The cell surface mucin MUC1 is an important host factor limiting Helicobacter pylori (H. pylori) pathogenesis in both humans and mice by providing a protective barrier and modulating mucosal epithelial and leukocyte responses. The aim of this study was to establish the time-course of molecular events in MUC1-modulated gene expression profiles in response to H. pylori infection in wild type (WT) and MUC1-deficient mice using microarray-determined mRNA expression, gene network analysis and Ingenuity Pathway Analysis (IPA). A time-course over the first 72 h of infection showed significantly higher mucosal loads of bacteria at 8 h of infection in Muc1^−/− mice compared with WT, confirming its importance in the early stages of infection (P = 0.0003). Microarray analysis revealed 266 differentially expressed genes at one or more time-points over 72 h in the gastric mucosa of Muc1^−/− mice compared with WT control using a threshold of 2-fold change. The SPINK1 pancreatic cancer canonical pathway was strongly inhibited in Muc1^−/− mice compared with WT at sham and 8 h infection (P = 6.08E-14 and P = 2.25 E-19, respectively) but potently activated at 24 and 72 h post-infection (P = 1.38E-22 and P = 5.87E-13, respectively). The changes in this pathway are reflective of higher expression of genes mediating digestion and absorption of lipids, carbohydrates, and proteins at sham and 8 h infection in the absence of MUC1, but that this transcriptional signature is highly down regulated as infection progresses in the absence of MUC1. Uninfected Muc1^−/− gastric tissue was highly enriched for expression of factors involved in lipid metabolism and 8 h infection further activated this network compared with WT. As infection progressed, a network of antimicrobial and anti-inflammatory response genes was more highly activated in Muc1^−/− than WT mice. Key target genes identified by time-course microarrays were independently validated using RT-qPCR. These results highlight the dynamic interplay between the host and H. pylori, and the role of MUC1 in host defense, and provide a general picture of changes in cellular gene expression modulated by MUC1 in a time-dependent manner in response to H. pylori infection.

细胞表面粘蛋白 MUC1 是一个重要的宿主因子限制幽门螺杆菌（H. pylori) 通过提供保护屏障和调节黏膜上皮细胞和白细胞反应在人和小鼠中的发病机制。本研究的目的是建立 MUC1 调节的基因表达谱中分子事件的时间过程，以响应幽门螺杆菌使用微阵列测定的 mRNA 表达、基因网络分析和 Ingenuity Pathway Analysis (IPA) 感染野生型 (WT) 和 MUC1 缺陷小鼠。感染前 72 小时的时间过程显示，在感染 8 小时时，黏膜细菌负荷显着增加。粘液1^-/-小鼠与 WT 相比，证实了其在感染早期阶段的重要性（磷= 0.0003)。微阵列分析显示 266 个差异表达基因在 72 小时内的一个或多个时间点在胃黏膜中粘液1^-/-小鼠与 WT 对照使用 2 倍变化的阈值进行比较。SPINK1 胰腺癌经典通路在粘液1^-/-小鼠在假感染和 8 小时感染时与 WT 相比 (磷= 6.08E-14 和磷= 2.25 E-19，分别）但在感染后 24 和 72 小时有效激活（磷= 1.38E-22 和磷= 5.87E-13，分别）。该途径的变化反映了在没有 MUC1 的情况下，在假感染和 8 小时感染中介导脂质、碳水化合物和蛋白质消化和吸收的基因的更高表达，但是随着感染的进展，这种转录特征被高度下调。 MUC1 的。未感染粘液1^-/-胃组织高度富集参与脂质代谢的因子的表达，与 WT 相比，8 小时感染进一步激活了该网络。随着感染的进展，抗菌和抗炎反应基因网络在粘液1^-/-比 WT 小鼠。使用 RT-qPCR 独立验证时程微阵列鉴定的关键靶基因。这些结果突出了主机和主机之间的动态相互作用幽门螺杆菌，以及 MUC1 在宿主防御中的作用，并提供了由 MUC1 以时间依赖性方式调节的细胞基因表达变化的总体情况，以响应幽门螺杆菌感染。