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Published on: February 17, 2023
Fusobacterium nucleatum enhances enterotoxigenic Bacteroides fragilis-mediated neuron loss and intestinal motility
Yue Zhang1, Ying Zhao1, Lu Zhang1
1Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory of Systems Medicine for Cancer, Hospital of Digestive Disease, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
Abstract:
Gut dysmotility is a common long-term effect of enterotoxigenic Bacteroides fragilis (ETBF) colonization but the underlying mechanisms are not clear. Here, using mouse colonization models, we found that ETBF-secreted B. fragilis toxin (BFT) causes loss of colonic myenteric neurons, which are crucial regulators of intestinal motility. BFT induced apoptosis in these neurons through the NOD1-RIPK2-CASP9-CASP3 pathway, leading to gut dysmotility that persisted even after the clearance of ETBF. Analyses of human inflammatory bowel disease and colorectal cancer patient cohorts showed a positive correlation between ETBF and Fusobacterium nucleatum abundance. In mice, F. nucleatum-derived 2-hydroxybutyric acid enhanced BFT production in ETBF by alleviating RprY-mediated suppression and aggravated neurotoxicity and dysmotility. This enteric neuron loss and dysmotility enhanced susceptibility to dextran sulfate sodium-induced colitis in mice. Therapeutically, a Bifidobacterium-based probiotic attenuated neuron toxicity and improved intestinal motility. Our findings reveal bacterial interactions regulating intestinal function and a potential clinical therapeutic approach to preventing outcomes of ETBF colonization.
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