|Research in the News: Ulcers - The Culprit Is H. Pylori (Grades 9-12)|
Ulcers: The Culprit is H. Pylori!
Stress doesn't cause ulcers. Bacteria do.
Ulcers. For most people, the word implies stress. Stomach ulcers have long been associated with stressful occupations, tension, and anxiety. For many years, doctors blamed the typical symptoms of ulcers–burning stomach pain and nausea–on stressful life situations.
The stress-ulcer theory dominated medical thinking for nearly a century, and was based on the observation that people under increased stress produce greater-than-normal amounts of stomach acid. The excess acid was believed to lead to inflammation (medically known as gastritis), which ultimately created an ulcer–an actual erosion or inflamed pitting of the stomach’s lining of epithelial cells.
Most stomach ulcers are caused by the bacterium H. pylori (purple), which burrows into the mucous lining of the stomach. The bacterium secretes an enzyme that produces ammonia, a strong base that damages stomach tissue, especially epithelial cells of the stomach lining. Immune system cells infiltrate the area of the ulcer to attack the bacteria, but this often leads only to further inflammation and damage. Drawing by Howard Bartner.
In the past decade, however, new research findings have confirmed that more than 90 percent of all cases of gastritis and ulcers are caused not by stress or acid, but by infection with Helicobacter pylori (H. pylori), a mobile, corkscrew-shaped bacterium that has the unique ability to adhere to and invade the stomach’s mucus lining, where it creates inflammation, ulcers, and possibly stomach cancer.
Ulcers are a major health problem for the 25 million Americans who experience stomach discomfort ranging from mild to excruciating and visit doctors for treatment about million times a year. The cost of prescription and over-the-counter ulcer medications, combined with lost wages from missed work, cost Americans more than 6 million dollars annually.
For many years, researchers assumed that the extremely acidic environment of the human stomach prevented any sort of microbial life from taking hold. Indeed, how could any organism survive in an environment dominated by the hydrochloric acid secreted by the stomach’s parietal cells? As it happens, however, scientists had observed bacteria in the stomach as long ago as the late 19th century. Investigators of the time had few of the analytical techniques now available to scientists, and they could do little more than record their observations, which most scientists ignored. The prevailing scientific opinion weighed against the idea that any sort of bacterial life form might survive in the stomach.
It was not until the early 1980s, when two young Australian physicians, Barry Marshall and Robin Warren of the Royal Perth Hospital in Perth, Western Australia, again raised the possibility that bacteria caused ulcers. Fueled by their own persistence and enthusiasm–and initially ridiculed by their colleagues–Marshall and Warren established beyond any doubt that H. pylori plays a critical role in creating gastritis and ulcers.
Barry Marshall and Robin Warren
But how does H. pylori survive an acid bath in the stomach, let alone cause inflammation or ulcers? William Coleman of the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health (NIH) in Bethesda, Maryland, says that H. pylori has several survival tools. “For starters, it doesn’t need nearly as much oxygen as we humans do,” he says. H. pylori thrives at much lower oxygen concentrations, a good adaptation to life in the recesses of the stomach lining.
In fact, H. pylori is optimally designed for living in the stomach epithelium, which is coated with mucus. “H. pylori is shaped like a corkscrew, which is great for burrowing and maintaining a grip in the thick mucus layer of the stomach,” says Coleman. “And it has flagellae that function as whip-like propellers, so it can swim nicely in the fluid environment of the stomach. H. pylori can adhere to the mucus wall and resist all the muscle contractions that normally empty the stomach. It has an outer cellular membrane that is impermeable to bile and other digestive juices. It also produces an enzyme called urease, which breaks down urea–a waste product found in all human fluids–into its chemical components, ammonia and carbon dioxide. The ammonia is a strong base and it neutralizes or reduces acidity in the stomach lining, which makes life much happier for H. pylori,” says Coleman.
Photograph of stomach tissue infected with H. pylori as seen through a microscope. In the micrograph, silver stained H. pylori bacteria appear as tiny black dots and lines.
After scientists established that H. pylori is not only present in the human stomach, but is a successful and long-term resident there, the next question was how the bacterium creates disease–gastritis, ulcers, and possibly cancer. Researchers have verified a strong link between H. pylori and an increased risk of cancer, a link so convincing that the World Health Organization, based in Geneva, Switzerland, has designated H. pylori as a class 1 carcinogen (cancer-causing agent). Class 1 status is reserved for the most dangerous carcinogens, most likely to be connected with the development of cancer in humans.
It is important to remember that H. pylori goes no deeper than the stomach’s viscous, pudding-like mucus layer. It never directly invades the epithelial cells that line the stomach. H. pylori damages the stomach’s lining by releasing irritating chemicals that, in turn, stimulate a human immune response. Infection-fighting white blood cells and antibodies are summoned from the bloodstream to the stomach lining, and it is this inflammatory reaction that creates the ulcer.
Martin Blaser of the Vanderbilt University School of Medicine in Nashville, Tennessee, theorizes that H. pylori’s provocation of inflammation is, in fact, the source of the bacteria’s nutrition. He suggests that the nitrogen-rich chemicals released when B lymphocytes (also called plasma cells) secrete antibodies become “food” for H. pylori. Blaser thinks that disease is an unfortunate of H. pylori’s interaction with stomach epithelial cells.
Blaser notes that although millions of people are infected with H. pylori, far fewer develop ulcers. Why this might be, and what it might mean for devising better medical therapy, remains to be answered.
Other questions also remain. How do humans initially become infected with H. pylori? How do the bacteria spread among us? Why are children in developing countries infected more often than children in developed countries? And what is the nature of the link between H. pylori and stomach cancer?
This last question, in particular, is drawing scientists' attention. They now theorize that H. pylori’s ability to cause long-term inflammation also causes changes in cells that, over decades, may result in cancer in some people.
The inner surface of human stomach tissue, seen in cross-section (left) and cut through its upwardly projecting villi (right) shows signs of inflammation, called gastritis. The bacterium H. pylori has caused the inflammation.
Wong-Ho Chow of the NIH’s National Cancer Institute is working with Blaser and other scientific colleagues around the country in an attempt to understand how H. pylori might cause stomach cancer.
Given what scientists know about H. pylori, should people be tested routinely for H. pylori infection, or be medically treated even if they have no symptoms? According to Blaser, the answer is no. The overall risk of developing gastric cancer remains relatively low in the population at large, and t here is, as yet, no evidence that treating people who have no symptoms of any sort has any long-term benefit.
The story of H. pylori–from verification of its existence only 16 years ago to current knowledge of the bacteria's ability to create ulcers and possibly cancer–is an exciting example of science at work. From the persistence of Marshall and Warren to the research at the NIH, scientists continue to piece together the puzzle of H. pylori’s ability to create ulcers and possibly cancer.
“And H. pylori isn’t the only kind of bacteria that survives in the human stomach,” says Blaser. “The more we learn, not only about H. pylori but about its cousins as well, the more we expand our ability to fight disease and build our basic scientific knowledge about the relationships between human and bacterial life.
Treating H. Pylori Infection
There are several techniques for confirming that a person is infected with H. pylori. The simplest is a blood test that detects antibodies against the bacteria. Most hospital and large health care organizations offer this testing. In private doctors’ offices and smaller clinics, special “breath tests” can measure increased levels of urease in an individual’s breath, which indicates the person is infected with H. pylori.
The current treatments for H. pylori infection include combinations of antibiotics, used after a doctor has verified the presence of an ulcer. A two-week course of antibiotic therapy, taken along with Pepto-Bismol, usually eradicates H. pylori infection. Pharmaceutical companies are now developing new medications that should be even more effective.
Barry Marshall: Persistance Paid Off
It was 1979. Robin Warren, a pathologist at the Royal Perth Hospital in Western Australia, was examining tissue samples from stomach biopsies under a microscope, and he noticed several areas of inflammation. In every case, he saw spiral-shaped bacteria close to the irritated areas, nestled just inside the stomach's thick mucus layer. Warren wondered how any bacteria could have survived their acidic voyage into the stomach, let alone slip into the mucus that coats the inner surface of the stomach.
Barry Marshall (left) and Martin Blaser (right) at the 1995 Lasker Awards ceremony.
With the aid of a young doctor named Barry Marshall, Warren tried to grow the bacteria on nutrient-coated culture dishes in the laboratory. They failed. Time after time, the researchers painted culture plates with a solution that contained the mystery bacteria, then left the dishes to incubate for two days. The result was always the same: no growth.
Then, in April 1982, Warren and Marshall left for the Easter holiday. When they returned to the lab after their five-day break, they were amazed to find thriving bacterial growth on the culture plates! Their problem had not been the culture process, but the length of time the bacteria needed to grow.
With this stroke of good luck, Warren and Marshall continued to investigate the bacteria, which belong to an entirely new genus, ultimately named Helicobacter (after its helical, or spiral, shape). They used the species name, pylori, because it refers to the region of the stomach near the pyloric valve, a common site for the development of ulcers. The pyloric valve opens from the stomach into the upper end of the intestine, known as the duodenum.
At this point in the research, Marshall had become convinced that H. pylori –as opposed to stress, acid, or aspirin overuse–was the cause of gastritis and probably of ulcers in most people.
In 1983, Marshall presented his hypothesis to an international meeting of distinguished specialists in infectious disease. Many of the scientists and physicians attending the meeting were shocked by the notion that bacteria cause gastritis and stomach ulcers. Marshall's ideas seemed to be the reckless notions of a scientific upstart. Attributing gastritis or ulcers to a bacterial infection seemed outlandish. Martin Blaser of Vanderbilt University School of Medicine in Nashville, Tennessee–a leading American researcher in infectious disease–called Marshall's ideas "preposterous."
Marshall, however, was certain he was on the right track. The results of his work with Warren were published in the respected British medical journal Lancet and research by other scientists supported the association between H. pylori and inflammation of the stomach lining. Most physicians, however, remained unconvinced.
The reluctance of his colleagues to accept the idea that H. pylori causes ulcers provoked Marshall to act. Intent on proving his point, he made himself the guinea pig. Marshall prepared a broth of active H. pylori and drank it.
"Those were frustrating times for me," Marshall recalled in a recent interview. "Most of the experts believed that the presence of H.pylori in those who turned up with ulcer problems was just a coincidence. I planned to give myself an ulcer, then treat myself, to prove that H. pylori can be a pathogen in normal people. I thought about it for a few weeks, then decided to just do it. Luckily, I only developed a temporary infection."
That "temporary infection" gave Marshall stomach pain, nausea, and vomiting–classic symptoms of gastritis or the early signs of an ulcer. While he was ill, he underwent an endoscopy, a procedure in which a doctor uses a flexible fiber-optic tube with a tiny video camera on the end to examine the inside of the digestive tract.
Within a week after ingesting the H. pylori, Marshall's stomach showed marked inflammation, with crowds of the distinctive spiral bacteria hovering around the areas of inflammation. Marshall became famous for this self-experimentation, and today researchers and doctors recognize H. pylori as the cause of more than 90 percent of ulcers worldwide. The U.S. Food and Drug Administration has approved several combinations of antibiotic drugs as therapy for active H. pylori infection.
Marshall, once scorned for what seemed to be a ridiculous idea, is now celebrated as a pioneer and a scientific visionary. Martin Blaser, who was initially skeptical about Marshall's hypothesis, has said that "science needs people with great vision, and Barry has vision." In 1995, Marshall received the Lasker Award, one of the highest honors in medical research.
"Rarely do the discoveries of a single individual change the lives of countless millions in the span of a decade," the Lasker Award committee wrote, "but the revolutionary research of Barry Marshall has accomplished just that. In so doing he has dispelled the darkness surrounding a chronic disease and lighted a pathway to a cure."
Barry Marshall's story tells much about the way innovative scientific work is often accomplished. Beginning with the difficulty of culturing H. pylori and the lucky accident of a five-day holiday break that allowed the bacteria to grow, the discovery and study of H. pylori has been pushed forward by intuition, intellectual courage, and serendipity. Moreover, Marshall demonstrated to his peers and to the world at large a powerful motivation to know the truth. He was willing to stand up to ridicule from other scientists and to infect himself with H. pylori in his quest to learn whether the bacterium causes infection and illness in human beings.
The biotechnology age has opened hundreds of new doors for young scientists," Marshall says. "If a testable hypothesis can be developed, then it's usually only a matter of the right steps to prove or disprove the hypothesis. The reward lies in major advances in how we diagnose and treat disease." Marshall is particularly excited about genetics research, a field of inquiry that he believes holds the promise of "understanding the true mechanisms of what are now mysterious disease processes. This is a very exciting time to be involved in medical science," he says.