alterations in gut microbial populations. The results highlight a far more complex outcome than anticipated of lard-based high fat diet on microbiota composition and host immune responses warranting further investigations on lard-components and in patients with IBD and CAC.