Helicobacter pylori bacteria have inhabited the stomach mucosa of men, women, and children throughout the world since before the emergence of the human species from Africa. They are currently one of the most prevalent microorganisms of humans and are responsible for the majority of peptic ulcers and gastric cancer, yet they were not isolated until 1982 and their role in disease was not acknowledged until 12 years later after much dissention from the medical and scientific communities. In developing nations, most people are colonized with these bacteria before the age of 10 years, and 70% to 90% of the people are eventually infected. In developed countries, the rate of infection is much lower (20% to 50%) and increases with age. Colonization of children in developed countries (currently approximately 10%) is believed to have been more common several decades ago (40% to 60%) because infection rate has been linked to socioeconomic conditions—infection is higher among individuals living in larger families or crowded conditions, those raised in poorer or less hygienic conditions, smokers, and those who consume less fruit, and such conditions are less common in developed areas now than in the past. In developed nations, however, groups with higher incidence of infection persist, including Native Alaskans in the United States. Once infected, people usually remain infected throughout their lives unless treated or unless severe chronic gastritis occurs, killing the bacteria. H. pylori infection is classified as emerging not because of its actual entry into the human population but rather due to our relatively recent discovery of the link between these bacteria and a variety of gastroduodenal diseases.

In 1875 and 1889, spiral bacteria were discovered in gastric ulcers and gastric aspirations and a potential role in causing peptic ulcers was first postulated. These and other findings of similar bacteria in gastric mucosa of dogs, cats, and monkeys were largely ignored, however, until 1979 and 1982 when two Australian researchers began the lengthy process of altering long-held views concerning gastric disease. At that time, infection with the spiralbacteria was suggested to lead to gastric disorders by Robin Warren, and following up on this hypothesis, the bacteria were successfully cultured and isolated by Barry Marshall. The bacteria were initially named Campylobacter pyloridis but were reclassified as Helicobacter pylori in 1989. Although Marshall and Warren’s work presented strong evidence that the bacterial infection caused conditions such as chronic gastritis and peptic ulcers, the scientific community preemptively rejected their findings because they contradicted conventional knowledge that taught that ulcers were due to stress and dietary factors and urged bed rest and bland food for ulcer sufferers, treatment modalities that did nothing to prevent ulcer recurrence. The validity of their claims was eventually proved by human volunteers ingesting the spiral bacteria and subsequently contracting peptic ulcers that were later cured by the eradication of the bacteria. In 1994, Marshall and Warren’s claims were substantiated by the National Institutes of Health, and persons throughout the world suffering from peptic ulcers and chronic gastritis were able to be cured by a relatively quick and simple treatment regimen. The dedication of these scientists in the face of firm opposition by most physicians and researchers has improved the quality of many persons’ lives. In recognition of their efforts, Warren and Marshall received the Nobel Prize in Medicine or Physiology in 2005. Recently, additional members of the Helicobacter genus have been discovered in domestic animals. Several of these species also infect humans’ stomach, intestines, gallbladder, and blood and are associated with gastrointestinal diseases, leading to the suggestion that infection of animals may lead to zoonotic transmission to humans.

H. pylori infection was also found to cause cancers, such as distal gastric adenocarcinomas and gastric MALT lymphomas. Eradication of H. pylori in Alzheimer’s disease patients was also found in one study to lead to increased cognitive and functional status two years later. Infection has been suggested to play a causal role in a subset of individuals with autoimmune thrombocytopenic purpura as well because antibodies against the bacteria’s urease B protein are cross-reactive with a glycoprotein found on human platelets and inhibited the aggregation of these cells. Interestingly, the bacteria have also been postulated to play a protective role against the development of gastroesophageal reflux disease, Barrett esophagus, and adenocarcinoma of the lower esophagus.

Almost all persons infected by H. pylori develop chronic gastric inflammation; however, many never develop any corresponding symptoms. Other infected persons do suffer from one or more upper abdominal disorders.

Peptic Ulcer Disease

The origin of peptic ulcer disease has long been a matter of contention. Certain peptic ulcers are known to be caused by aspirin and other nonsteroidal anti-inflammatory drugs, excessive alcohol use, or other illnesses such as Crohn’s disease or Zollinger-Ellison syndrome. But the cause of approximately 80% of ulcers was unknown until it was discovered that H. pylori bacteria were almost always present in such ulcers. Eradication of the bacteria dramatically decreased the rate of ulcer recurrence, which had been greater than 30% in the first year in patients continuing acid-suppressive therapy without killing the bacteria.

Most people who are infected with H. pylori (90% of those in developed regions) do not develop peptic ulcers. Ulcers occur more readily in individuals infected by cagA+ strains of H. pylori and strains that produce more vacuolating cytotoxin (described in the discussion of the causative agent). Environmental and genetic factors also affect the chances that an infected person will develop an ulcer. These factors include cigarette smoking, having blood type O, and certain major histocompatibility class II antigens. Ulcer location may be a function of age of infection, for people living in developing regions where colonization generally occurs during childhood tend to produce gastric ulcers, whereas people living in developed regions where colonization occurs later in life have a higher prevalence of duodenal ulcers. Alterations in gastric acid production may lead to the production of duodenal gastric metaplasia, in which the duodenal epithelium cells assume a more gastriclike morphology, enhancing the ability of H. pylori to colonize this region. The presence of duodenal gastric metaplasia and infection with H. pylori is associated with increased risk of developing duodenal ulcers.

Gastric Cancer

Chronic inflammatory responses directed against H. pylori lead to long-term destruction of the normal gastric mucosal architecture (chronic gastritis) as the gastric glands that secrete “gastric juice” are lost and replaced by fibrotic and intestinal metaplastic cells differing in histological type (intestinal metaplasia). The gastric glands are responsible for the secretion of the digestive enzyme pepsin, hydrochloric acid, intrinsic factor (required for vitamin B12 absorption and red blood cell production), and the mucus that protects the mucosal cells lining the stomach from acid-related damage. Chronic gastritis and intestinal metaplasia increase the risk for gastric cancer by 5- to 90-fold, depending on their severity and the type of metaplasia. Individuals whose metaplastic cells are similar to colon epithelium have a higher risk than those whose cells are similar to small intestinal epithelium. People infected with H. pylori are most likely to develop the inflammatory conditions that cause gastric cancer, and infection with these bacteria is linked to cancer of the distal stomach. Because of the link between H. pylori infection and gastric cancer, the World Health Organization’s International Agency for Research on Cancer classified these bacteria as a class I carcinogen in 1994. As socioeconomic conditions have improved over the past six decades in developed countries, the rate of infection with H. pylori and the prevalence of gastric cancer have decreased from 30 cases per 100,000 persons per year to 5 cases per 100,000. Perhaps the decreasing incidence of H. pylori infection in developing countries will have a similarly positive effect on gastric cancer occurrence. As with peptic ulcers, cagA+ strains of bacteria cause more severe inflammation and are associated with a higher risk for developing gastric cancer.

Helicobacter pylori