Human Defensin-5 and Akkermansia muciniphila Prevent and Mitigate Radiation-Induced Gut Microbiota Dysbiosis, Mucosal Barrier Dysfunction and Systemic Response

The mechanism underlying radiation-induced dysbiosis of gut microbiota is poorly defined. This study examined the effect of radiation on the intestinal Paneth cell defensin expression and its impact on microbiota composition and mucosal tissue injury using the mouse model of total body irradiation. Ionizing radiation reduced the expression of Paneth cell defensins and depleted defensin peptides in the intestinal luminal contents. Defensin down regulation was paralleled by the alteration of gut microbiota composition, mucosal barrier dysfunction, and increased plasma endotoxins. HD5, the human defensin, delivered in the diet 24 hours before irradiation partially attenuated radiation-induced alteration of microbiota composition and blocked radiation-induced intestinal epithelial TJ and AJ disruption, mucosal barrier dysfunction, endotoxemia, and systemic inflammation. HD5 administered 24 hours after irradiation reversed microbiota dysbiosis, TJ and AJ disruption, barrier dysfunction, endotoxemia, and systemic inflammation. The defining feature of microbiota composition in HD5-treated mice was the high relative abundance of Akkermansia muciniphila. Supplementation of diet with A. muciniphila before or after irradiation prevents and reverses radiation-induced microbiota dysbiosis, epithelial junctional disruption, mucosal permeability, and systemic effects. These data demonstrate that radiation down-regulates Paneth cell defensin expression, and HD5 supplementation prevents and mitigates radiation-induced gut injury and systemic response. Furthermore, A. muciniphila, a signature feature of HD5 treatment, also prevents and reverses radiation-induced gut injury and systemic effects.