単一遺伝子PTPN2が腸内環境と炎症性腸疾患リスクに与える影響(How a Single Gene Shapes Gut Health and IBD Risk)

2026-01-23 カリフォルニア大学リバーサイド校(UCR)

<関連情報>

• https://news.ucr.edu/articles/2026/01/23/how-single-gene-shapes-gut-health-and-ibd-risk
• https://www.tandfonline.com/doi/full/10.1080/19490976.2025.2559029
• https://www.tandfonline.com/doi/full/10.1080/19490976.2025.2526136

腸管上皮PTPN2は免疫誘導抗菌反応によって病原菌のコロニー形成を制限する Intestinal epithelial PTPN2 limits pathobiont colonization by immune-directed antimicrobial responses

Pritha Chatterjeea,Marianne R. Spalinger,Charly Acevedo,Alina N. Santos,Casey M. Gries,Salomon M. Manz, …
Gut Microbes  Published:15 Sep 2025
DOI:https://doi.org/10.1080/19490976.2025.2559029

GRAPHICAL ABSTRACT

ABSTRACT

Loss of activity of the inflammatory bowel disease (IBD) susceptibility gene, protein tyrosine phosphatase non-receptor type 2 (PTPN2), is associated with altered microbiome composition in both human subjects and mice. Furthermore, expansion of the bacterial pathobiont, adherent-invasive E. coli (AIEC), is strongly linked to IBD pathogenesis. The mechanism by which intestinal epithelial cells (IEC) maintain equilibrium between commensal microbiota and immune cells to restrict invading pathobionts is poorly understood. Here, we investigated the role of IEC-specific PTPN2 in regulating AIEC colonization. Tamoxifen-inducible, intestinal epithelial cell-specific Ptpn2 knockout mice (Ptpn2^∆IEC) and control Ptpn2^fl/fl mice were infected with either noninvasive E. coli K12, or fluorescent-tagged mAIEC (mAIEC^red) for four consecutive days or administered PBS. Subsequently, bacterial colonization in mouse tissues was quantified. mRNA and protein expression were assayed in intestinal epithelial cells (IECs) or whole tissue lysates by PCR and Western blot. Tissue cytokine expression was determined by ELISA. Intestinal barrier function was determined by in vivo administration of 4 kDa FITC-dextran (FD4) or 70kDa Rhodamine-B dextran (RD70) fluorescent probes. Confocal microscopy was used to determine the localization of tight-junction proteins. Ptpn2^∆IEC mice exhibited increased mAIEC^red – but not K12 – bacterial load in the distal colon compared to infected Ptpn2^fl/fl mice. The higher susceptibility to mAIEC^red infection was associated with altered levels of antimicrobial peptide (AMPs). Ileal RNA expression of the alpha-defensin AMPs, Defa5, and Defa6, as well as MMP7, was significantly lower in Ptpn2^∆IEC vs. Ptpn2^fl/fl mice, after mAIEC^red but not K12 infection. Furthermore, we observed an increased tight junction-regulated permeability determined by elevated in vivo FD4 but not RD70 permeability in Ptpn2^∆IEC-K12 mice compared to their respective controls. This effect was further exacerbated in Ptpn2^∆IEC mAIEC-infected mice. Further, Ptpn2^∆IEC mice displayed lower IL-22, IL-6, IL-17A cytokine expression post mAIEC infection compared to Ptpn2^fl/fl controls. Recombinant IL-22 reversed the FD4 permeability defect and reduced bacterial burden in Ptpn2^∆IEC mice post mAIEC challenge. Our findings highlight that the intestinal epithelial PTPN2 is crucial for mucosal immunity and gut homeostasis by promoting anti-bacterial defense mechanisms involving coordinated epithelial-immune responses to restrict pathobiont colonization.

PTPN2 rs1893217 IBDリスクアレルはJAK-STAT-CEACAM6軸を介してAIEC浸潤に対する感受性を高める The PTPN2 rs1893217 IBD risk allele increases susceptibility to AIEC invasion by a JAK-STAT-CEACAM6 axis

Pritha Chatterjee,Vinicius Canale,Stephanie J. King,Ali Shawki,Hillmin Lei,Alina N. Santosa,…
Gut Microbes  Published:07 Jul 2025
DOI:https://doi.org/10.1080/19490976.2025.2526136

ABSTRACT

Inflammatory bowel disease (IBD) patients often exhibit expansion of the gut pathobiont, adherent-invasive E. coli (AIEC). Loss of activity of the IBD susceptibility gene, protein tyrosine phosphatase type 2 (PTPN2), causes gut microbiota dysbiosis in IBD patients, while Ptpn2 knock-out (Ptpn2-KO) mice display AIEC expansion. CEACAM6, a host cell surface glycoprotein, is exploited by AIEC to attach to and enter intestinal epithelial cells (IECs). Here, we investigated how IEC-specific PTPN2 restricts AIEC invasion. Intestinal biopsies from IBD patients heterozygous (CT) or homozygous (CC) for the PTPN2 SNP (single nucleotide polymorphism) rs1893217 were stained for CEACAM6. HT-29 IECs were transfected with control shRNA (PTPN2-CTL), or a shRNA targeted toward PTPN2 (PTPN2-KD). The rs1893217 SNP was inserted (PTPN2-KI), or a complete knock-out of PTPN2 (PTPN2-KO) was generated, by CRISPR-Cas9 gene editing of Caco-2BBe IECs. Adherence and invasion assays were performed with either the human IBD AIEC isolate, LF82, or a novel fluorescent-tagged mouse adherent-invasive E. coli (mAIEC^red). IL-6 and the pan-JAK inhibitor tofacitinib were administered to interrogate JAK-STAT signaling. Protein expression was determined by western blotting and densitometry. CEACAM6 expression was elevated in IBD patients carrying the PTPN2 rs1893217 SNP (CT, CC) compared to wildtype (TT) IBD patients. HT-29 and Caco-2BBe cell lines deficient in PTPN2 expressed significantly higher levels of CEACAM6. Further, PTPN2-KI and PTPN2-KO cell lines displayed greater invasion by LF82 and mAIEC^red. CEACAM6 was further elevated by IL-6 in PTPN2–deficient IECs vs. untreated controls. STAT1 and 3 silencing partially reduced CEACAM6 protein expression. Tofacitinib significantly reduced the elevated CEACAM6 protein expression and the higher AIEC adherence and invasion in PTPN2-KI and PTPN2-KO IECs. Our findings highlight a crucial role for PTPN2 in restricting pathobiont entry into host cells and suggest a role for JAK-inhibitors in mitigating AIEC colonization in IBD-susceptible hosts.