Matching Wits Against Helicobacter pylori Infection, a Very Clever Foe

“He who laughs last laughs best.”

English proverb

“The bottom line. H. pylori is not merely a cause of indigestion or ulcers. It is a common, treatable chronic infection responsible for hundreds of thousands of stomach-cancer deaths and a major, potentially preventable global cancer burden."

World Health Organization and International Agency for Research on Cancer

Helicobacter pylori, a Gram-negative, spiral-shaped bacterium that colonizes the lining of the human stomach, is the cause of peptic ulcers, inflammation of the stomach (gastritis), and gastric cancer. Approximately 43.1% to 50% of the world’s population is infected with H. pylori.

Last week, the New England Journal of Medicine (NEJM) published a review article on H. pylori infection that expounds on the elegance of H. pylori and its monumental discovery. (Hong, L., Megraud, F., Marshall, B.J. “Helicobacter pylori Infection—Advances, Challenges, and the Road Ahead,” New England Journal of Medicine, October 22, 2026). Reading that article prompted me to revisit this interesting pathogen and its discovery in this week’s post.

The discovery of H. pylori. All the discoveries of the more than 1,500 bacterial species known to infect humans deserve recognition.  But, in my opinion, none of these discoveries is more interesting and consequential than that of H. pylori, a discovery that has “revolutionized the prevention and treatment of gastritis, peptic ulcers, and most important, gastric cancer.”

Prior to 1982, the medical community believed that psychological stress and too much stomach acid caused peptic ulcer disease. Patients were told to relax, eat bland food and take acid-reducing medicine. Nonetheless, their ulcers came back again and again. Then two Australian physicians, J. Robin Warren, a pathologist, and Barry Marshall, a young physician-in-training, noticed curved bacteria in biopsies of inflamed stomachs and begin to wonder if a bacterium was the real culprit. (Pincock, S., “Nobel Prize winners Robin Warren and Barry Marshall,” The Lancet, October 22, 2005).

Their breakthrough has a touch of luck, reminiscent of Alexander Fleming’s discovery of penicillin, when a stray mold happened to land on a culture plate of staphylococci and killed them. Marshall’s and Warren’s attempts to grow the bacterium had repeatedly failed because it grows so slowly. Then culture plates were inadvertently left in an incubator over the Easter weekend of 1982, and when they were checked the bacterium H. pylori was fully visible.

When Marshall and Warren proposed that bacteria cause ulcers, they faced a torrent of derision. As Dr. Marshall later said, “To gastroenterologists, the concept of a germ causing an ulcer was like saying the Earth is flat.”

Frustrated that no one would listen, Marshall took a bold step. In 1984, he swallowed a broth containing the bacterium. Within days, he developed gastritis, and a biopsy confirmed that H. pylori had colonized his stomach. Antibiotics cured him. It was a dramatic, albeit reckless, demonstration that H. pylori could cause disease in a healthy person. Nonetheless, many clinicians still remained unmoved.

It wasn’t until the early 1990s, that the evidence of Marshall and Warren became impossible to ignore. Then the causative role of H. pylori in gastritis, in ulcers of the stomach and duodenum , and in gastric cancer was firmly established, and antibiotics became the standard treatment for ulcers. In 2005, Marshall and Warren had the last laugh; they received the Nobel Prize for their paradigm-shifting discovery.

Pathogenesis of H. pylori infection (recap). Chemically speaking, the stomach is considered one of the harshest environments in the human body, filled with acid strong enough to kill most, but not all, pathogens. H. pylori is one of these exceptions; it not only survives there, it thrives.

H. pylori  has been coevolving with humans for more than 100,000 years. In that time, the bacterium has developed a number of virulence factors. For example, it makes urease, an enzyme that neutralizes the acidity of the stomach. It has motility which enables the bacterium to penetrate the mucous layer and reach the epithelium. Lipopolysaccharide, an important outer membrane component of this Gram-negative bacterium, camouflages it from immune recognition. These and a host of other virulence factors enable H. pylori to colonize the host, evade the immune system, invade tissues and cause disease.

 The diseases H. pylori causes. H. pylori infection is one of the most common chronic bacterial infections worldwide. Most people with chronic infection remain asymptomatic. In a subset of people, the H, pylori infection can progress to:

• Gastritis, or inflammation of the stomach lining, which can cause pain, nausea and indigestion;

• Peptic ulcers, open sores in the lining of the stomach or duodenum that can bleed and the hemorrhages can be life-threatening:

• Atrophic gastritis, a severe form of gastritis in which the stomach lining becomes thin and scarred;

• Gastric MALT lymphoma, a rare cancer of the immune tissue in the stomach wall; and

• Gastric cancer (adenocarcinoma), the most serious outcome of all.

Treatment and prevention. H. pylori infection can be found, treated and, in a vast number of cases, cured. Diagnostic test include urea breath tests, fecal antigen tests or endoscopy with mucosal biopsy. Treatment usually consists of a proton-pump inhibitor to suppress acid production and two or three antibiotics (clarithromycin, metronidazole, and amoxicillin). The good news is that antibiotic treatment can heal most H. pylori-related ulcers and reduce future stomach-cancer risk.

About 760,000 new cancer cases worldwide were attributable to H. pylori. This makes it the leading infectious cause of cancer worldwide. In 2025, the International Agency for Research on Cancer published a study that projected the lifetime burden of stomach cancer among people born between 2008 and 2017 is 15.6 million people, of which 76% are attributable to H. pylori—meaning, they’re potentially preventable. The principle prevention opportunity is to identify infected people and eradicate the bacterium with appropriate antibiotic-based treatment.

Future directions. Managing H, pylori infection, from early diagnosis to wise treatment choices, is complex and calls for the expertise of multidisciplinary teams. The development of an effective vaccine to prevent or clear H. pylori infection would be a major step forward. It would be the ideal strategy for controlling this pathogen and preventing gastric cancer.

But. as is underscored in the NEJM article cited above, “[a] critical lesson from previous failures is that H. pylori has remarkable immune-evasion strategies to persist in the human stomach. Consequently, future vaccine development must incorporate strategies designed to counteract these immune-evasion mechanisms.”

It appears to me that H. pylori has the upper hand, at least so far. But with proper research support, I’m sure we can eventually outwit this very clever foe and, perhaps like Marshall and Warren in 2005, have the last laugh.