Ever heard that stomach ulcers are caused by stress? Turns out it’s a lot more complicated than that.
Stomach (or peptic) ulcers are just one component of a complex web of interactions between the human body and one of the thousands of bacterial species that make up our microbiomes (the community of bacterial species that live in and on our bodies). Helicobacter pylori, the bacterium that resides in the nearly inhospitable acidic environment that is the human stomach, has only recently begun to be understood.
Dr. Barry Marshall of the University of Western Australia and Dr. Martin Blaser of Rutgers University gave a joint presentation in the Demystifying Medicine series titled “The Split Personality of Helicobacter Pylori.”
“The only good Helicobacter pylori is a dead [one]” is the philosophy of many gastroenterologists, Blaser said. Marshall and his colleague Dr. Robin Warren identified the bacteria’s association with gastritis (inflammation of the stomach lining), and peptic ulcers in 1982.
The earliest recorded observation of the spiral-shaped bacteria was 100 years earlier in 1892, but they had never been successfully cultured outside the stomach before and thus no one paid much attention to them. Many researchers didn’t believe Marshall and Warren’s findings at first—including Blaser.
“Never publish a paper that shows results in 100 percent of patients because no one will believe it,” Marshall laughed.
It was also a commonly held belief that the human stomach was too acidic for microbial life. The research community came around eventually, and Marshall and Warren shared the 2005 Nobel Prize in Physiology or Medicine for their work with H. pylori.
Marshall and other researchers found that most people with duodenal and gastric ulcers also have H. pylori. Bismuth subsalicylate (the active ingredient in Pepto-Bismol) turned out to be one drug already in existence that killed helicobacter. Bismuth, behaving as an antibiotic, along with other common antibiotics were found to quash H. pylori in ulcer patients, thus allowing the ulcer to heal and largely preventing relapse.
Blaser and colleagues showed that H. pylori was the most important risk factor for the most common type of stomach cancer (non-cardia), which affects the lower portions of the stomach. According to Blaser, helicobacter-positive individuals may have upwards of a 6-fold greater risk of developing non-cardia gastric cancer.
Blaser, a physician and microbiologist, became interested in the relationship between helicobacter and humans. Was it truly all bad, or were there hidden benefits to the human host?
Today, approximately half of the global population carries H. pylori. Most infected individuals do not develop ulcers or gastric cancer and may not have any adverse symptoms at all. Blaser proposed that the bacteria actually had a “split personality”—that it caused some deleterious effects but also some beneficial ones.
Blaser and others obtained helicobacter samples from patients around the world and sequenced their DNA with fascinating results: modern helicobacter strains can be traced to ancestral ones that flourished thousands of years ago. This ordination is consistent with the idea that humans have been carrying helicobacter since before the out-of-Africa event, which was 58,000 years ago, he revealed. “As humans diverged around the world, so did their helicobacter…[and it probably] has been in humans and our ancestors since before we were humans.”
By definition, that makes H. pylori a co-evolved colonizing persistent microbe. But, Blaser asked, what happens to the host when that microbe is lost?
As Blaser studied H. pylori, he noticed an interesting trend. Since the bacteria had first been measured in human populations in the early 1900s, its prevalence has decreased steadily and significantly. In 1915, it was found in about 60 percent of Americans. By the 1990s, that percentage had fallen to less than 10. The reason for the decline is suspected to be improved sanitation, chlorinated water, and widespread usage of antibiotics.
The incidence of asthma and other allergic responses has increased in the post-war period, Blaser said, and researchers have identified a link between asthma and a condition called GERD (gastroesophageal reflux disease), in which stomach acid flows into the esophagus.
The human stomach has a pH of 1.5-3.5. This acidity aids in digestion by breaking down food and also kills pathogens such as viruses and bacteria. Most bacteria cannot survive in pH less than 3. So, how does H. pylori survive in this hostile environment?
It produces an enzyme called urease, Marshall said. Urea is a compound found in stomach acid, and the urease enzyme made by H. pylori breaks down urea and forms ammonia, an alkaline (less acidic) substance.
“The helicobacter form a less acidic buffer around them with urease,” Marshall explained. “Normal people have urea in their stomach acid, but people with H. pylori don’t because the bacteria is using it up.”
Less stomach acid could potentially be helpful in conditions like acid reflux and GERD. Damage from stomach acid in the esophagus and upper stomach (gastric cardia) is a risk factor for adenocarcinomas, so scientists speculate that reduced stomach acid may diminish acid damage and the likelihood of esophageal and gastric cardia cancers. Blaser provided evidence that H. pylori is bad for the lower stomach and duodenum, but protective for the upper stomach and esophagus.
Both Marshall and Blaser share a willingness to include themselves in their research. In order to test his initial hypothesis that helicobacter causes gastritis, Marshall drank two petri dishes of the bacteria.
“It was tasteless, thankfully,” he laughed. He developed gastritis 10 days later and ultimately took antibiotics to rid himself of the bacteria.
Blaser made an important discovery: cytotoxin-associated gene A (cagA), by studying antibodies in his own blood that identified this important protein in the H. pylori strain he was carrying in his stomach.
The presence of this gene allows researchers to divide H. pylori populations into cagA+ and cagA- strains. CagA produces a toxin that alters the structure of stomach lining cells and allows helicobacter to attach more easily. The toxin can cause chronic inflammation over time. Studies have shown that cagA+ strains are associated with an increased risk in non-cardia gastric cancer, and reduced risk of gastric cardia and esophageal adenocarcinoma.
However, a study from Blaser’s group in New York showed that people with cagA+ helicobacter were less likely to develop asthma or developed it later in life, and their other independent blinded studies confirmed these findings. The bacteria may offer some protection from infections—individuals with H. pylori had a stronger immune response to a live oral typhoid vaccine than those without.
H. pylori is also known to regulate ghrelin, the “hunger hormone.” In people with helicobacter populations, ghrelin was high before eating and fell after a meal, while individuals without helicobacter still had higher ghrelin levels after eating.
So, “is the only good helicobacter pylori a dead helicobacter pylori?” Blaser asked. “I don’t think so. [It] is an ancestral member of the human microbiota. Its disappearance has consequences, both good and bad. That is the future of medicine.”
He and Marshall discussed a future where people could be infected with H. pylori at an early age to reap the bacteria’s benefits, and then treated for the infection later in life before complications could take effect. Both agreed it was a radical idea, but not out of the question.
“We’ve changed the ecology of the stomach,” Blaser said, “[but] the logic is leading back to that.”