Researchers have been able to disable bacteria that cause ulcers by removing the bacteria’s ability to get close to the stomach wall.
This new knowledge about how the immune system responds to H. pylori infections could be used to screen for patients more susceptible to stomach ulcers and cancer, and perhaps to create more targeted therapies for those already affected.
In order to both survive and cause inflammation in the stomach, bacteria need to get to the side of the stomach “and set up shop there, living adjacent to your stomach cells, in a little kind of cozy home,” says Karen Ottemann, whose study was published this week in the early online edition of the Proceedings of the National Academy of Sciences. Unlike the acidic middle of the stomach, “the pH is closer to neutral and there’s food coming out of the cells,” she notes.
Ottemann found that the bacteria’s ability to move away from an acidic environment and towards one with food, called chemotaxis, was crucial to causing inflammation in the stomach. “To live really cozy like that,” she explains, “they need to be able to swim, and they need to be able to know where they’re going to direct their swimming.”
By swimming close to host cells, the bacteria are normally able to send out proteins that cause the cells of the stomach wall to burst. This cell death, combined with the presence of the bacteria in the stomach, puts the body’s immune system on high alert.
But removing the gene that allows bacteria to do chemotaxis prevented them from being able to hover near their host cells in mouse stomachs. Instead, the bacteria swam aimlessly, unable to aim their destructive proteins at host cells.
The mere presence of H. pylori in the stomach is not enough to start a severe immune response, since the body could just be responding to dead floating bacteria. Without the second crucial component—cell death—the immune system will not trigger damaging inflammation. “Many bacteria have this ability to do chemotaxis,” says Ottemann, “but they had not been studied in very much detail in terms of how the ability to do chemotaxis was used inside of infected animals or humans.”
More than half of people are infected with H. pylori, but over eighty percent of those infected never experience any negative symptoms. Patients who do have symptoms may be the victims of a “frustrated immune system” struggling to rid itself of H. pylori while causing more damage to the body’s own cells than to the bacteria, according to immunologist Martha Zuniga at the University of California, Santa Cruz.
Vicki Auerbach Stone, who studies the immune system, says the research paints a fuller picture of all the necessary conditions for H. pylori to have its effect. While scientists mostly study the molecules that are the immediate cause of inflammation, there are other factors that have to be in place in order for the molecule to accomplish its goal. “And chemotaxis is an example of something like that,” she says. “It’s getting the bacteria to the right place to have an effect.”
Since only a small number of people with H. pylori infections have severe reactions, while most cases go unnoticed, researchers hope that this new knowledge about the specific kind of immune response H. pylori can generate will help them to single out people who are more likely to experience symptoms of infection.
Zuniga is interested in these different immune response profiles, asking, “What distinguishes people that can have an H. pylori infection and not even know it for their entire lives from the people who develop pathology—who get ulcers, or ultimately cancer?”
“My own personal prediction would be that it’s the severity of the immune response,” she explains, “and that genetic differences among different people would predispose you to give a very strong anti-inflammatory response that isn’t very effective at clearing bacteria, but that does cause pathology.”
Part of H. pylori’s effectiveness is in its ability to manipulate the immune system. The first stage of the immune response, called the innate response, detects both the presence of the bacteria in the stomach and the death of stomach wall cells. These two events combined set off a cascade of events resulting in the second adaptive response, which recruits cells that can target the infection more specifically.
But H. pylori is able to trick the innate immune system into setting off the wrong kind of adaptive response: one that does not target the bacteria very effectively, but that does cause intense inflammation. People who experience symptoms of a H. pylori infection have adaptive immune responses that send out more highly inflammatory immune cells, which cause rampant damage along the lining of the stomach. The bacteria thrive in inflamed areas, and the immune response ends up targeting the body’s cells rather than getting rid of the bacteria. This results in chronic inflammation.
But without chemotaxis, the bacteria were unable to trick the innate immune system. Even though the genetically altered bacteria continued to survive in the mouse’s stomachs, they did not cause damage. With this new knowledge about the behavior of ulcer-causing bacteria, researchers can begin to imagine how it might be applied to preventing ulcers and stomach cancer.
In addition to identifying people whose immune systems are more likely to have dramatic responses, bacteriologists like Daniel Kadouri, who works on developing therapies that use bacteria, speculate it might be possible to use probiotics to make the stomach a less hospitable environment for H. pylori by interfering with its ability to do chemotaxis.
Matt Traxler, a microbiologist at the Harvard Medical School, points out that developing therapies that target chemotaxis in H. pylori could also have more widespread applications. Chemotaxis is a common ability among bacteria, since most bacteria use whip-like tails called flagella to move around, and chemotaxis helps determine in which direction the bacteria should move.
If scientists devise a way to prevent H. pylori from doing chemotaxis in the stomach, Traxler imagines, they might be able to apply that knowledge to many other pathogens that also use chemotaxis to damage their hosts.
As evidence grows that having H. pylori in the stomach may lead to some health benefits, such as the prevention of esophageal cancer and asthma, these modified, less harmful bacteria are of interest to immunologists. However, Ottemann and others concede that using these modified bacteria purely as a treatment tool is a distant prospect that requires much more research into both effectiveness and safety.
“I think there’s a lot of interest in the idea that you might want to control your microbial flora so as to either promote a health state or to demote a disease state,” says Ottemann. But for the moment with H. pylori, “I just think we’re a little ways off from that.”