Two culprits account for most peptic ulcers: infection with the bacterium Helicobacter pylori and regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen or aspirin. Together these explain the vast majority of stomach and duodenal ulcers. But the full list of triggers extends well beyond those two, ranging from rare tumors and viral infections to blood-flow problems and autoimmune diseases. Understanding the less common causes matters because ulcers that don’t respond to standard treatment often have an unusual driver that needs its own specific fix.
H. pylori Infection
H. pylori remains the single most common cause of peptic ulcers worldwide. The spiral-shaped bacterium burrows into the mucus layer that protects your stomach lining, then deploys a suite of toxins and adhesion tricks that let it survive in an environment most organisms cannot tolerate. Once established, it triggers chronic inflammation that weakens the mucosal barrier, creating the conditions for an ulcer to form.1Journal of Pure and Applied Microbiology. Molecular Mechanisms of Helicobacter pylori Infection: A Review What makes H. pylori tricky is that many people carry it for years without symptoms. Only a fraction go on to develop ulcers, and why some do and others don’t involves a mix of bacterial strain, host genetics, and environmental co-factors like smoking.
For most of the twentieth century, doctors blamed ulcers on stress and spicy food. The bacterial hypothesis had actually surfaced decades earlier but was prematurely abandoned until Barry Marshall and Robin Warren revived it in the 1980s, eventually winning a Nobel Prize.2PubMed Central. Rethinking the history of peptic ulcer disease and its relevance for network epistemology That paradigm shift is worth remembering because it reshaped treatment entirely: what had been a chronic, relapsing condition managed with antacids became something curable with a short course of antibiotics.
NSAIDs and Other Medications
NSAIDs are the other heavyweight ulcer cause. They damage the stomach and duodenal lining through multiple routes: topical irritation of the surface cells, suppression of protective prostaglandin production, reduced blood flow to the mucosa, and interference with the stomach’s ability to repair day-to-day wear.3PubMed. How do NSAIDs cause ulcer disease? Prostaglandins are signaling molecules that help maintain the mucus-bicarbonate barrier, stimulate blood flow, and promote cell turnover. When NSAIDs shut that system down, the lining becomes far more vulnerable to acid damage. The risk climbs with higher doses, longer use, and when you’re also taking blood thinners or corticosteroids.
Medications beyond NSAIDs can also injure the upper digestive tract, though less commonly. Pill esophagitis, where a tablet lodges in the esophagus and erodes the wall, has been reported with antibiotics, bisphosphonates used for osteoporosis, and potassium supplements. In one documented case, the combination of a large pill and the acidic properties of clavulanic acid (part of the common antibiotic amoxicillin-clavulanate) was enough to ulcerate the esophageal wall directly.4PubMed Central. Amoxycillin-Clavulanic Acid-Induced Esophageal Ulcer: An Unusual Cause Swallowing pills with plenty of water and staying upright afterward isn’t just a suggestion on the label; it’s a real protective measure.
Stress Ulcers in Critical Illness
The idea that “stress causes ulcers” has a complicated relationship with reality. Everyday psychological stress is not a proven direct cause of peptic ulcers on its own, though it can worsen symptoms and may slow healing. But severe physiological stress, the kind that accompanies major burns, head injuries, sepsis, or prolonged intensive care, absolutely can cause ulcers. These so-called stress ulcers result from a sharp drop in blood flow to the stomach lining during critical illness.
Burn patients are a well-studied example. Research on burn patients receiving ulcer prevention treatment found that two factors independently predicted who still developed ulcers: epigastric pain and having burns covering more than 20% of the body surface. Among those who went on to endoscopy, about 70% had gastric ulcers, roughly 18% had duodenal ulcers, and the remainder had both.5PubMed Central. A revised risk analysis of stress ulcers in burn patients receiving ulcer prophylaxis Ulcers named after the physicians who first described them in specific settings, Curling ulcers in burn patients and Cushing ulcers in brain-injury patients, are part of the same stress-ulcer family. They develop because the body diverts blood away from the gut during a crisis, leaving the stomach lining unprotected against its own acid.
Ischemic Gastropathy
Outside the ICU, reduced blood flow to the stomach can cause ulcers on its own, a condition called ischemic gastropathy. This happens when the arteries feeding the stomach narrow or become blocked, typically from atherosclerosis, blood clots, or vasculitis. It can present as either sudden severe pain with bleeding or as chronic, smoldering abdominal discomfort that worsens after eating.6Clinical Gastroenterology and Hepatology. Gastric Ischemia: Pathogenesis, Diagnosis, and Management
Ischemic gastropathy is uncommon because the stomach has a rich network of overlapping blood vessels, so blockage in one artery is usually compensated by others. When the collateral supply also fails, though, the result can be severe ulceration that mimics gastric cancer on imaging.7PubMed Central. Ischemic Gastropathic Ulcer Mimics Gastric Cancer In one documented case, severe narrowing of two major abdominal arteries caused a gastric ulcer that looked malignant but resolved completely once blood flow was restored through surgery.8PubMed. Ischemic gastropathy: an unusual cause of abdominal pain and gastric ulcers Ischemic ulcers are easy to miss because doctors rarely consider blood-flow problems when they see an ulcer, defaulting instead to the usual suspects of H. pylori and NSAIDs.
Zollinger-Ellison Syndrome
Some ulcers resist treatment no matter what you throw at them. When standard acid-suppressing drugs fail and ulcers keep recurring, one rare but important possibility is Zollinger-Ellison syndrome (ZES). This condition is driven by a gastrinoma, a small tumor that pumps out enormous quantities of gastrin, the hormone that tells your stomach to produce acid. The result is acid hypersecretion so severe that the stomach and duodenum are constantly bathed in far more acid than the lining can handle, leading to recurrent peptic ulcers, chronic diarrhea, and severe reflux.9PubMed Central. Gastrinoma and Zollinger Ellison syndrome: A roadmap for the management between new and old therapies
Gastrinomas most often arise in the pancreas or duodenum. Diagnosis hinges on finding very high gastrin levels in the blood alongside extremely acidic stomach contents.10Radiology Case Reports. Zollinger-Ellison syndrome: Revelation of the gastrinoma triangle ZES accounts for a very small share of all ulcer cases, but identifying it matters enormously because the treatment is fundamentally different: rather than eradicating a bacterium or stopping a painkiller, you need to locate and often remove the tumor itself.
Viral and Fungal Infections
H. pylori gets most of the attention, but other microorganisms can cause ulceration, particularly in people whose immune systems are compromised. Cytomegalovirus (CMV) and herpes simplex virus (HSV) are the best-known viral offenders. Both tend to target the esophagus and upper GI tract in transplant recipients, people on long-term immunosuppressive drugs, and those with advanced HIV.
The two viruses produce different-looking ulcers on endoscopy. HSV typically causes small, punched-out erosions with yellow rims, most often in the lower esophagus. CMV ulcers tend to be larger, deeper, and more linear.11PubMed Central. Esophageal Cytomegalovirus and Herpes Simplex virus co-infection in an immunocompromised patient: Case report and review of literature CMV esophagitis ranks as the third most common infectious esophagitis after Candida and HSV, and it occurs especially when immune function is profoundly depressed.12PubMed Central. Cytomegalovirus Esophagitis in an Immunocompromised Patient Occasionally the two viruses show up together, complicating both diagnosis and treatment.13PubMed Central. Esophagitis in a Post-Liver Transplant Patient: A Case of Cytomegalovirus and Herpes Simplex Virus-1 Coinfection
Fungal ulcers are rarer still. Candida species live harmlessly in most people’s guts, kept in check by normal stomach acidity and a functional immune system. When those defenses are disrupted, whether by steroids, uncontrolled diabetes, cancer treatment, or even the altered environment around a pre-existing ulcer, Candida can invade the stomach wall and form ulcers that grow surprisingly large.14Journal of Gastroenterology and Liver Diseases. Candida Associated Giant Non-Healing Gastric Ulcer in an Immunocompetent Host Fungal gastric ulcers have even been reported in otherwise healthy individuals, as in one case of a 25-year-old woman who developed a Candida-driven gastric ulcer shortly after giving birth.15PubMed Central. Giant fungal gastric ulcer in an immunocompetent individual
Autoimmune and Systemic Inflammatory Diseases
Crohn’s disease is usually associated with the lower intestines, but it can affect any part of the digestive tract from mouth to anus. When it strikes the stomach or duodenum, it can produce aggressive ulcers that test negative for H. pylori and respond poorly to standard acid-suppression therapy. In a case series, upper GI Crohn’s ulcers shared three features: they appeared in multiple locations, they were H. pylori-negative, and they followed an unusually severe course, with most patients needing endoscopic or surgical intervention despite proton pump inhibitor treatment.16PubMed Central. Aggressive Helicobacter pylori-negative peptic ulceration as the initial manifestation of Crohn’s disease In some patients, these stubborn ulcers turned out to be the first sign of Crohn’s before any intestinal symptoms appeared.17Military Medicine. Upper Gastrointestinal Manifestations of Crohn’s Disease: Differential Diagnosis and Treatment of an Uncommon Presentation of Crohn’s Disease
Behçet’s disease is another systemic condition that causes ulcers, though it targets different tissues. It is a chronic, relapsing inflammatory vascular disorder best known for recurrent mouth sores and genital ulcers, along with eye inflammation and skin lesions.18PubMed Central. Gastrointestinal Behçet’s disease: A review The GI tract can be involved too, and Behçet’s intestinal ulcers have a distinctive appearance: deep, oval-shaped, clean-edged craters that can penetrate through the full thickness of the bowel wall.19PubMed Central. Behçet’s disease with intestinal involvement: a case report and review of the literature Because Behçet’s is rare and its intestinal involvement even rarer, diagnosis is often delayed.20PubMed. Gastrointestinal Behçet’s disease: Manifestations, diagnosis, and management
Radiation and Caustic Injury
Radiation therapy aimed at cancers in the chest or abdomen can damage the stomach as a bystander organ. Ionizing radiation generates massive amounts of reactive oxygen species that overwhelm the stomach lining’s antioxidant defenses. The cascade of damage kills mucosal cells faster than they can be replaced, eventually leading to erosion, ulceration, and in severe cases, long-term atrophy of the stomach wall.21PubMed Central. Radiation-induced gastric injury during radiotherapy: molecular mechanisms and clinical treatment Radiation ulcers can appear weeks to months after treatment ends, and they tend to heal slowly because the underlying tissue has been structurally weakened.
Swallowing strongly acidic or alkaline substances, whether accidentally or intentionally, causes immediate chemical burns to the esophagus and stomach. Substances at the extremes of the pH scale are intensely corrosive to the upper digestive tract.22PubMed Central. Management of esophageal caustic injury In severe cases this can progress to full-thickness destruction of the stomach wall and even perforation into the abdominal cavity.23American Journal of Case Reports. Clinical Spectrum and Management of Caustic Ingestion: A Case Series Presenting Three Opposing Outcomes Caustic ingestion is a surgical emergency, and the damage pattern depends on whether the substance is acidic (which tends to injure the stomach more) or alkaline (which tends to injure the esophagus more).
Smoking, Alcohol, and Sleep
Smoking does not usually start an ulcer on its own, but it is one of the most reliable ways to make an existing ulcer worse and delay healing. Research shows it reduces mucosal blood flow, suppresses cell growth factors needed for repair, and increases tissue-damaging free radicals in the stomach lining.24PubMed. Alcohol drinking and cigarette smoking: a “partner” for gastric ulceration In one study, smoking cut gastric mucosal blood flow roughly in half.25PubMed. The effect of cigarette smoking on gastric acid secretion and gastric mucosal blood flow in man
Alcohol compounds the problem. On its own, alcohol disrupts the mucosal barrier and damages the stomach’s surface cells. Combined with smoking, the effect is more than additive: animal research found that smoke exposure amplified alcohol-induced gastric damage by driving down protective prostaglandins and increasing the accumulation of inflammatory white blood cells in the stomach wall.26PubMed. The potentiating actions of cigarette smoking on ethanol-induced gastric mucosal damage in rats The two habits together are substantially worse than either alone.
Sleep deprivation is a less intuitive contributor, but the evidence is growing. Mucosal blood flow naturally rises during deep sleep stages, supporting the stomach lining’s repair cycle. When sleep is fragmented or cut short, that protective boost doesn’t happen, and the mucosa becomes more vulnerable. A large Taiwanese follow-up study found that longer sleep duration and better sleep quality were both associated with lower rates of peptic ulcer disease, likely because adequate sleep supports the mucosal blood flow and hormonal rhythms that keep the stomach lining intact.27PubMed Central. Long sleep duration and good sleep quality reduced incident peptic ulcer disease in a large Taiwanese population follow-up study A Mendelian randomization study similarly linked insomnia traits to increased ulcer risk, and animal work has shown that depriving rats of REM sleep causes visible mucosal damage and ischemia.28PubMed Central. Effects of Insomnia on Peptic Ulcer Disease Using Mendelian Randomization
Genetic Susceptibility
Some people seem primed for ulcers regardless of whether they carry H. pylori or take NSAIDs, and genetics appear to play a real role. A twin study estimated that genetic factors account for roughly 62% of the liability to peptic ulcer disease, with the remaining variance explained by individual-specific environmental factors.29JAMA Internal Medicine. Are Genetic Influences on Peptic Ulcer Dependent or Independent of Genetic Influences for Helicobacter pylori Infection? That is a surprisingly high heritability estimate. It doesn’t mean ulcers are “genetic diseases” in the way cystic fibrosis is, but it does mean that your baseline vulnerability to developing an ulcer under any given set of triggers is partly inherited.
One specific genetic marker that has been identified is elevated serum pepsinogen I, a pepsin precursor produced by the stomach lining. Studies of families with a high incidence of duodenal ulcers found that elevated pepsinogen I levels cluster in patterns consistent with a dominant inheritance trait.30PubMed. Genetic and evolutionary implications in peptic ulcer disease People who inherit this tendency produce more aggressive digestive enzymes, making their duodenal lining more susceptible to damage even when other risk factors are modest.
Idiopathic Ulcers
After testing for H. pylori, reviewing medication use, and ruling out rarer causes, some ulcers remain unexplained. These are classified as idiopathic peptic ulcers, and their share of total ulcer cases has been quietly rising as H. pylori infection rates fall in developed countries. Idiopathic ulcers tend to show up in older adults, often alongside other chronic conditions. They favor the antrum (the lower portion of the stomach), recur more frequently than H. pylori-associated ulcers, and heal more slowly with standard acid-suppression drugs.31Gastroenterological Endoscopy. DIAGNOSIS AND TREATMENT OF IDIOPATHIC GASTRIC ULCERS
What causes them remains an open question. Age-related weakening of the mucosal defense system and chronic low-level physiological stress are thought to contribute, but no single mechanism has been pinned down. For clinicians, idiopathic ulcers are frustrating because there’s no target to eliminate, no infection to eradicate, no drug to discontinue. Management relies on long-term acid suppression and careful monitoring for recurrence.
When an Ulcer Might Not Be an Ulcer
One important reason to take ulcers seriously, especially gastric ulcers that don’t heal as expected, is that some turn out to be malignant. A gastric cancer can look remarkably like a benign ulcer on imaging, and even at endoscopy the distinction is not always clear. Research on this problem found that malignant ulcers tended to be larger than a centimeter across and were more often associated with warning symptoms like appetite loss, unexplained weight loss, and nausea, but these features overlap enough with benign disease that visual inspection alone over-diagnosed malignancy.32PubMed Central. Gastric cancer detection in gastric ulcer disease Endoscopic ultrasound has improved the picture: one study found that wall thickness greater than 5 mm beneath the ulcer was the strongest independent predictor of malignancy.33PubMed. The usefulness of endoscopic ultrasonography in differentiation between benign and malignant gastric ulcer
This is why gastric ulcers typically get biopsied during endoscopy and followed up to confirm healing. A duodenal ulcer that responds to treatment and resolves is reassuring. A gastric ulcer that lingers or looks atypical warrants a harder look, because the treatment for cancer is obviously very different from the treatment for a benign sore.
The Brain-Gut Connection
The nervous system has a more direct hand in stomach ulcers than most people realize. The vagus nerve, the main parasympathetic highway between the brain and the gut, controls acid secretion, stomach motility, and mucosal blood flow. Animal research has shown that stimulating certain brain pathways triggers a cascade of gastric effects: increased acid output, increased pepsin secretion, stronger stomach contractions, and, when sustained, hemorrhagic mucosal lesions. These effects were mediated through the vagus nerve and cholinergic receptors in the stomach wall.34PubMed. Central nervous system action of TRH to stimulate gastric function and ulceration The same experiments showed that centrally driven gastric stimulation could worsen ulcers caused by aspirin or other irritants, suggesting that neurological conditions or states of heightened autonomic drive could amplify ulcer risk on top of other triggers.
This finding helps explain why emotional distress, while not a standalone ulcer cause the way H. pylori is, can still play a meaningful supporting role. Chronic activation of the parasympathetic system pushes the stomach toward a more aggressive acid-secreting state, which, layered on top of an existing vulnerability like H. pylori colonization or NSAID use, may tip the balance toward ulceration. The old folk wisdom that stress causes ulcers wasn’t entirely wrong; it just had the mechanism backward and overstated its independence as a cause.