Helicobacter pylori can cause stomach cancer


More than half of the people in the world host colonies of a bacterium called Helicobacter pylori in their stomachs.

Although it’s harmless to many, H. pylori can cause stomach cancer as well as ulcers and other gastric conditions.

Doctors tend to prescribe multiple antibiotics to defeat the microbe, but that strategy can lead to antibiotic-resistant superbugs.

What is Helicobacter pylori?

Helicobacter pylori, or H. pylori, is a spiral-shaped bacterium that grows in the mucus layer that coats the inside of the human stomach.

To survive in the harsh, acidic environment of the stomach, H. pylori secretes an enzyme called urease, which converts the chemical urea to ammonia.

The production of ammonia around H. pylori neutralizes the acidity of the stomach, making it more hospitable for the bacterium.

In addition, the helical shape of H. pylori allows it to burrow into the mucus layer, which is less acidic than the inside space, or lumen, of the stomach. H. pylori can also attach to the cells that line the inner surface of the stomach.

Although immune cells that normally recognize and attack invading bacteria accumulate near sites of H. pyloriinfection, they are unable to reach the stomach lining.

In addition, H. pylori has developed ways of interfering with local immune responses, making them ineffective in eliminating this bacterium (12).

H. pylori has coexisted with humans for many thousands of years, and infection with this bacterium is common.

The Centers for Disease Control and Prevention (CDC) estimates that approximately two-thirds of the world’s population harbors the bacterium, with infection rates much higher in developing countries than in developed nations.

Although H. pylori infection does not cause illness in most infected people, it is a major risk factor for peptic ulcer disease and is responsible for the majority of ulcers of the stomach and upper small intestine. More information about H. pylori and peptic ulcer disease is available from the National Institute of Diabetes and Digestive and Kidney Diseases.

In 1994, the International Agency for Research on Cancer classified H. pylori as a carcinogen, or cancer-causing agent, in humans, despite conflicting results at the time. Since then, it has been increasingly accepted that colonization of the stomach with H. pylori is an important cause of gastric cancer and of gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Infection with H. pylori is also associated with a reduced risk of esophageal adenocarcinoma.

H. pylori is thought to spread through contaminated food and water and through direct mouth-to-mouth contact. In most populations, the bacterium is first acquired during childhood. Infection is more likely in children living in poverty, in crowded conditions, and in areas with poor sanitation.  

What is gastric cancer?

Gastric cancer, or cancer of the stomach, was once considered a single entity. Now, scientists divide this cancer into two main classes: gastric cardia cancer (cancer of the top inch of the stomach, where it meets the esophagus) and non-cardia gastric cancer (cancer in all other areas of the stomach).

Gastric cancer is the second most common cause of cancer-related deaths in the world, killing approximately 738,000 people in 2008 (3). Gastric cancer is less common in the United States and other Western countries than in countries in Asia and South America.

Overall gastric cancer incidence is decreasing. However, this decline is mainly in the rates of non-cardia gastric cancer (4). Gastric cardia cancer, which was once very uncommon, has risen in incidence in recent decades (5).

Infection with H. pylori is the primary identified cause of gastric cancer. Other risk factors for gastric cancer include chronic gastritis; older age; male sex; a diet high in salted, smoked, or poorly preserved foods and low in fruits and vegetables; tobacco smoking; pernicious anemia; a history of stomach surgery for benign conditions; and a family history of stomach cancer (67).

H. pylori has different associations with the two main classes of gastric cancer. Whereas people infected with H. pylori have an increased risk of non-cardia gastric cancer, their risk of gastric cardia cancer is not increased and may even be decreased.

What evidence shows that H. pylori infection causes non-cardia gastric cancer?

Epidemiologic studies have shown that individuals infected with H. pylori have an increased risk of gastric adenocarcinoma (1,2,812). The risk increase appears to be restricted to non-cardia gastric cancer. For example, a 2001 combined analysis of 12 case–control studies of H. pylori and gastric cancer estimated that the risk of non-cardia gastric cancer was nearly six times higher for H. pylori-infected people than for uninfected people (8).

Additional evidence for an association between H. pylori infection and the risk of non-cardia gastric cancer comes from prospective cohort studies such as the Alpha-TocopherolBeta-Carotene (ATBC) Cancer Prevention Study in Finland (13). Comparing subjects who developed non-cardia gastric cancer with cancer-free control subjects, the researchers found that H. pylori-infected individuals had a nearly eightfold increased risk for non-cardia gastric cancer (14).    

Now, a finding by UCLA scientists may lead to a better approach.

The researchers have determined the molecular structure of a protein that enables H. pylori to stay alive in the stomach, and elucidated the mechanism by which that protein works.

Z. Hong Zhou, the study’s corresponding author and a UCLA professor of microbiology, immunology and molecular genetics, said the findings answer questions that have been sought ever since 2005, when two Australian scientists won a Nobel Prize for their discovery of H. pylori and its role in gastritis and peptic ulcer disease.

The UCLA study, which was published online by Science Advances, was co-led by Keith Munson, a recently retired senior researcher in UCLA’s Division of Digestive Diseases.

H. pylori thrives in the harsh environment of the stomach due to its urea channel, a protein in the bacterium’s inner cell membrane that detects the environment’s acidity and acts as a gate.

When conditions in the stomach grow too acidic, the urea channel opens to let in a compound called urea.

Urea is normally excreted as a waste product in urine, but it also can be found in relatively small concentrations in the stomach. H. pylori uses it as raw material for neutralizing the acid that otherwise would kill the bacterium.

The research revealed the three-dimensional molecular structure of the urea channel, both when it is open and when it’s closed, using cryo-electron microscopy, or cryo-EM, an imaging technique that detects electrons rebounding from frozen samples.

Comparing the open and closed channels offered insight into the changes that take place when the “gate” opens, and the cryo-EM images provided previously unseen details that are important for understanding the activity of the protein, which is shaped like a hexagonal prism.

Zhou, Munson and their colleagues also engineered variations of the urea channel, shuffling different amino acids into key spots.

They tested those variations at different levels of acidity to see which substitutions interfered with the protein’s action.

The experiments enabled the scientists to identify which parts of the urea channel are involved in sensing acidity and altering its shape to let in urea.

The UCLA discovery could lead to future research on ways to fight H. pylori more effectively by sabotaging its survival mechanism.

“The urea channel is a viable drug target for eradication of this human pathogen, which remains a significant health risk throughout the world,” said Zhou, who also is director of the UCLA Electron Imaging Center for NanoMachines at the California NanoSystems Institute at UCLA.

The findings also represent a technical advance.

“We believe this is the highest resolution yet attained by cryo-EM for a membrane protein showing minimal mass outside the membrane,” Zhou said.

More information: Yanxiang Cui et al. pH-dependent gating mechanism of the Helicobacter pylori urea channel revealed by cryo-EM, Science Advances (2019). DOI: 10.1126/sciadv.aav8423
Provided by University of California, Los Angeles


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