The autoimmune susceptibility gene, <i>PTPN2</i> , restricts expansion of a novel mouse adherent-invasive <i>E. coli</i>

Abstract

Inflammatory bowel disease (IBD) pathogenesis involves significant contributions from genetic and environmental factors. Loss-of-function single-nucleotide polymorphisms (SNPs) in the protein tyrosine phosphatase non-receptor type 2 (<i>PTPN2</i>) gene increase IBD risk and are associated with altered microbiome population dynamics in IBD. Expansion of intestinal pathobionts, such as adherent-invasive <i>E. coli</i> (AIEC), is strongly implicated in IBD pathogenesis as AIEC increases pro-inflammatory cytokine production and alters tight junction protein regulation - suggesting a potential mechanism of pathogen-induced barrier dysfunction and inflammation. We aimed to determine if <i>PTPN2</i> deficiency alters intestinal microbiome composition to promote expansion of specific bacteria with pathogenic properties. In mice constitutively lacking <i>Ptpn2</i>, we identified increased abundance of a novel mouse AIEC (<i>m</i>AIEC) that showed similar adherence and invasion of intestinal epithelial cells, but greater survival in macrophages, to the IBD-associated AIEC, LF82. Furthermore, <i>m</i>AIEC caused disease when administered to mice lacking segmented-filamentous bacteria (SFB), and in germ-free mice but only when reconstituted with a microbiome, thus supporting its classification as a pathobiont, not a pathogen. Moreover, <i>m</i>AIEC infection increased the severity of, and prevented recovery from, induced colitis. Although <i>m</i>AIEC genome sequence analysis showed >90% similarity to LF82, <i>m</i>AIEC contained putative virulence genes with >50% difference in gene/protein identities from LF82 indicating potentially distinct genetic features of <i>m</i>AIEC. We show for the first time that an IBD susceptibility gene, <i>PTPN2</i>, modulates the gut microbiome to protect against a novel pathobiont. This study generates new insights into gene-environment-microbiome interactions in IBD and identifies a new model to study AIEC-host interactions.