Fusobacterium Nucleatum Exacerbates Colitis By Damaging Intestinal Epithelial Barrier And Inducing Aberrant Inflammation

Inflammatory bowel disease(IBD)is a chronic nonspecific inflammatory disease whose etiology remains unclear.It is believed that the pathogenesis of IBD is a combination of genetic factor,environment factor,immune factor,and intestinal flora disturbance,among which intestinal flora disturbance has attracted increasing attention worldwide.Several bacteria associated with IBD and colorectal cancer were measured in fecal samples of IBD patients,we found that Fusobacterium nucleatum(Fn),Clostridium difficile,adherent-invasive Escherichia coli were abundant in IBD patients,among which Fn has the most significant correlation with IBD.Fusobacterium nucleatum(Fn)is a gram-negative anaerobe characterized by colonization and invasion.Recently,a multicenter cohort study has reported that Fn was significantly enriched in newly diagnosed IBD patients than in healthy populations.Thus,we aim to investigate whether and how Fn contributes to IBD pathogenesis and progression.We found Fn was significantly correlated with disease activity of IBD patients,and aggravated colitis in a mice model with Fn administration was observed.Mechanistically,our studies have revealed that Fn could damage epithelial integrity and upregulate epithelial permeability by regulating the expression and distribution of tight junction proteins ZO-1 and occludin.Moreover,we discovered that Fn exerted pro-inflammatory ability by promoting secretion of inflammatory cytokines(IFN-γ,TNF-α,IL-1β,IL-6,and IL-17),activation of STAT3 signaling pathway,and inducing the proliferation of CD4~+T cell and differentiation of Th1 and Th17 subsets.Taken together,our experiment indicated that Fn contributed to colitis by damaging the intestinal barrier and stimulating aberrant inflammation,and the possible mechanisms were also revealed.In conclusion,we believe that measuring and targeting Fn help provide a new insight in optimizing clinical management in IBD patients,especially refractory and frequently-relapsing IBD patients.