Transcriptional profile in the colon in response to C. rodentium infection

The identification of Atg16L1 as a susceptibility gene has implicated antibacterial autophagy in the pathogenesis of Crohn's disease, a major type of inflammatory bowel disease (IBD). However, the role of Atg16L1 during extracellular bacterial infections of the intestine has not been sufficiently examined and compared to the function of other IBD susceptibility genes such as Nod2. We now find that Atg16L1 mutant mice are extraordinarily resistant to intestinal disease induced by the model bacterial pathogen Citrobacter rodentium. We further demonstrate that Atg16L1 deficiency alters the intestinal environment to mediate an enhanced immune response that is dependent on monocytic cells, and that Atg16L1/Nod2 double mutant mice lose this advantage. These results reveal an unappreciated immuno-suppressive function of an IBD gene, and raise the possibility that gene variants that affect the autophagy pathway were evolutionarily maintained to protect against certain life-threatening infections. Twenty samples have been analyzed. All are colonic tissue from mice. Controls are uninfected WT mice, uninfected Atg16L1 mutant mice (Atg16L1HM) (n=3/genotype). Treatment conditions are tissue from WT and Atg16L1 mutant mice 6 days after C. rodentium infection (n=4/genotype) and 15 days after infection (n=3/genotype).将Atg16L1鉴定为易感基因的研究，提示抗菌自噬参与克罗恩病的发病机制；克罗恩病作为一类主要的炎症性肠病(IBD)，其发病与抗菌自噬密切相关。然而，相较于Nod2等其他IBD易感基因的功能，Atg16L1在肠道胞外细菌感染过程中所发挥的作用尚未得到充分研究与对比。本研究发现，Atg16L1突变小鼠对模型病原菌鼠柠檬酸杆菌(Citrobacter rodentium)诱导的肠道疾病具有显著抗性。本研究进一步证实，Atg16L1缺陷可改变肠道微环境，介导依赖单核细胞的增强型免疫应答；而Atg16L1/Nod2双突变小鼠则丧失了这一抗性优势。上述结果揭示了一类IBD易感基因此前未被认知的免疫抑制功能，并提出一种可能性：影响自噬通路的基因变异在进化过程中得以保留，或用于抵御某些致命性感染。本研究共分析20份样本，所有样本均为小鼠结肠组织。对照组包含未感染的野生型(Wild Type, WT)小鼠与未感染的Atg16L1突变小鼠(Atg16L1HM)，每组基因型对应3份样本。处理组样本分别来自鼠柠檬酸杆菌感染后6天、15天的野生型与Atg16L1突变小鼠：感染后6天组每组基因型对应4份样本，感染后15天组每组基因型对应3份样本。