Could Iron Deficiency Trigger Celiac Disease? Why New Research and Clinical Trials Are Needed
New research raises an intriguing possibility: iron deficiency may be more than a consequence of Celiac Disease. Could iron deficiency also contribute to the development of Celiac Disease?
Overview
For decades, physicians have recognized that Celiac Disease can cause iron deficiency and iron deficiency anemia (IDA). Gluten-triggered intestinal damage can interfere with iron absorption, resulting in nutritional deficiencies.
But what if the relationship also works in the opposite direction? Could iron deficiency, with or without anemia, contribute to the development of Celiac Disease?
In our earlier article on iron deficiency anemia, we explored this possibility following research by Drs. Isabel A. Hujoel and Margaux L. A. Hujoel.
This companion article now examines the proposed biological mechanisms illustrated in our infographic above and the research needed to investigate whether iron deficiency contributes to Celiac Disease.
"All disease begins in the gut" -- Hippocrates
The Hujoel Research: Challenging Conventional Thinking
In 2024, the Hujoel researchers published Investigating the role of iron status in the development of coeliac disease: a Mendelian randomisation study in BMJ Open Gastroenterology. Using Mendelian randomization (MR), a method that examines genetic variants associated with biological characteristics, they investigated whether iron status might influence Celiac Disease risk.
Their findings suggested that genetically predicted higher serum iron was associated with approximately 35% lower odds of Celiac Disease.
"This study suggests that iron deficiency may play a role in coeliac disease development. A causal relationship should ideally be confirmed with clinical trials, and if affirmative, should be followed by prevention studies. More broadly, this study raises questions of the potential ties between iron deficiency and gluten-sensitivity, and the potential implications of dietary restrictions and avoidant restrictive food intake disorders which are common in coeliac disease, inflammatory bowel disease, and irritable bowel syndrome."
According to the Dr. Hujoel's article, "We aimed to evaluate the relationship between iron status and coeliac disease through the use of Mendelian randomisation (MR). MR is a statistical method that capitalises on the random allocation of single nucleotide polymorphisms (SNPs) at conception. Through this random allocation and the use of genetic variants which are inherently non-modifiable as instruments for modifiable exposures, MR can avoid confounding factors and can suggest causality as long as certain assumptions hold. These assumptions specify that the instrument must be associated with the exposure, that the instrument does not impact the outcome outside of the exposure of interest, and that the instrument does not influence other potential exposures which may have an impact on the outcome of interest. Crucially for this study, by relying on SNPs associated with iron status, and not on iron status itself, MR may avoid the confounding impact of coeliac disease causing iron deficiency."
This does not establish that iron deficiency causes Celiac Disease or that iron supplementation prevents it. However, it raises an important question: Does iron deficiency precede Celiac autoimmunity, or is it an early consequence of undiagnosed disease?
The researchers called for clinical trials to investigate causality and, if supported, subsequent prevention studies.
Understanding the Infographic: Five Potential Biological Stages
Our infographic combines established biological mechanisms with proposed connections that we seek to investigate through further research.
Stage 1: Iron Deficiency—With or Without Anemia
Iron supports cellular metabolism, intestinal health, and immune function -- not merely red blood cell production.
Iron deficiency can occur before anemia develops, potentially affecting biological processes even when hemoglobin remains normal.
Iron availability influences immune regulation and the gut microbiome. Relevant processes include hepcidin, a liver-produced hormone regulating iron absorption and storage, and lactoferrin, an iron-binding protein involved in antimicrobial defense and inflammation.
Iron availability may also influence short-chain fatty acids (SCFAs), microbial metabolites that support intestinal health.
Could insufficient iron disrupt these systems in ways that increase susceptibility to Celiac Disease?
Stage 2: Intestinal Barrier Dysfunction
The intestinal lining acts as a protective barrier, allowing nutrients to be absorbed while restricting potentially harmful substances, including incompletely digested gluten peptides.
Gluten peptides can cross the intestinal epithelium through two distinct pathways:
2A - Paracellular transport: Movement between intestinal epithelial cells, regulated by tight junctions.
2B - Transcellular transport: Movement through intestinal epithelial cells, including receptor-mediated transport involving CD71 (transferrin receptor 1).
Our hypothesis proposes that iron deficiency could influence pathway 2A and/or 2B, and potentially increase the passage of gluten peptides across the intestinal barrier.
Importantly, CD71-mediated transport of intact gliadin peptides has been demonstrated in active Celiac Disease, but whether iron deficiency promotes this mechanism before disease onset remains unknown. Stage 3 examines this CD71 pathway in greater detail.
Stage 3: CD71-Mediated Gluten Transport
CD71 (transferrin receptor 1) is a cell-surface receptor responsible for cellular iron uptake. When iron availability decreases, certain cells increase CD71 expression to acquire more iron.
In a landmark 2008 study, Matysiak-Budnik and colleagues demonstrated that CD71 can mediate the transport of secretory IgA–gliadin complexes across the intestinal epithelium in patients with active Celiac Disease.
This process, known as transcytosis, allows intact, potentially immunogenic gliadin peptides to cross intestinal epithelial cells rather than being fully degraded.
Our hypothesis raises a critical question: Could iron deficiency increase intestinal CD71 expression or activity, facilitating gliadin transport and potentially contributing to the initiation of Celiac autoimmunity?
Although CD71-mediated gliadin transport has been demonstrated in active Celiac Disease, its proposed role as an iron-deficiency-driven mechanism preceding disease onset remains unproven.
Stage 4: Immune System Activation
Iron is essential for normal immune function, including the maintenance of intestinal immune cells that help regulate inflammation and protect the intestinal barrier.
In 2023, Xiong and colleagues demonstrated that CD71-mediated iron uptake supports the maintenance and function of group 3 innate lymphoid cells (ILC3s), which contribute to intestinal barrier protection and immune homeostasis.
These findings raise the possibility that iron deficiency could impair ILC3 function, potentially weakening intestinal immune regulation.
In genetically susceptible individuals carrying HLA-DQ2 or HLA-DQ8, gluten-derived peptides can undergo modification by tissue transglutaminase 2 (TG2), enhancing their presentation to gluten-reactive CD4+ T cells. This contributes to inflammatory immune responses and the production of Celiac-associated antibodies, including anti-TG2 and endomysial antibodies (EMA).
Could iron deficiency create an intestinal environment in which increased gluten-peptide exposure combines with impaired immune regulation to promote Celiac autoimmunity?
This proposed connection between iron deficiency, ILC3 dysfunction, and the initiation of Celiac Disease requires further investigation.
Stage 5: Celiac Disease and a Potential Vicious Cycle
Once Celiac Disease develops, gluten-triggered inflammation can damage intestinal villi, reducing the surface area available for nutrient absorption.
This can cause or worsen iron deficiency.
Our infographic illustrates a potential vicious cycle: iron deficiency might contribute to intestinal or immune dysfunction, possibly even causing Celiac Disease, while Celiac-related intestinal damage subsequently worsens iron deficiency.
The latter relationship is established. The former requires further investigation.
The Stealth Villain: Could Temporary Iron Deficiency Leave Lasting Changes?
One intriguing possibility is that iron deficiency could act as a stealth villain, much like a hacker who infiltrates a computer network, alters its software and databases, and disappears before the intrusion is discovered.
Imagine the hacker compromising both the system's software and hardware.
The software represents immune regulation -- the biological instructions determining which substances the immune system tolerates and which provoke an inflammatory response.
The hardware represents physical intestinal structures, including epithelial cells and tight junctions protecting the intestinal barrier.
Could temporary iron deficiency interfere with either system during a critical period of childhood development (i.e., in the first 1,000 days of development)?
Now imagine that the hacker leaves. Iron levels return to normal, and the original deficiency is no longer detectable. Yet some biological changes might persist.
Could transient iron deficiency leave a lasting vulnerability contributing to Celiac Disease months or years later?
According to the World Health Organization (WHO), iron deficiency is the most common nutritional deficiency worldwide, affecting people of all ages, particularly young children. Although iron deficiency may resolve as dietary intake, iron requirements, or other contributing factors change, could even a temporary deficiency trigger intestinal and immune changes that contribute to the subsequent development of Celiac Disease? The causal hypothesis is that iron deficiency may precede and help initiate Celiac autoimmunity, rather than simply arise as a consequence of the disease. This remains unproven, underscoring the importance of studying iron status before Celiac autoimmunity begins—not merely at or after diagnosis.
Unanswered Questions: Roadmap for Research
The infographic raises five important questions:
Cause and/or consequence? Does iron deficiency precede Celiac autoimmunity, or is it an early manifestation of undiagnosed disease?
A transient trigger? Could temporary iron deficiency produce lasting intestinal or immune changes after iron levels normalize?
Biological mechanisms? Could iron deficiency alter intestinal permeability, CD71-mediated gluten transport, ILC3 function, or immune tolerance?
Other contributing factors? How might iron status interact with genetic susceptibility, infections, antibiotics, and the gut microbiome?
Prevention? Could correcting iron deficiency reduce the development or progression of Celiac autoimmunity?
Answering these questions requires coordinated research.
Genetic studies should strengthen the Hujoel findings and distinguish iron-related effects from nearby Celiac susceptibility genes.
Laboratory studies should investigate the proposed intestinal barrier, CD71, microbiome, and immune mechanisms.
Longitudinal studies of genetically susceptible children should examine iron status before Celiac-specific antibodies first appear, including transient deficiencies.
Clinical trials should investigate whether medically appropriate iron repletion changes intestinal permeability, immune biomarkers, or other relevant outcomes. If causality is supported, prevention studies could evaluate whether intervention reduces Celiac Disease risk.
Why This Research Aligns With NIH's Autoimmunity Priorities
The National Institutes of Health has identified understanding autoimmune disease origins, environmental influences, and prevention as very important research priorities.
The NIH-Wide Strategic Plan for Autoimmune Disease Research, FY2026–2030 emphasizes investigating mechanisms and risk factors underlying autoimmunity, including research involving children.
NIH's NOURISH Autoimmunity Challenge similarly highlighted relationships between nutrition, immune function, and autoimmune disease.
Celiac Journey was recognized among the NOURISH winning teams for a separate proposal involving Celiac Disease flares and serum proteomics. Read about our NIH award.
The iron-deficiency hypothesis represents another research pasture consistent with NIH's broader scientific interest in nutrition and autoimmunity.
Celiac Disease offers a particularly valuable research model because scientists know its dietary trigger -- gluten -- and important genetic susceptibility factors, including HLA-DQ2 and HLA-DQ8.
Understanding whether iron deficiency influences the earliest stages of Celiac autoimmunity could also inform research into other autoimmune disorders.
Conclusion: A Question Worth Answering
The Hujoel research challenges the assumption that iron deficiency is exclusively a consequence of Celiac Disease.
Our infographic illustrates plausible biological pathways through which iron deficiency might contribute to intestinal dysfunction and abnormal immune activation. These connections remain hypotheses, not established causes.
We encourage NIH, academic medical centers, and researchers to investigate these relationships through genetic studies, laboratory research, longitudinal cohorts, and clinical trials.
The goal is not to prove a predetermined theory. It is to determine whether iron deficiency contributes to Celiac Disease -- and whether understanding that relationship could ultimately help prevent it.
For decades, we have understood that Celiac Disease can cause iron deficiency.
It is time to perform clinical trials to investigate whether iron deficiency can also help cause Celiac Disease.
Selected Scientific References
This article discusses an emerging scientific hypothesis. Iron supplementation has not been demonstrated to prevent Celiac Disease and should only be undertaken according to appropriate medical guidance.
