New Genetic Connection Discovered Between Iron Deficiency and Crohn’s Disease
A groundbreaking study conducted by biomedical scientists at the University of California, Riverside School of Medicine has unveiled new insights into the genetic underpinnings of iron deficiency anemia in patients with inflammatory bowel disease (IBD). This research elucidates the role of a specific gene mutation—PTPN2 loss-of-function—in disrupting iron metabolism, thereby worsening one of the most […]

A groundbreaking study conducted by biomedical scientists at the University of California, Riverside School of Medicine has unveiled new insights into the genetic underpinnings of iron deficiency anemia in patients with inflammatory bowel disease (IBD). This research elucidates the role of a specific gene mutation—PTPN2 loss-of-function—in disrupting iron metabolism, thereby worsening one of the most debilitating complications commonly experienced by individuals suffering from chronic intestinal inflammation. The findings, published in the International Journal of Molecular Sciences, suggest novel therapeutic avenues that may transform treatment protocols for IBD-related anemia.
Inflammatory bowel disease encompasses a spectrum of chronic inflammatory disorders, primarily Crohn’s disease and ulcerative colitis, characterized by persistent inflammation of the gastrointestinal tract. Beyond the gastrointestinal manifestations, IBD often leads to systemic complications, among which iron deficiency anemia reigns as the most prevalent. This anemia severely compromises patient quality of life, manifesting in chronic fatigue, diminished physical performance, and exacerbated disease burden, especially during flare-ups. Despite iron supplementation being a standard treatment, many patients fail to respond adequately, posing a longstanding clinical conundrum.
The recently published study delves into the molecular basis for this inadequate response by focusing on the gene encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2). This gene plays a pivotal role in immune regulation and intracellular signaling. The investigators identified that approximately 14-16% of the general population and 19-20% of IBD patients harbor a loss-of-function mutation in PTPN2. Such mutations impair the gene’s normal function, fundamentally altering cellular processes that govern iron absorption and homeostasis.
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Leveraging serum samples from IBD patients, the research team discovered significant disruptions in the expression of iron-regulating proteins among carriers of the PTPN2 loss-of-function variants. Notably, these alterations result in diminished levels of key proteins responsible for iron uptake in intestinal epithelial cells—the primary site for dietary iron absorption. This impairment elucidates why oral iron supplements often fail to correct anemia in this subgroup, as the absorptive machinery itself is dysfunctional.
Further validation was achieved through genetic knockout models in mice, where deletion of PTPN2 induced pronounced anemia and defective iron absorption. The murine models demonstrated a marked reduction in the expression of critical iron-handling proteins within the intestinal lining, confirming a direct mechanistic link between PTPN2 function and iron homeostasis. These preclinical findings provide compelling evidence that genetic factors compound the severity of systemic symptoms experienced by IBD patients.
Declan McCole, lead author and esteemed professor of biomedical sciences at UCR, emphasized the clinical significance of these results. He noted that understanding how a patient’s genetic background influences iron handling could revolutionize personalized treatment strategies for anemia in IBD. Current therapeutic approaches predominantly emphasize controlling intestinal inflammation; however, these findings underscore the necessity to consider genetic variations that may hinder nutrient absorption independent of inflammatory status.
First author Hillmin Lei, a doctoral researcher in McCole’s laboratory, highlighted the translational potential of this research. She explained that recognizing PTPN2 mutations as a biomarker could guide clinicians to tailor iron supplementation methods, potentially favoring intravenous iron administration over oral formulations in genetically susceptible patients. This targeted approach could prevent the inefficacy and gastrointestinal side effects often associated with oral iron therapy.
The implications extend beyond anemia management, addressing broader physiological challenges in IBD patients. Iron is indispensable not only for hemoglobin synthesis but also for a range of cellular metabolic processes vital to energy production and immune function. Thus, disruptions in iron absorption reverberate across multiple biological systems, exacerbating patient morbidity. This study importantly links genetic predisposition to these systemic effects, offering a more comprehensive understanding of IBD pathophysiology.
Significantly, the research was conducted in collaboration with multiple international institutions, including the City of Hope, University Hospital Zurich, and the Swiss IBD Cohort, ensuring a robust and diverse patient dataset. Such partnerships enhance the generalizability of the findings and pave the way for future multicenter clinical trials aimed at refining therapeutic regimens based on genetic screening.
The research was supported by notable funding agencies such as the National Institutes of Health, the Swiss National Science Foundation, and a joint City of Hope-UC Riverside Biomedical Research Initiative award. These grants underscore the high scientific priority assigned to dissecting the intricate relationship between genetics, inflammation, and nutrient metabolism in complex chronic diseases like IBD.
Ultimately, this study marks a substantial advance in our understanding of how genetic variants in PTPN2 compromise iron metabolism and contribute to the stubborn persistence of anemia in IBD patients. It challenges the conventional one-size-fits-all approach to anemia treatment and encourages a paradigm shift toward precision medicine, where genotype-informed strategies could optimize patient outcomes and quality of life.
Further investigations are warranted to explore the full spectrum of molecular mechanisms by which PTPN2 orchestrates iron regulation and to assess the efficacy of alternative iron supplementation protocols in genetically predisposed populations. This research lays a critical foundation for such endeavors, heralding a future where genetic insights inform and enhance therapeutic interventions for chronic inflammatory diseases.
As the global burden of IBD continues to rise, uncovering the genetic factors that exacerbate disease complications is paramount. Through meticulous molecular characterization and innovative animal model experimentation, the team at UC Riverside has illuminated a key biological pathway linking genetic mutations to impaired nutrient absorption. This knowledge promises to catalyze the development of more effective treatments, alleviating the silent toll of iron deficiency anemia among millions of IBD sufferers worldwide.
Subject of Research: Cells
Article Title: PTPN2 Regulates Iron Handling Protein Expression in Inflammatory Bowel Disease Patients and Prevents Iron Deficiency in Mice
News Publication Date: 3-Apr-2025
Web References: http://dx.doi.org/10.3390/ijms26073356
References: Mdpi International Journal of Molecular Sciences article DOI 10.3390/ijms26073356
Image Credits: McCole lab, UC Riverside
Keywords: PTPN2, inflammatory bowel disease, Crohn’s disease, iron deficiency anemia, intestinal epithelial cells, iron absorption, oral iron therapy, intravenous iron supplementation, genetic mutation, protein tyrosine phosphatase non-receptor type 2, nutrient absorption, chronic inflammatory disorders
Tags: chronic intestinal inflammation complicationsgenetic connection between iron deficiency and Crohn’s diseaseinflammatory bowel disease and anemiaInternational Journal of Molecular Sciences findingsiron deficiency anemia in chronic diseasesiron supplementation challenges in Crohn’s diseasemolecular basis of anemia in IBDnovel therapeutic approaches for IBDpatient quality of life in IBDPTPN2 gene mutation and iron metabolismsystemic effects of inflammatory bowel diseaseUniversity of California Riverside School of Medicine research
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