DIETARY FIBER DEPRIVATION QUELLS COLONIC INFLAMMATION BY TARGETING GUT PATHOBIONTS IN A NEW MODEL OF CROHN’S DISEASE

Abstract

Abstract Crohn’s disease (CD) is a chronic intestinal inflammatory disorder that results from a dysregulated mucosal immune response to symbiotic bacteria in genetically susceptible individuals. While genetic predispositions to CD have been well documented, the overall contribution of genetic factors to disease development remains unclear. Indeed, abnormal interactions between microbes and the immune system have been identified as the core defect leading to chronic intestinal inflammation. We used a “multi-hit” genetic approach to study the complex interplay between host immunity and microbes in the context of CD. We have found that the combined deficiency of NOD2 and phagocyte NADPH oxidase (i.e. CYBB), two CD susceptibility genes, triggers microbiota-dependent and spontaneous TH1-type colitis in mice that is accompanied by the pathological hallmarks seen in CD patients. Disease was induced by Mucispirillum schaedleri, a gram-negative mucus-dwelling anaerobe. The absence of the two anti-microbial genes (i.e. NOD2 and CYBB) resulted in a marked accumulation of M. schaedleri in the gut lumen, the colonic mucus layer and ultimately a focal penetration of the intestinal wall. Accumulation of M. schaedleri was associated with impaired recruitment of neutrophils in the intestine and subsequently inefficient elimination of the bacterium. Among the environmental factors associated with CD, diet shapes the composition of the gut microbiota and can be used to manage disease symptoms. Our experiments have shown that consumption of a fiber-free diet leads to a depletion of the colonic mucus layer and increased proximity between microbes and the gut epithelium. Interestingly, these experimental conditions are effective at inhibiting intestinal inflammation observed in our model of CD-like colitis when used both as a preventive and as a therapeutic approach. In addition to shaping the overall gut microbiota composition, this dietary intervention specifically alters the abundance and/or localization of the disease-causing M. schaedleri in the double mutant mice. Our results provide direct evidence that a specific intestinal microbe can, in conjunction with impaired bacterial clearance, trigger CD-like disease. Our results also indicate that dietary approaches can be successfully used to target microbial-driven intestinal pathology.