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.

辐射诱导的肠道菌群失调（radiation-induced dysbiosis of gut microbiota）的潜在机制目前尚未阐明。本研究采用全身照射（total body irradiation）小鼠模型，探究了辐射对肠道潘氏细胞防御素（intestinal Paneth cell defensin）表达的影响，以及其对菌群组成与黏膜组织损伤的作用。电离辐射可降低潘氏细胞防御素的表达，并耗竭肠腔内容物中的防御素肽类。防御素表达下调与肠道菌群组成改变、黏膜屏障功能障碍及血浆内毒素水平升高同步发生。于辐照前24小时通过膳食补充的人类防御素5（HD5），可部分减轻辐射诱导的菌群组成改变，并阻断辐射引发的肠上皮紧密连接（tight junction, TJ）与黏着连接（adherens junction, AJ）破坏、黏膜屏障功能障碍、内毒素血症及全身性炎症反应。若于辐照后24小时给予HD5，则可逆转菌群失调、TJ与AJ破坏、屏障功能障碍、内毒素血症及全身性炎症反应。经HD5干预的小鼠，其肠道菌群组成的标志性特征为嗜黏蛋白阿克曼菌（Akkermansia muciniphila）的相对丰度显著升高。于辐照前后通过膳食补充嗜黏蛋白阿克曼菌（A. muciniphila），可预防并逆转辐射诱导的菌群失调、上皮连接破坏、黏膜通透性增高及全身性效应。本研究数据表明，辐射可下调潘氏细胞防御素的表达；补充HD5可预防并减轻辐射诱导的肠道损伤与全身性应答反应。此外，作为HD5干预的标志性特征，嗜黏蛋白阿克曼菌同样可预防并逆转辐射引发的肠道损伤及全身性效应。