# H. pylori as a primary cause of peptic ulcer disease: research update

Dated 5 October 2026. Local prepublication addendum; archived grade unchanged.

Eradication trials strongly support a causal contribution to infected peptic-ulcer disease. NSAID-associated, idiopathic and time-dependent bleeding outcomes define remaining questions rather than overturning the established infected-disease result.

## Research timeline

Electronic year is used where recorded; issue year is retained in each source card. The chronology is selected, not exhaustive, and does not establish priority or causation.

| Year | Primary study | Design and finding | Inference limit |
|---|---|---|---|
| 1985 | [Attempt to fulfil Koch's postulates for pyloric Campylobacter.](https://pubmed.ncbi.nlm.nih.gov/3982345/) | Single-volunteer oral challenge. Bacterial ingestion produced histologically documented gastritis. | Gastritis in one volunteer is not a controlled demonstration of chronic ulcer sufficiency. |
| 1992 | [Effect of treatment of Helicobacter pylori infection on the long-term recurrence of gastric or duodenal ulcer. A randomized, controlled study.](https://pubmed.ncbi.nlm.nih.gov/1558340/) | Randomized eradication/ulcer recurrence study. Eradication markedly reduced long-term gastric and duodenal ulcer recurrence. | Failure to eradicate and NSAID exposure remained relevant. |
| 1993 | [Eradicating Helicobacter pylori infection lowers gastrin mediated acid secretion by two thirds in patients with duodenal ulcer.](https://pubmed.ncbi.nlm.nih.gov/8174954/) | Paired physiological eradication study. Gastrin-mediated acid secretion decreased after eradication in duodenal-ulcer patients. | Paired mediator change does not isolate acid secretion as the only causal route. |
| 1993 | [Effect of ranitidine and amoxicillin plus metronidazole on the eradication of Helicobacter pylori and the recurrence of duodenal ulcer.](https://pubmed.ncbi.nlm.nih.gov/8419816/) | Antibiotic plus ranitidine randomized trial. Eradication reduced recurrent duodenal ulcer compared with placebo antibiotics. | Applies to infected recurrent-ulcer patients, not every ulcer etiology. |
| 1997 | [Randomised trial of eradication of Helicobacter pylori before non-steroidal anti-inflammatory drug therapy to prevent peptic ulcers.](https://pubmed.ncbi.nlm.nih.gov/9329511/) | Randomized eradication before NSAID treatment. Eradication reduced ulcer occurrence during subsequent naproxen use. | Prevention at NSAID initiation differs from established chronic NSAID use. |
| 2001 | [Preventing recurrent upper gastrointestinal bleeding in patients with Helicobacter pylori infection who are taking low-dose aspirin or naproxen.](https://pubmed.ncbi.nlm.nih.gov/11274623/) | Recurrent-bleeding prevention randomized trial. Eradication and acid suppression differed by aspirin versus other NSAID use. | Drug-specific co-causation limits a universal eradication-only strategy. |
| 2009 | [High incidence of mortality and recurrent bleeding in patients with Helicobacter pylori-negative idiopathic bleeding ulcers.](https://pubmed.ncbi.nlm.nih.gov/19445937/) | Idiopathic bleeding-ulcer cohort. H. pylori-negative, non-NSAID ulcers had substantial recurrent-bleeding risk. | Negative tests and etiological classification require careful validation. |
| 2022 | [Helicobacter pylori eradication for primary prevention of peptic ulcer bleeding in older patients prescribed aspirin in primary care (HEAT): a randomised, double-blind, placebo-controlled trial.](https://pubmed.ncbi.nlm.nih.gov/36335970/) | HEAT aspirin-user randomized trial. Early bleeding prevention benefit was not sustained with longer follow-up. | Time-varying effects and low event incidence matter; later HTA reporting is the same trial. |

## Research gaps

### G1: Why does bleeding-prevention benefit vary with time?

Evidence anchors: [P36335970](https://pubmed.ncbi.nlm.nih.gov/36335970/), [P8419816](https://pubmed.ncbi.nlm.nih.gov/8419816/), [P1558340](https://pubmed.ncbi.nlm.nih.gov/1558340/).

Competing explanation: Reinfection, competing disease, medication changes or time-dependent susceptibility may contribute.

Discriminating test and controls: Extended randomized-trial follow-up with repeat infection testing, medication ascertainment and prespecified time-varying/competing-risk analyses.

### G2: Which patients need both eradication and protection against another cause?

Evidence anchors: [P9329511](https://pubmed.ncbi.nlm.nih.gov/9329511/), [P11274623](https://pubmed.ncbi.nlm.nih.gov/11274623/), [P36335970](https://pubmed.ncbi.nlm.nih.gov/36335970/).

Competing explanation: NSAIDs or aspirin can damage mucosa independently of infection.

Discriminating test and controls: Factorial or comparative randomized prevention designs stratified by drug exposure and ulcer history; monitor eradication and bleeding rather than symptoms alone.

### G3: What explains verified infection-negative ulcers?

Evidence anchors: [P19445937](https://pubmed.ncbi.nlm.nih.gov/19445937/), [P11274623](https://pubmed.ncbi.nlm.nih.gov/11274623/).

Competing explanation: False-negative testing, occult drug exposure or distinct idiopathic biology may explain residual cases.

Discriminating test and controls: Prospective repeat-test classification after appropriate washout, verified drug exposure and longitudinal endoscopic/bleeding outcomes.

### G4: How much benefit is mediated by altered acid physiology?

Evidence anchors: [P8174954](https://pubmed.ncbi.nlm.nih.gov/8174954/), [P8419816](https://pubmed.ncbi.nlm.nih.gov/8419816/).

Competing explanation: Inflammatory or mucosal effects may operate alongside gastrin/acid changes.

Discriminating test and controls: Time-ordered physiological measurements within eradication studies and complementary mediator perturbation; distinguish statistical mediation from necessity.

## Methods and access

Case-specific Consensus records assisted gap discovery, chronology and targeted paper questions. Shared template wording about an amyloid-specific Deep follow-up is not evidence of a Deep run for this topic; the dated source records establish the actual use and access limits. Primary identifiers, selected abstract passages, correction notices and available primary-body passages were cross-checked. Generated absence cells, duplicate milestones and unsupported access claims were rejected.

This focused addendum does not establish 50–70 complete primary Methods/Results examinations per review. Baseline reading receipts and scores retain their original scope.

Checked timeline sources: 8; selected full-text checks: 0; abstract-excerpt checks: 8; metadata-only historical anchors: 0. Complete papers examined in this update: 0.

Historical scorecards declare schema 5.4. This enrichment uses HSEF v5.3 causal distinctions without retrospectively relabelling or rescoring those files.

Targeted paper-check scope: Primary abstract/metadata checked. Additional Consensus full-text details remain provider-reported because a separately readable body was unavailable in this update.