How Common Heartburn Medications Might Trigger Celiac Disease in Genetically Susceptible People
Imagine a medication so widely used that 14 billion dollars are spent on it annually in the United States alone—a drug that has become the go-to solution for everything from occasional heartburn to serious digestive disorders. This is the reality of proton pump inhibitors (PPIs), one of the most prescribed medication classes worldwide. Since the introduction of omeprazole in 1989, PPIs have revolutionized the treatment of acid-related gastrointestinal conditions, providing relief for millions of sufferers 1 .
Annual PPI spending in the US
First PPI (omeprazole) introduced
Among most prescribed drug classes
But emerging research is revealing a potential dark side to these ubiquitous medications, particularly for people with specific genetic markers. Recent studies suggest that long-term PPI use might be linked to the development of celiac disease, especially in individuals carrying the HLA-DQ2 and HLA-DQ8 genes—the same genes that predispose people to this autoimmune disorder triggered by gluten 1 7 . This connection represents a fascinating medical puzzle where a common treatment for digestive issues might inadvertently contribute to an entirely different digestive condition.
Proton pump inhibitors work by targeting the parietal cells in your stomach lining, effectively shutting down their ability to produce gastric acid. This acid suppression provides relief for conditions like esophagitis, peptic ulcers, and severe reflux. However, the effects of PPIs extend far beyond simple symptom management, creating significant changes throughout the digestive system 1 .
When PPIs reduce stomach acidity, they fundamentally alter the digestive environment. The elevated pH (less acidic environment) impairs the function of digestive enzymes that normally break down proteins into smaller components. This incomplete protein digestion allows larger, potentially immunogenic protein fragments—including gluten—to pass through the stomach undigested 5 . Additionally, research indicates that PPIs may "increase gastric mucosal permeability," creating openings that allow these larger protein particles to enter the body more easily and potentially trigger immune responses 5 .
Perhaps the most profound impact of PPIs lies in their effect on the gut microbiome. By reducing stomach acidity, these medications remove a crucial barrier that normally limits bacterial growth in the upper gastrointestinal tract. Recent studies have shown that PPI users experience significant bacterial overgrowth, particularly of Streptococcus and Lactobacillus species in the stomach 1 .
The consequences extend throughout the digestive system:
Celiac disease isn't caused by genetics alone, but without specific genetic markers, developing the condition is extremely rare. Over 99% of celiac patients carry at least one of two genetic variants: HLA-DQ2 or HLA-DQ8 3 6 . These genes code for specialized immune system proteins that play a crucial role in triggering the abnormal immune response to gluten 2 .
The presence of HLA-DQ2 or HLA-DQ8 significantly influences celiac disease risk, but the specific combination matters:
| Genetic Profile | Celiac Disease Risk |
|---|---|
| One copy of DQ2 or DQ8 | ~3% |
| Two copies (homozygous) | ~10% |
| General population (no DQ2/DQ8) | <0.1% |
Table based on data from the National Celiac Association 6
These HLA molecules function like specialized "presentation platforms" that bind to gluten fragments and display them to immune cells. In susceptible individuals, this display triggers an abnormal immune response that damages the small intestinal lining, leading to the classic symptoms and nutrient malabsorption associated with celiac disease 2 . The connection between these genetic markers and PPIs lies in how the medications might create conditions that activate this previously dormant genetic potential.
The potential link between acid-suppressing medications and celiac disease first gained serious attention in the scientific community following a 2013 Swedish study that examined nearly 3000 celiac patients and 14,584 matched controls. The researchers discovered something striking: 16% of celiac patients had a prior PPI prescription compared to only 4% of controls—a fourfold difference that remained statistically significant even after adjusting for socioeconomic factors 5 .
This association appeared across all age groups but was particularly strong in patients younger than 20 and in those prescribed both PPIs and H2 receptor antagonists (another class of acid-suppressing medications). Interestingly, the connection persisted even when the researchers excluded PPI prescriptions made in the year immediately before celiac diagnosis, attempting to account for the possibility that early celiac symptoms might have prompted the prescriptions 5 .
Researchers have proposed several explanations for how PPIs might contribute to celiac disease development in genetically susceptible individuals:
By raising stomach pH, PPIs impair the enzyme activity that normally breaks down gluten into less harmful fragments 5
PPIs may compromise the barrier function of both the stomach and intestinal lining 5
The microbiome alterations caused by PPIs may create an inflammatory environment 1
PPIs may directly affect immune system regulation, potentially lowering tolerance to dietary antigens 5
These mechanisms might work together to create a "perfect storm" where someone with HLA-DQ2 or HLA-DQ8 genes, previously tolerant to gluten, loses that tolerance when their digestive environment is altered by PPI therapy.
One of the most comprehensive investigations into the PPI-celiac connection was published in JAMA Network Open in April 2025. This retrospective study leveraged the extensive database of Maccabi Healthcare Services in Israel, analyzing data from 79,820 children born between 2005 and 2020. The research employed two distinct methodological approaches to overcome limitations that had plagued previous studies 4 8 .
The study design included:
This dual-method approach allowed researchers to assess whether previously observed associations might be influenced by "health care utilization bias"—the possibility that children receiving more medical attention (and thus more likely to get PPIs) might also be more likely to receive celiac disease testing 4 .
The findings revealed a striking discrepancy between the two research methods:
| Study Design | Participants | Celiac Autoimmunity in PPI Users | Celiac Autoimmunity in Non-Users | Statistical Significance |
|---|---|---|---|---|
| Cohort Design | 79,820 children | 1.6% (310/19,955) | 1.0% (610/59,865) | Significant (HR: 1.52) |
| Test-Negative Case-Control | 24,684 children | 5.0% (309/6,176) | 4.6% (858/18,508) | Not Significant (OR: 1.07) |
Data compiled from the 2025 Israeli study 4
The cohort study showed a 52% increased risk of developing celiac disease autoimmunity among children exposed to acid-suppressive therapy in early life, with an even stronger effect (65% increased risk) for those using the medications for more than one month 4 .
However, the test-negative design—which the authors argued might better control for health care utilization bias—found no significant association between early PPI exposure and subsequent celiac disease autoimmunity 4 . This suggests that the observed link in the cohort study might be influenced by factors unrelated to the biological effects of the medications themselves.
Understanding how researchers investigate the PPI-celiac disease connection requires familiarity with their essential tools and methods:
| Research Tool | Function in PPI-Celiac Research |
|---|---|
| HLA Genotyping | Identifies HLA-DQ2/DQ8 status using PCR-based methods on blood, saliva, or buccal swabs 3 |
| Anti-Transglutaminase (TG2) ELISA | Measures celiac disease autoantibodies in serum; used to diagnose celiac autoimmunity 4 |
| 16S rRNA Gene Sequencing | Analyzes microbiome composition in gastric and duodenal samples 1 |
| Glucose Hydrogen Breath Test | Detects small intestinal bacterial overgrowth (SIBO), common in PPI users 1 |
| Multiplex Ligation-dependent Probe Amplification (MLPA) | Technique for HLA-DQ2/DQ8 genotyping; validates against established PCR methods 3 |
Despite growing interest in this potential connection, many questions remain unanswered. The causal relationship between PPI use and celiac disease development remains uncertain, with the most recent research suggesting earlier findings might have been influenced by confounding factors 4 . The exact mechanisms by which PPIs might trigger loss of gluten tolerance in genetically susceptible individuals need further clarification.
Future research priorities include:
The emerging picture highlights the importance of personalized medicine—considering a patient's genetic background when prescribing medications intended for long-term use 1 7 .
For now, the uncertain connection between PPIs and celiac disease suggests cautious rather than alarmist approaches:
for HLA-DQ2/DQ8 might be considered before initiating long-term PPI therapy, especially in younger patients
should follow the "lowest effective dose for shortest necessary duration" principle
of potential celiac disease (bloating, diarrhea, fatigue, nutrient deficiencies) is important for long-term PPI users
without consulting a healthcare provider, as uncontrolled acid-related conditions carry their own risks
The potential link between proton pump inhibitors and celiac disease represents a fascinating example of how medical treatments can have unintended consequences, particularly for genetically susceptible individuals. While the latest research suggests the connection may be weaker than initially thought, the story continues to evolve as scientists employ more sophisticated methods to untangle this complex relationship 4 .
What remains clear is that both PPIs and celiac disease involve sophisticated biological systems—acid production, immune recognition, microbiome ecology—that interact in ways we're only beginning to understand. For patients and providers, this evolving story underscores the importance of informed medication use, attention to individual genetic risk factors, and the recognition that even the most common treatments deserve periodic reevaluation in light of new evidence.
As research continues, the hope is that we'll develop increasingly personalized approaches to gastrointestinal health that effectively treat acid-related symptoms without inadvertently creating new challenges elsewhere in the digestive system.