A team of researchers at the University of California, Riverside (UCR) School of Medicine has identified a genetic mutation that disrupts iron absorption in patients with Crohn’s disease, providing new insight into the persistent anemia that affects a high percentage of people with inflammatory bowel disease (IBD). The findings, published in the International Journal of Molecular Sciences, detailed how patients carrying a loss-of-function mutation in the PTPN2 gene (protein tyrosine phosphatase non-receptor type 2) show a significant reduction of blood proteins that regulate iron levels.
“This discovery sheds light on a critical mechanism that links a patient’s genetics to their ability to absorb and regulate iron, which is essential for maintaining healthy blood and energy levels,” said senior author Declan McCole, PhD, a professor of biomedical sciences at UCR. “Our findings offer an explanation for why some IBD patients remain iron-deficient despite oral supplementation.”
Researchers were driven to investigate PTPN2 because of its role regulating inflammation and its prior association with IBD risk, since anemia, and especially iron deficiency anemia, is the most common non-intestinal complication of IBD. The loss-of-function mutation in the PTPN2 gene is carried by 14% to 16% of the general population and 19% to 20% of those with IBD. For this work the research team sought to understand whether PTPN2 might also affect iron metabolism, independent of inflammatory activity.
“Anemia is the most common extraintestinal manifestation of inflammatory bowel disease (IBD). Iron deficiency is the most frequent cause of anemia in IBD; however, the mechanisms involved are still poorly understood,” the researchers wrote in the study’s abstract.
To explore this, the team analyzed serum from IBD patients who had been genotyped for the rs1893217 PTPN2 variant. They also used mouse models with different Ptpn2 genotypes—wild-type, heterozygous, and knockout—to examine systemic iron levels, blood characteristics, and the expression of proteins responsible for iron transport. Radiotracer assays using 55Fe were performed to assess the mice’s ability to absorb dietary iron.
“Serum proteomic analyses revealed that the ‘iron homeostasis signaling pathway’ was the main pathway downregulated in Crohn’s disease (CD) patients carrying the PTPN2 risk allele, independent of disease activity,” the researchers wrote.
Mice lacking PTPN2 exhibited hallmark features of anemia including low hemoglobin levels, diminished serum and tissue iron, and elevated serum hepcidin. Oral iron absorption was impaired, and duodenal epithelial cells in knockout mice showed reduced levels of DMT1, the protein responsible for transporting iron across the intestinal lining.
“The only way the body can obtain iron is through intestinal absorption from food, making this discovery particularly significant,” said first author Hillmin Lei, a doctoral student in the McCole lab. “Disruption of this pathway by genetic variants like those in PTPN2 could help explain why some IBD patients fail to respond to oral iron therapy, a commonly prescribed treatment for anemia.”
This work builds on earlier studies showing that PTPN2 negatively regulates inflammatory pathways, particularly the JAK1–STAT3 axis. The gene’s role in modulating immune responses had been linked to IBD, but its connection to systemic nutrient regulation was previously unexplored.
The research showed that patients with the PTPN2 variant had alterations in key blood proteins, such as reduced transferrin (TF) and soluble transferrin receptor 1 (TFR1), which are critical for iron transport and the production of red blood cells. These patients may suffer from “functional iron deficiency,” in which iron stores are adequate but not bioavailable to red blood cell precursors.
The study also found discrepancies between Crohn’s disease and ulcerative colitis patients in how iron-handling proteins were regulated, suggesting disease-specific mechanisms influenced by genetic factors. Additionally, in the mouse models lacking PTPN2, non-heme iron levels in the liver, spleen, and intestines were markedly reduced.
Though the study demonstrates a clear mechanistic link between PTPN2 mutation and impaired iron absorption, it also highlights unresolved questions. For instance, the precise pathway by which loss of PTPN2 leads to reduced DMT1 expression remains unknown. The researchers suggested that inflammatory cytokines like TNF-α or post-translational regulatory mechanisms involving the adapter protein NDFIP1, may play a role in this process.
The team plans to study whether targeting PTPN2-related pathways could improve anemia management in IBD. This could include identifying biomarkers for poor response to oral iron and testing whether intravenous iron therapy is more effective in patients with the PTPN2 mutation.
“It opens new avenues for targeted therapies that go beyond inflammation control to address systemic complications like anemia,” McCole said. “This includes prioritizing patients who carry loss-of-function PTPN2 variants to be treated for anemia with systemic intravenous iron supplementation rather than oral iron, which may be poorly absorbed.”
