Sunday, May 11, 2025
5/11/2025
A Novel Role for PTPN2 in Intestinal Epithelial Barrier Regulation - SUMMARY/ABSTRACT Compromised intestinal barrier function and alterations in intestinal microbes are critical factors contributing to many autoinflammatory diseases such as Inflammatory Bowel Disease (IBD), celiac disease and Type 1 diabetes, and affect ~24 million Americans (www.niehs.nih.gov). Genetic contributions to these diseases include the increased association with loss-of-function single-nucleotide polymorphisms (SNPs) in the protein tyrosine phosphatase non-receptor type 2 (PTPN2) gene. Moreover, PTPN2 was identified as a major influence on microbiome composition across multiple patient cohorts.In mice constitutively lacking Ptpn2, we identified substantial changes in gut microbiota populations highlighted by increased abundance of a novel mouse adherent-invasive E. coli (AIEC). This mouse AIEC was able to colonize mouse intestine, exacerbate colitis onset, and delay recovery from colitis. Moreover, we now report that PTPN2 loss compromises Paneth cells which have critical roles in preserving intestinal mucosal-microbial homeostasis. We also identify that epithelial PTPN2 deletion reduces Paneth cell antimicrobial peptide expression, and increases susceptibility to pathogen infection. Thus, we hypothesize that PTPN2 serves as a “microbial modulator” by regulating innate defense mechanisms of epithelial cells to protect the intestine against bacterial ‘dysbiosis’, including expansion of, and colonization with, the disease-relevant pathobiont, AIEC. The goals of this proposal are to determine how loss of PTPN2 activity disrupts i) Paneth cell antimicrobial properties; and ii) how does PTPN2 regulate other (non-Paneth cell) features of epithelial antimicrobial defense and intracellular bacterial handling. Expected Outcomes & Impact: This proposal will increase our broader understanding of the molecular basis by which host factors preserve the intestinal barrier and microbial homeostasis, and lead to development of new approaches and targets to restore host-microbe relationships in diseases such as IBD.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).