Untreated Helicobacter pylori (H. pylori) infection was associated with higher colorectal cancer (CRC) risk in two Chinese randomized trial cohorts, while eradication treatment was linked to lower CRC risk after nearly 30 years in one cohort but not overall after 13.8 years in another, according to findings published in Gut.
The study, based on two randomized trial cohorts from Linqu, Shandong Province, China, adds to evidence that H. pylori may have implications beyond gastric cancer. The apparent benefit of treatment differed between cohorts and appeared most pronounced with longer follow-up and among participants with higher genetic or bacterial virulence-related risk.
“The primary clinical takeaway from our two trials is that Helicobacter pylori infection associates with elevated colorectal cancer risk, and anti-H. pylori treatment delivers long-term colorectal cancer protection,” said study author Wen-Qing Li, PhD, of Peking University Cancer Hospital and Institute in Beijing.
The analysis included the Shandong Intervention Trial, or SIT, and the Mass Intervention Trial in Linqu, Shandong Province, or MITS. SIT included 3,365 participants and was initiated in 1995, with follow-up through 2024. MITS included 180,284 participants and began in 2011, with follow-up through 2024.
Although the original trial outcomes focused on gastric lesion progression or gastric cancer incidence, major cancer diagnoses were systematically collected during follow-up. Investigators evaluated the association between H. pylori infection and incident colorectal cancer in observational analyses comparing untreated H. pylori-positive participants with H. pylori-negative participants. They also assessed colorectal cancer risk according to randomized H. pylori treatment assignment among H. pylori-positive participants.
Infection was linked to higher colorectal cancer risk
In both cohorts, untreated H. pylori infection was associated with a higher risk of colorectal cancer.
In SIT, investigators documented 39 incident colorectal cancer cases over 29.4 years of follow-up. Compared with H. pylori-negative participants, H. pylori-positive participants who received placebo had nearly three times the risk of colorectal cancer (hazard ratio [HR], 2.96; 95% CI, 1.30–6.71).
In MITS, investigators documented 599 colorectal cancer cases over 13.8 years of follow-up. H. pylori-positive participants assigned to symptom alleviation treatment also had a higher risk of colorectal cancer compared with H. pylori-negative participants, though the association was more modest (HR, 1.27; 95% CI, 1.04–1.55). In a time-stratified analysis, the increased risk was evident after 10 years of follow-up.
Treatment findings differed by cohort
In SIT, anti-H. pylori treatment was associated with a lower colorectal cancer risk compared with placebo (HR, 0.47; 95% CI, 0.22–0.99), corresponding to a 53% relative risk reduction. The reduction was greater among participants with successful eradication (HR, 0.38; 95% CI, 0.15–0.94).
“The 29.4-year follow-up in the Shandong Intervention Trial demonstrated that H. pylori treatment reduced CRC risk by 53%, highlighting its long-term protective potential,” Dr. Li said.
In MITS, however, treatment was not associated with an overall reduction in colorectal cancer risk after 13.8 years of follow-up (HR, 1.17; 95% CI, 0.95–1.43). Dr. Li said that although MITS did not show reduced colorectal cancer risk across all participants, “the protective effect appears most pronounced in high-risk subgroups.”
High-risk subgroups appeared to benefit more
The MITS analysis also looked at genetic predisposition to colorectal cancer and markers of more virulent H. pylori infection.
Participants in the top 10% of a colorectal cancer polygenic risk score were considered to have high genetic risk. H. pylori-positive participants with high genetic risk had a 3.09-fold higher risk of colorectal cancer compared with H. pylori-negative participants with low genetic risk.
Seropositivity to four H. pylori antigens — CagA, HpaA, Omp, and HP0305 — was associated with increased colorectal cancer risk, particularly among participants at high genetic risk.
Treatment also appeared more favorable in these higher-risk groups. In exploratory analyses, anti-H. pylori treatment was associated with lower colorectal cancer risk among participants at high genetic risk (HR, 0.39; 95% CI, 0.16–0.94). Among participants who had high genetic risk and were seropositive for three or four key virulence factors, treatment was associated with a 64% lower colorectal cancer risk (HR, 0.36; 95% CI, 0.15–0.88).
“Patients with high CRC genetic risk and seropositive for 3-4 key virulence antigens experience markedly greater CRC risk reduction after anti-H. pylori treatment,” Dr. Li said. “Special attention should be paid to prioritize H. pylori screening and treatment for those individuals.”
Clinical implications and cautions
For clinicians, the findings broaden the conversation around H. pylori beyond gastric cancer, particularly for patients who already have other colorectal cancer risk factors.
“When evaluating gastrointestinal cancer risks, clinicians should consider informing H. pylori-infected patients of their elevated susceptibility to both gastric cancer and CRC,” Dr. Li said. “Anti-H. pylori treatment may be offered to reduce long-term cancer risk.”
At the same time, Dr. Li emphasized that cancer prevention benefits may take years to emerge and should not replace recommended cancer screening.
“The cancer-protective benefits of anti-H. pylori treatment may be observed over decades for both gastric cancer and CRC,” Dr. Li said. “Patients receiving anti-H. pylori therapy should continue regular cancer screening if screening is already indicated by comprehensive risk stratification.”
The study had several limitations. The trials were originally designed for gastric cancer prevention, not colorectal cancer risk reduction. The infection analyses were post hoc observational analyses within trial cohorts, and the case-cohort analyses of genetic susceptibility and virulence factors were exploratory. The authors also noted that MITS may require longer follow-up to detect a colorectal cancer treatment benefit, and colonoscopy use was not recorded.
Dr. Li said the subgroup findings need independent validation, and future work should address cost-effectiveness, residual cancer risk after treatment, and how lifestyle factors may interact with H. pylori treatment.
“Integrated risk prediction models incorporating CRC genetic susceptibility, H. pylori infection/treatment status, and lifestyle exposures are needed to accurately identify individuals at high CRC risk,” Dr. Li said.
The authors reported no competing interests.