FS4-Radiation/Microbiome/HD5/A muciniphila study

<strong>Background:</strong> The mechanisms underlying radiation-induced dysbiosis of gut microbiota are poorly defined. This study examined the effect of radiation on intestinal Paneth cell a-defensin expression and its impact on microbiota composition and mucosal tissue injury using the mouse model of total body irradiation. <strong>Results:</strong> Ionizing radiation reduced the expression of Paneth cell a-defensins and depleted a-defensin peptides in the intestinal luminal contents. a-Defensin down-regulation was paralleled by the alteration of gut microbiota composition, mucosal barrier dysfunction, and increased plasma endotoxins. HD5, the human a-defensin, delivered in the diet 24 hours before irradiation, partially attenuated radiation-induced alteration of microbiota composition and blocked radiation-induced intestinal epithelial tight junction (TJ) and adherens junction (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. A defining feature of microbiota composition in HD5-treated mice was the high relative abundance of <em>Akkermansia muciniphila</em>. Supplementation of diet with <em>A. muciniphila</em> before or after irradiation prevented and reversed radiation-induced microbiota dysbiosis, TJ and AJ disruption, mucosal permeability, and systemic effects. <strong>Conclusions:</strong> These data demonstrate that radiation down-regulates Paneth cell a-defensin expression and HD5 supplementation can prevent and mitigate radiation-induced gut injury and systemic responses. Furthermore, supplementation with <em>A. muciniphila</em>, a defining feature of HD5 treatment, can also prevent and reverse radiation-induced gut injury and systemic effects.