AUTHOR=Sheng Yong H. , Ng Garrett Z. , Summers Kim M. , Every Alison L. , Price Gareth , Hasnain Sumaira Z. , Sutton Philip , McGuckin Michael A. 

TITLE=Influence of the MUC1 Cell Surface Mucin on Gastric Mucosal Gene Expression Profiles in Response to Helicobacter pylori Infection in Mice

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=10

YEAR=2020

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2020.00343

DOI=10.3389/fcimb.2020.00343

ISSN=2235-2988

ABSTRACT=<p>The cell surface mucin MUC1 is an important host factor limiting <italic>Helicobacter pylori (H. pylori</italic>) 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 <italic>H. pylori</italic> 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 <italic>Muc1</italic><sup>−/−</sup> mice compared with WT, confirming its importance in the early stages of infection (<italic>P</italic> = 0.0003). Microarray analysis revealed 266 differentially expressed genes at one or more time-points over 72 h in the gastric mucosa of <italic>Muc1</italic><sup>−/−</sup> mice compared with WT control using a threshold of 2-fold change. The SPINK1 pancreatic cancer canonical pathway was strongly inhibited in <italic>Muc1</italic><sup>−/−</sup> mice compared with WT at sham and 8 h infection (<italic>P</italic> = 6.08E-14 and <italic>P</italic> = 2.25 E-19, respectively) but potently activated at 24 and 72 h post-infection (<italic>P</italic> = 1.38E-22 and <italic>P</italic> = 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 <italic>Muc1</italic><sup>−/−</sup> 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 <italic>Muc1</italic><sup>−/−</sup> 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 <italic>H. pylori</italic>, 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 <italic>H. pylori</italic> infection.</p>