Fusobacterium Nucleatum Exacerbates Colitis by Damaging Epithelial Barrier and Inducing Aberrant Inflammation

Aim: Recently, accumulating evidence has revealed strong association between intestinal microbiota alteration and inflammatory bowel disease (IBD). Fusobacterium (F.) nucleatum is a gram-negative anaerobe. A multicenter cohort study reported that F. nucleatum was enriched in newly diagnosed IBD patients. Here, we aimed to explore the pathogen of IBD and its pathogenic mechanism.

Methods: Several bacteria associated with IBD or colorectal cancer were measured in fecal samples of 91 IBD patients and 43 healthy people. Mice with dextran sulfate sodium (DSS)-induced colitis and Caco-2 model system were used to explore the pathogenicity of F. nucleatum. Barrier damage was evaluated by transmission electron microscope, permeability of fluorescein isothiocyanate-dextran, transepithelial electrical-resistance and immunofluorescence. Protein level of cell-cell junction and activation of STAT3 signaling pathway were detected by immunohistochemistry and immunoblot. Cytokines secretion and T cell differentiation were measured by quantitative real-time polymerase chain reaction and flow cytometry.

Results: F. nucleatum was significantly enriched in feces of IBD patients and its abundance was correlated with patients’ disease activity. Administration of F. nucleatum markedly exacerbates colitis in DSS mice model. Mechanistically, F. nucleatum damaged epithelial integrity and increased permeability by regulating the expression and distribution of tight junction proteins ZO-1 and occludin. Moreover, F. nucleatum promoted secretion of cytokines (TNF-α, IFN-γ, IL-1β, IL-6, and IL-17), activated STAT3 signaling pathway, and induced proliferation of CD4+ T cell and differentiation of Th1 and Th17 subsets.

Conclusions: Our finding suggests that F. nucleatum could damage intestinal barrier and induce aberrant inflammation, which exacerbate colitis. This article is protected by copyright. All rights reserved.

Keywords: Fusobacterium nucleatum; colitis; inflammation; inflammatory bowel disease; intestinal barrier.