SIMPLE SUGAR TRIGGERS SPONTANEOUS COLITIS DEVELOPMENT INIL10 -/- MICE

Abstract

Abstract The Western diet characterized by high fat and high sugar is considered a risk factor for inflammatory bowel disease (IBD) such as colitis. However, the precise role of sugar in colitis pathogenesis is poorly understood. We, therefore, investigated the role of glucose, a simple sugar, in colitis pathogenesis using IBD susceptible Il10-/- mice. We fed healthy 14-week old Il10-/- mice with 10% glucose in drinking water for 5 week and monitored body weight changes. Sugar fed Il10-/- mice spontaneously developed severe colitis, characterized by higher body weight loss and increased diarrhea, and shorter colon lengths. In agreement, there was higher expression of pro-inflammatory cytokines and chemokines in glucose-fed mice. Since colitis induction in Il10-/- mice is microbiota dependent, development of spontaneous colitis is often irregular. To induce colitis uniformly in all mice, glucose-fed and control Il10-/- mice were treated with a piroxicam-fortified diet. Alternatively, healthy Il10-/- mice were administered with a piroxicam-fortified diet for 5 days followed by feeding with high-glucose or regular drinking water. In both instances, glucose-fed Il10-/- mice lost more body weight and developed worse colitis. Increased colitis pathogenesis of glucose-fed Il10-/- mice was associated with increased inflammatory response, activation of inflammatory signaling pathways, induction of cell death, and erosion of mucus layer. Consistent to reduced mucus layer, there was increased bacterial colonization on the colonic mucosa and higher activity of bacteria-derived mucolytic enzymes in the gut lumen of sugar-fed Il10-/- mice. Notably, high sugar diets altered the composition of gut microbiota, particularly the abundance of mucus degrading bacteria, such as Akkermansia muciniphila and Bacteroides sp., was increased. Together these data suggest that high-sugar diet predisposes spontaneous colitis and enhances colitis pathogenesis by promoting the growth of mucus degrading bacteria in the gut of Il10-/- mice.