Running Head: Helicobacter Pylori: Pathogen Or Opportunist

Research in Allied Health 1

Running Head: Helicobacter pylori: Pathogen or Opportunist?

Helicobacter pylori: Pathogen or Opportunist?

Jessica R. Patterson

East Tennessee State University

December 1, 2005

Research in Allied Health
Abstract

H. pylori is often considered to play a pathogenic role in ulcers and other gastrointestinal problems. However, some studies support the theory that H. pylori is a member of the human flora that becomes opportunistic in some cases. Tests show that H. pylori is indigenous to the human stomach and can be traced back thousands of years. Furthermore, studies show that H. pylori may prevents oesophageal reflux and cancer. Tests also have been performed that suggest H. pylori may prevent diarrheagenic diseases in childhood. These findings provide evidence that the eradication of H. pylori may result in negative effects to the human population.

Introduction

An unknown bacteria was discovered in 1982 by Barry Marshall and Robin Warren. They received a Nobel prize for their discovery of the bacteria, which was later named Helicobacter pylori. The bacteria Helicobacter pylori were found to be small microaerophilic gram negative rods that habitually colonize the human stomach ( Passaro, Chosy, and Parsonnet, 2002). H. pylori is the only bacteria that colonizes the human stomach (Oliver, n.d.). While 80% of H. pylori live in the gastric mucus, some may attach to the epithelial cells of the gastric mucus by means of adherence pedestals. Also, the bacteria move in a corkscrew motion by multiple polar sheathed flagella which allow them to drill into the mucus layer of the stomach. H. pylori produces an enzyme, urease, that reduces host urea into ammonia and carbon dioxide. This allows the acidity of the human stomach to be neutralized so that H. pylori can inhabit it. In addition, the production of carbon dioxide allows for H .pylori testing by the means of a breath test (Passaro et al, 2002).

As a fairly new discovery, there is still much that is not known about H. pylori. A great deal of controversy exists concerning H. pylori’s role in the gastrointestinal system. It has been theorized that the bacteria causes dyspepsia and peptic ulcer disease, as well as other gastric complications. It is estimated that 50% of people in developed countries and 90% of people in developing countries are positive for H. pylori (Passaro et al, 2002). Therefore it has also been considered that perhaps H. pylori is a natural resident of the gastric flora that may be beneficial and simply behaves opportunistically in some members of the population.

Problem Statement

It is very important that H. pylori be further investigated. This bacteria is often eradicated as a treatment for peptic ulcers. However, the elimination of this bacteria could potentially have some serious drawbacks. This paper will attempt to evaluate and support the theory that Helicobacter pylori is member of the natural human flora that is beneficial but becomes opportunistic in some individuals.

Review of the Literature

There is now much evidence to support the theory H. pylori is a natural resident of the human stomach and has been there for thousands of years. One such study was performed on subjects from Venezuela. Tests were performed to support the hypothesis that H. pylori is an ancient inhabitant of humans. Strains of H. pylori are very diverse, and within all loci examined extensive polymorphism and multiple information sites are present and can be used to detect phylogenies (the evolutionary relationship among organisms). Particularly, genotypes associated with Europe and East Asia have been recognized. Three H. pylori loci that have previously shown to have phylographic affinity were analyzed for two populations of different ethnic origin from Venezuela. East Asian H. pylori genotypes were found for each of the loci in a group of Amerindian subjects from Amazonia, but were not found in a Mestizo group from Caracas. These results imply that Amerindians carried H. pylori when they migrated from Asia at least 11,000 years ago. This study exhibits evidence that H. pylori has been a resident of the human stomach for thousands of years while causing little disease to humans. Therefore it is plausible that colonization of H. pylori in the human stomach is of little harm and may even be beneficial (Ghose, Perez-Perez, Dominguez-Bello, Pride, Bravi, and Blaser, 2002).

Other studies have made similar claims. Blaser says that the investigation of non human primates has revealed indigenous gastric biota sometimes indistinguishable from H. pylori. In addition, studies of humans who have had little or no contact with modern civilization show positivity for H. pylori. H. pylori has been found in all human populations in which it has been tested for. Furthermore, H. pylori antigens have even been detected in the stools from South American mummies (1998). These claims all maintain the hypothesis that H. pylori is natural flora of the human stomach. If this is indeed the case, why is H. pylori associated with peptic ulcers and other diseases in some people?

Blaser claims that if H. pylori does cause problems in some individuals, it is not unlike other members of the human flora. For example, Candida albicans is resident in humans most of our lives but can cause illness during pregnancy, while on antibiotics or for diabetes mellitus patients. Another example is Bacteroides species, they are our most prevalent colonizers but can cause life-threatening infection if translocated to certain areas of the body. It is very conceivable that H. pylori also behaves this way and only causes disease in certain circumstances (1998) Arakawa, et al also claim that humans could not have existed with H. pylori as an enteric resident for over 5000 years with such a high positivity rate if the bacteria were truly harmful. They compare H. pylori to antibodies, certainly some patients are caused harm by H. pylori, however, antibodies are good for most people but in a few cases they attack the body, such as in autoimmune disorders. If antibodies were eradicated, most people would become ill and few would benefit. The same may be true for H. pylori, it may only cause problems in certain individuals(2000). Colonization of H. pylori in the human stomach results in chronic gastritis, infiltration of the lamina propria and epithelium with immunocytes and inflammatory cells. All people that are positive for H. pylori exhibit this, yet most of them are asymptomatic. Therefore, the presence of H. pylori is normal in those humans, and should not be considered a diseased state (Blaser, 1998). It is conceivable that H. pylori may be both pathogenic and symbiotic, which can be described as amphibiotic. In such a case, change could cause one characteristic to overcome the other (Blaser, 1998).

One pathogenic example of H. pylori is its link to ulcers and gastric cancer However, some studies show that H. pylori may not be a causative agent of gastric cancer. According to Passaro, et al, there are two types of H. pylori infection. Most people are infected only in the gastric antrum of the stomach. Such patients usually have high levels of gastrin in serum, increased acid output, susceptibility to duodenal ulcers and a decreased risk of gastric cancer. Some patients develop infections that include the body of the stomach in addition to the antrum. These patients are more likely to have decreased acid output, gastric ulcers and gastric cancer. This shows that H. pylori are more prevalent in duodenal ulcers than in gastric ulcers which are more closely associated with gastric cancer (2002). Passaro, et al, also state that 90% of patients with duodenal ulcers are infected with H. pylori and ulcer recurrence rates decrease from 95% to 12% after H. pylori eradication. Additionally, 50% to 80% of patients with gastric ulcers are infected with H. pylori. However this correlation is not strong because of the large number of medication related gastric ulcers (2002).

A study performed in 2000 also investigated the role of H. pylori in ulcers. According to a study performed at a Japanese hospital, idiopathic duodenal ulcers, ulcers not associated with either NSAIDs (non-steroidal anti-inflammatory drugs) or H. pylori, are rare and occur 0.3% to 1.4% of the time. Idiopathic gastric ulcers occur at a rate of 10%, which suggests that H. pylori has a closer relationship with duodenal ulcers than gastric ulcers. The low rate of H. pylori-negative gastric ulcers may be coincidental based on the high incidence of H. pylori infection in the Japanese population. After six months, 20% of duodenal ulcers recurred after successful eradication of H. pylori. The analysis showed 56% ulcer recurrence in H. pylori-positive patients, meaning 44% of H. pylori-positive patients maintained ulcer free. Therefore, 37% of the duodenal ulcers in H. pylori-positive patients may not have been H. pylori-caused. In a follow up study of symptomatic recurrence, ulcers recurred in 11% of patients who received H. pylori eradication therapy successfully, but did not occur in 44% of patients still positive for H. pylori. As a result, H. pylori non-causing duodenal ulcers existed in 28% of the patients. These studies excluded NSAID users, and indicate that H. pylori-non caused ulcers are common in non-NSAID users and in these cases H. pylori acted as an opportunistic. It is estimated that about 20%-40% of H. pylori-positive ulcers are H. pylori-non-causing ulcers. According to the study, H. pylori-negative ulcers are not increasing, but are just more evident due to eradication of H. pylori as a therapy (Arakawa, Higuchi, Fujiwara, Tominaga, Watanabe, Shiba and et al, 2000).

There has been a decline in peptic ulcer disease and gastric cancer and a rise in reflux oesophagitis, Barrett’s esophagus and oesophageal cancer in the 20th century in developed western countries (Ahmed, 2005) . This is thought to be partially due to a decline in H. pylori positivity as a result of improved hygiene and use of antibiotics (“Helicobacter pylori,” 2005). The presence of cagA+ H pylori strains reduce the acidity of the stomach, and it is believed that the increase in pH caused be H. pylori may prevent oesophageal reflux, Barrett’s esophagus and adenocarcinoma of the esophagus (Ahmed, 2005).

In reference to H. pylori’s possible beneficial role in humans, Barrett’s esophagus ( a lesion that preludes oesophageal cancer) is less common is people who are infected by H. pylori (Passaro, et al, 2002). A clinical study was performed on 105 reflux oesophagitis patients in Japan, 36 of which tested positive for H. pylori infection (34.3%). Recent reports have indicated that H. pylori infection and atrophy of the gastric corpus were lower in patients with reflux esophagitis than in the control subjects. This suggests that H. pylori infection may have protective effects against reflux oesophagitis by means of gastric hyposecretion. Therefore the intent of the study was to examine gastric acid secretion and H. pylori infection. Analysis of the H pylori infected subjects revealed less severity of gastritis and atrophy of the corpus with increased acid secretion in patients with reflux oesophagitis than in those without. Results of the study suggest that most Japanese patients with reflux oesophagitis are not positive for H. pylori infection and do not develop gastritis, atrophy of the gastric corpus of gastric hyposecretion. Conclusive to the study, H. pylori infection could be preventative to reflux oesophagitis due to gastric hyposecretion (Koike, Ohara, Sekine, Iijima, Abe, Kato, et al, 2001).

There have been other possible beneficial aspects of H. pylori studied as well. For example, Blaser claims that H. pylori positivity may reduce the susceptibility to lethal enteric childhood infections such as typhoid and other diseases. In such a case, the benefit of H. pylori in early life would outweigh the risk of disease later in life (1998). In consistency with Blaser’s hypothesis, it has been claimed that H. pylori positivity may have an inverse relationship with childhood diarrheagenic diseases. H. pylori-positive subjects were found to have more IgA-secreting cells in the gastric antrum and higher systemic IgA levels after oral vaccination for cholera than H. pylori-negative subjects. This suggests H. pylori may have a potential benefit against intestinal pathogens. H. pylori also may secrete antibacterial peptides which prevent colonization by other bacterial species These findings support the hypothesis that H. pylori may be protective against exogenous diarrheagenic pathogens. A study to test this hypothesis was performed on German school children. 12.3 % of the sample of 2477 were positive for H. pylori. 43% of the children were reported on a questionnaire submitted to the children’s parents to have had diarrhea within 3 months prior to the study. More H. pylori-positive children had “never” for frequency of diarrhea selected on their questionnaire than H. pylori-negative children. The study ultimately found an inverse relationship between H. pylori positivity and reported diarrhea. This study further supports the claim that H. pylori may be protective against diarrheageneal pathogens. In addition the study showed no association between H. pylori positivity and abdominal pain and vomiting (Rothenbacher, Blaser, Bode, and Brenner, 2000).

In addition to possible benefits of H. pylori colonization, there may be drawback to the eradication of H. pylori in the event that it is found to be a causative agent of ulcers. According to Arakawa, et al, H. pylori eradication treatment for ulcers can often have negative results. For example, resistant H. pylori organisms increase and reflux oesophagitis possibly increases in the case that H. pylori eradication fails. Additionally, studies have shown that H. pylori-positive NSAID users are at less risk for gastrointestinal bleeding that H. pylori-negative NSAID users and H. pylori-negative NSAID arthritis patients had more gastric mucous hemorrhages than H. pylori-positive patients. The reason for this is not known but it is thought to have some connection to the fact that concentrations of gastric mucosal prostaglandin E2 are higher in H. pylori-positive patients. Therefore eradication of H. pylori may lead to some unknown pitfall for humans possibly in the form of an increase in reflux esophagi is and oesophageal and fundic carcinomas (2002). Passaro, et al also claim that there is no indication that H. pylori eradication improves the symptoms of non-ulcer dyspepsia and gastro oesophageal reflux symptoms may even be intensified by H. pylori eradication therapy (2002).

Arakawa further ascertains that before we continue to eradicate H. pylori from the human stomach, several factors need to be studied to determine whether such an effort would be beneficial or harmful to the human population. The infected strains need to typed to identify virulence markers that influence disease-causing propensity. Also, genotyping for specific alleles will allow the detection of populations at high risk for malignancy. In addition the distribution of infection within the stomach and its relationship to host phenotype, age, nutrition, diet and other infections (2002).

Methods

A study formulated to investigate the role of H. pylori in ulcers alone could be conducted as follows. The study would be designed to show the measurements of H. pylori-positivity among subjects diagnosed with ulcers compared to subjects who are not. The study participates, 3000 randomly selected adults of mixed ethnicity and sex between the ages of 18 and 65 and determined to have ulcers by means of endoscopic examination would be selected from the University Physician’s Clinics. A control group of 3000 matched subjects not having been previously treated for ulcers, H. pylori infection or dyspepsia would also be selected. An informed consent would be obtained from all the participants after the complete study, along with the medical testing and written questionnaires that would be implemented, were approved by the University IRB. The IRB should not identify any possibility of psychological or physical harm to the patients when they review the methods and Scales of Measurement that would be implemented in the study. The study would follow HIPPA guidelines and patient confidentiality would be maintained throughout the study. The study would be non-experimental since H. pylori positivity or negativity would already be determined and there would be no treatment imposed upon the subjects they would be merely tested. The participants medical records would be obtained and the participants would be asked to fill out a written questionnaire composed of open ended questions in reference to the nature of their symptoms and medical history.

Based on the records and patient questionnaires, subjects exhibiting ulcers that had been previously treated with H. pylori eradication therapy or with NSAIDs would not be included. The remaining subjects would then be tested for H. pylori-positivity by serological and C-urea breath tests. These two groups would be further divided into H. pylori-positive and H. pylori-negative groups, resulting in four groups. Random selection was not performed in this study since it was non-experimental. Since randomization did not occur, descriptive statistics were used. The data would be non-parametric and the results of the H. pylori positivity testing would be categorized as interval data. Independent group t tests would then be used to analyze the resulting data. Since the selection was not random, it can be hard to infer what the study shows about the entire human population. If results show H. pylori negativity in a substantial number of patients exhibiting symptoms of ulcers or dyspepsia, and H. pylori positivity in a similar number of control subjects who were asymptomatic, this would support the hypothesis that H. pylori is not causative, only opportunistic and it resides in all or most humans.