How H. pylori thrives in highly acidic stomach
pH-sensitive binding mechanism key to bacteria’s staying-power and virulence
The medical community used to think that the stomach’s highly acidic environment made it a relatively sterile organ. But the unexpected discovery in 1982 that the Helicobacter pylori bacteria caused inflammation and peptic ulcers shattered that belief and earned the discoverers the Nobel Prize in Physiology or Medicine in 2005.
Since then, volumes of research have been conducted, and H. pylori is recognized as one of the most common infections worldwide and as the causative agent for peptic ulcer disease and gastric cancer.
But exactly how does H. pylori thrive under such harsh conditions and the rapid turnover of cells lining the stomach?
H. pylori’s ingenious survival mechanism
An international team of reseachers led by Thomas Borén at Umeå University and including Jay Solnick, professor internal medicine at UC Davis, has discovered the mechanism that gives the bacteria such staying-power and ability to cause chronic infection.
“H. pylori lives in the stomach attached to the cell lining and overlying mucus, where it escapes the toxic effects of acid in the gastric space,” Solnick said. “But it faces a dilemma, because the cells of the stomach lining have frequent turnover and are sloughed into the lumen, where they are cleared. H. pylori solves this problem by having a pH sensitive adhesion protein, BabA, that allows H. pylori to rapidly detach from old cells before they reach the brunt of the gastric acid environment so they can migrate back to new cells on the surface of the stomach lining to recycle the infection.”
The research findings are published in the March 9 issue of the journal Cell Host & Microbe.
The researchers studied the adhesion mechanisms using detailed biochemical analyses and state-of-the-art genetic systems, combined with unique H. pylori clinical strains and biopsy-materials collected from individual patients and animals over a span of many years.
H. pylori thrives in the gastric epithelium and in the very thin layer of overlying mucus that protects the stomach wall from the peptic acid, a special niche that is hostile to nearly all other microbes. The study shows that the BabA adhesin responds to changes in acidity. Low pH-levels, such as that of gastric acid, disrupts the BabA’s binding activity. However, the binding is restored by acid neutralization, i.e. when H. pylori returns to the more neutral environment in the stomach cell-lining. Furthermore, the number of pH-sensor sequences in the BabA adhesin’s binding domains determine its pH responsiveness.
“Our findings suggest that BabA enables H. pylori to tightly adhere to the mucosal layer. But the pH-responsiveness also allows the bacterium to escape a certain death by detaching from epithelial- and mucus cells that are shed into the gastric juice,” said Jeanna Bugaytsova, researcher at Department of Medical Biochemistry and Biophysics and first-author of the article.
A mechanism that evolves
About H. pylori
According to the U.S. Centers for Disease Control and Prevention, about 70 percent of the developing worlds’ population and 30 to 40 percent of the U.S. population carries H. pylori, which can change rapidly according to new gastric conditions and disease. Many carriers develop symptoms of gastritis and about one in five will, at some point in their life, develop peptic ulcers, in many cases a fast and deadly disease.
Both gastritis and peptic ulcer disease are treated with antibiotics; treatments that often require two to three different kinds of antibiotics and still do not cure all patients. Chronical H. pylori inflammation can at worst cause gastric cancer, a highly mortal and hard-to-treat form of cancer that affects 1 million people yearly worldwide.
According to the researchers, the acid sensitivity of BabA differs between H. pylori strains and different regions of the stomach. The researchers also show how diversity and adaptation in BabA adhesins’ pH-sensitivity is driven by inflammation and disease progression. Changes in BabA binding properties, through mutation and recombination with BabA-related genes, evolve due to differences between individual hosts and changes in gastric acidity over time. Such changes could be due to gastric disease development or the consequence of long-term use of acid-suppressing drugs that cause changes to the stomach pH-levels, i.e. changes that contribute to more rapid adaptation by mutations of H. pylori.
“These processes generate diverse H. pylori subpopulations, in which BabA’s adaptive evolution contributes to the pathogen’s persistence and ability to cause severe gastric disease,” said Borén, who is a professor at the Department of Medical Biochemistry and Biophysics at Umeå University in Sweden. Other research institutions participating in the large collaborative effort include SciLifeLab in Solna, Gothenburg and Örebro universities, and in Belgium, Germany, France, UK, Ireland, Greece, Ukraine, India and the U.S.