Background/Aim: Inflammatory bowel disease (IBD) involves several factors including genetic predisposition and gut dysbiosis including proliferation of pathobionts such as adherent-invasive Escherichia coli (AIEC). Mice lacking the IBD risk gene Ptpn2 display expansion of murine AIEC strain (UCR-PP2), and reduction of the protective commensal, segmented filamentous bacteria (SFB). SFB stimulates intestinal IgA responses and maintains immune homeostasis. IgA can bind to SFB, thus helping control its colonization, and bind to other bacteria thereby restricting expansion of pathobionts including AIEC. Host defenses such as IgA and the antimicrobial, inflammatory marker protein lipocalin-2 (Lcn2), restrict bacterial overgrowth and help maintain microbial balance. This study aims to determine whether constitutive or intestinal epithelial cell (IEC)-specific loss of Ptpn2 alters microbial balance, IgA and Lcn2 expression, thereby providing insight into how PTPN2 shapes commensal–pathobiont dynamics in the gut. Methods: Mouse models used were whole-body Ptpn2-wild-type (WT), heterozygous (Het) and Ptpn2 constitutive knockout (KO) mice; or tamoxifen (TMX)-induced IEC specific Ptpn2 knockout mice (Ptpn2∆IEC) and control littermates (Ptpn2fl/fl). qPCR was used to quantify SFB. Internal transcribed spacer (ITS) rRNA sequencing was used to determine bacteria abundance in luminal content. qPCR was used to quantify pIgR, and Lcn2 expression in Ileum IECs. ELISA was used to quantify IgA expression in serum and Ileal luminal content. Results: ITS analysis of luminal content showed reduced SFB and increased mAIEC in Ptpn2-KO mice compared to their WT and Het littermates (P< 0.05; n=9). Lcn2 expression was increased in Ileum IECs of Ptpn2-KO mice compared to WT and Het littermates (P< 0.05; n=4-8). Serum IgA (P< 0.001; n=4-5) and Ileal luminal IgA levels (P< 0.05; n=4-5) were both increased in KO mice compared to WT littermates. No change was seen in expression of the dimeric IgA transporter, pIgR, in Ileal IEC in Ptpn2-KO mice vs. WT littermates (n=4-5). In Ptpn2∆IEC mice, SFB abundance was reduced in fecal pellets (P< 0.001; n=8). Quantifying SFB levels before and after TMX injection within individual Ptpn2∆IEC and Ptpn2Cre-ve mice confirmed that PTPN2 deletion - but not TMX treatment by itself - reduced SFB abundance (P< 0.05; n=7). ITS analysis showed no change in mAIEC abundance in Ileal luminal contents in Ptpn2∆IEC compared to their control littermates (n=3). In contrast to whole-body Ptpn2-KO mice, Lcn2 was decreased in Ileal IECs of Ptpn2∆IEC mice (P< 0.05; n=5-8). No change in serum or Ileal luminal IgA was observed in Ptpn2∆IEC mice compared to floxed controls (n=3–4). pIgR expression in Ileal IEC in Ptpn2∆IEC mice was also unchanged (n=6-8). Conclusion: Elevated serum and intestinal IgA in Ptpn2-KO mice, coupled with unchanged pIgR expression in both KO and Ptpn2∆IEC mice, indicates that altered IgA levels likely result from inflammation and/or microbiota driven changes, rather than altered epithelial transcytosis of IgA. Notably, loss of PTPN2 in the epithelium is sufficient to suppress antimicrobial protein expression (Lcn2). Our findings identify unique role(s) of epithelial vs systemic PTPN2 in maintaining commensal–pathobiont balance. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Saad et al. (Fri,) studied this question.