The epithelial barrier forms the interface between luminal microbes and the host immune system and is the first site of exposure to many of the environmental factors that trigger disease activity in chronic inflammatory bowel disease (IBD). Disruption of the epithelial barrier, in the form of increased intestinal permeability, is a feature of IBD and other inflammatory diseases, including celiac disease and type 1 diabetes. Variants in genes that regulate or belong to the JAK-STAT signaling pathway are associated with IBD risk. Inhibitors of the JAK-STAT pathway are now effective therapeutic options in IBD. This review will discuss emerging evidence that JAK inhibitors can be used to improve defects in intestinal permeability and how this plays a key role in resolving intestinal inflammation.
Background Anemia is the most common extraintestinal complication of inflammatory bowel disease (IBD) and is a risk factor for Crohn’s disease (CD) onset. Iron deficiency is the most common cause of anemia in IBD; however, the mechanisms involved are poorly understood. Here, we investigated the role of the IBD risk gene, protein tyrosine phosphatase non‐receptor type 2 (PTPN2), in regulating iron homeostasis. Methods Proteomic analyses were performed on serum from IBD patients genotyped for the IBD‐associated loss‐of‐function rs1893217 PTPN2variant (n=10/genotype). Constitutive Ptpn2 wild type (WT), heterozygous (Het), and knockout (KO) 3‐week‐old mice were analyzed for serum iron content, liver non‐heme iron and liver expression of the iron regulatory hormone, hepcidin (Hamp1). Protein and RNA from duodenal epithelial cells (DECs) were assayed by western blotting and qPCR. Localization of the brush border ferrous iron transporter, DMT1, in duodenal tissue was determined by immunohistochemistry (IHC). Results Iron homeostasis genes, the iron carrier transferrin (TF) and the transferrin receptor (TFRC), were reduced (‐log p‐value = 10.7) in CD patients with the PTPN2 risk variant. Ptpn2‐KO mice had reduced i) serum iron (p<0.001; n=11); ii) serum TF saturation (p<0.01; n=9); and iii) liver non‐heme iron levels (p<0.01; n=10), vs. Ptpn2‐WT and Het mice. This indicated that PTPN2 loss decreased serum and liver iron storage. Moreover, Ptpn2‐KO mice had reduced liver expression of Hamp1 (p<0.01; n=7), likely suppressed by low serum iron. DEC gene expression of ferritin (Fth1), an intracellular iron storage molecule, was reduced (p=0.048; n=5) while Tfrc1, a mediator of basolateral cellular iron uptake, was significantly increased (p=0.0048; n=6) in Ptpn2‐KO mice. Reduced FTH1 expression (p=0.007; n=12) in DECs of Ptpn2‐KO mice was confirmed by western blot, indicating reduced intracellular iron storage. DMT1 expression was unchanged (n=6), whereas IHC showed reduced apical membrane DMT1 in duodenal epithelium of Ptpn2‐KO mice (n=6), suggesting a possible mechanism of impaired intestinal non‐heme iron uptake. Conclusions CD patients with the PTPN2 loss‐of‐function rs1893217 SNP display alterations in serum iron handling proteins. Loss of PTPN2 activity in mice causes features of anemia including iron deficiency associated with mislocalization of the duodenal transporter DMT1. These findings identify a major role for PTPN2 in regulating iron homeostasis.
Background In addition to a physical barrier, the intestinal epithelium generates a chemical barrier to the luminal microbiota by secreting various antimicrobial factors. Alterations in the gut microbiota and expansion of pathobionts such as adherent‐invasive Escherichia coli (AIEC) are associated with inflammatory bowel disease (IBD) pathogenesis. Our previous work showed, mice deficient for the expression of the IBD risk gene, Ptpn2, exhibit pronounced expansion of a novel murine adherent‐invasive Escherichia coli (mAIEC) strain. This study aimed to investigate how PTPN2 expression in intestinal epithelial cells restricts mAIEC colonization in vivo. Methods We generated tamoxifen‐inducible, intestinal epithelial cell‐specific knockout mice (Ptpn2∆IEC). Ptpn2∆IEC and control littermates (Ptpn2fl/fl) were infected with either PBS, non‐invasive E. coli K12, or fluorescent‐tagged mAIEC (mAIECred)for 4 consecutive days. After euthanasia, bacterial colonies were enumerated in mouse tissues. mRNA and protein expression were assayed in intestinal epithelial cells (IECs) by PCR and Western blot. Results Ptpn2∆IEC mice exhibited intestinal region‐specific higher mAIECred ‐ but not K12 ‐ bacterial load in distal colon tissue compared to Ptpn2fl/fl mice (P=0.038; n=9‐12). To identify if the higher susceptibility to mAIECred infection was associated with altered host defenses, we measured levels of anti‐microbial peptide (AMPs) in these mice. Ileal RNA expression of the alpha‐defensin AMPs, Defa5 and Defa6, were significantly lower (P=0.008, 0.0182 respectively; n=3‐5) in Ptpn2∆IEC vs. Ptpn2fl/fl mice, after mAIECred infection but not K12 infection. Further, expression of the protease matrilysin‐7 (MMP7) ‐ which is responsible for the proteolytic cleavage of alpha‐defensins – was significantly decreased in ileum and distal colon of Ptpn2∆IEC mice post mAIECred infection compared to Ptpn2fl/fllittermates (P=0.042, 0.007; n=4‐6). REG3γ, an AMP that acts largely against gram‐positive bacteria, was unchanged in all conditions. However, ileal IEC lysozyme protein expression was lower in PBS and K12, but not mAIECred, infected Ptpn2∆IECmice (P= 0.067, 0.0165 respectively; n=8) compared to control Ptpn2fl/fl mice. Conclusion Intestinal epithelial PTPN2 plays a major role in regulating intestinal bacterial defenses and gut regional variations in pathobiont colonization.
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