A challenge: nearly 20 per cent of all cancer deaths derive from infections. Those guilty include, among other organisms, Helicobacter pylori. As the German Society for Digestive and Metabolic Diseases (DGVS) reported at its annual meeting, six to ten per cent of all children are infected, the trend is a decreasing one. This is in and of itself good news, however four in ten adults over the age of 40 carry the bacteria inside them.
The bacteria are usually transmitted via the fecal-oral route at a young age and embed themselves in the stomach lining. Patients do not always notice this – many infections run their course silently. Only in every fifth case does a gastritis or a duodenal ulcer or ventricular ulcer occur. There exist diverse variants of the pathogen itself. Scientists are particularly interested in the CagA gene (cytotoxin-associated gene A). It encodes for a 120-145 kilodalton oncoprotein possessing a central role in the development of gastric carcinomas: H. pylori injects this protein directly into the parietal cells via special secretion. CagA binds to integrin receptors for translocation. Once in the cell, signal transduction is altered. Another point: whoever consumes a lot of salt not only intervenes in molecular processes of the gastric mucosa. Sodium chloride causes H. pylori to secrete more CagA. Receptors of the dangerous protein are interesting as a target for new drug agents. It seems – at least in vitro – that a short peptide fragment of 100 amino acids including the CagA-binding region is suitable as an inhibitor.
Welcome to the Community
So much for theory. Why some people become ill with gastritis and ulcers, but others remain asymptomatic despite still having the germ, is a scientific mystery. Other germs could be playing a central role here, suspects Karen M. Ottemann from the University of California. She treated mice using antibiotics, which changes the bacterial population in the stomach. After some time, among those microorganisms which increased were Clostridia. Ottemann compared possible responses to H. pylori and detected fewer CD4+ T-helper cells in the stomach wall than in the comparison groups. Her hope: probiotic stomach bacteria could perhaps make eradications superfluous, in order to not lose protective effects when it is not necessary. In animals, H. pylori protects, for example, against asthma. What’s more, the authors consider scrutiny of bacterial populations suitable for making predictions on the risk of gastric diseases.
Tons of stomach bacteria
That is part of the future, currently only diagnostics and pharmacotherapy remain as options. When a high-speed process is required in order to detect the germ, breath tests based on 13C-labeled urea have proven themselves for the task. H. pylori produces CO2 via urease132 – measurable in the breath via infrared spectroscopy or mass spectrometry. Also, stool tests, for detection of bacterial surface antigens, are on the market. In the instance of a positive finding, evidence is much in favour of an eradication – even without there being gastrointestinal symptoms. Proof: doctors in South Korea as part of screening programs have screened 5,000 subjects using breath tests and when required performed eradications. Within the observation period of eight years, they were able to decrease incidence of stomach cancer by 25 per cent. However, the eosophagitis rate increased slightly. From a health economics’ perspective, screening programs in this range are hardly feasible. Nevertheless, asymptomatic patients at risk should be examined before, for instance, undergoing a long-term treatment using nonsteroidal anti-inflammatory drugs.
Elimination with three-pronged or four-pronged attack
If H. pylori is detected, gastroenterologists treat patients using a triple therapy. In the “French triple”, pantoprazole, clarithromycin and amoxicillin come into use. The “Italian triple”, involving pantoprazole, clarithromycin and metronidazole remains an alternative. Clarithromycin-resistances are increasingly becoming a problem. Therefore gastroenterologists rely on quadruple therapy using a proton pump inhibitor, tetracycline, metronidazole and a bismuth salt. Bismuth, the old friend from earlier centuries, is bactericidal in the stomach and forms a protective film made up of hydroxides. Researchers have now compared the two strategies. Using the quadruple therapy, H. pylori was sucessfully eliminated in 80 per cent of cases. The triple therapy scored only with 55 per cent of the subjects. In regions with proven higher clarithromycin-resistance levels, physicians should therefore consider performing an immediate quadruple therapy, advises the updated Maastricht IV / Florence Consensus Report. In Germany bismuth plus Metronidazole plus Tetracycline (Pylera®) is available as a combination, omeprazole must in addition be prescribed.
Scoring with the treatment sequence
Revising the therapeutic regimen remains one alternative. Fellow researchers from Taiwan have dedicated themselves to this task. They assigned 900 patients with H. pylori into several randomised groups: participants in the S-10 group received five days lansoprazole plus amoxicillin followed by lansoprazole, clarithromycin plus metronidazole for another five days. In the S14 group, the period was extended to seven plus seven days. As part of the triple therapy (T-14) patients were given lansoprazole, amoxicillin plus clarithromycin over 14 days. The eradication rate differed from group to group: 91 per cent (S-14), 87 per cent (S-10) and 82 per cent (T-14). Thereby S-14 shows a statistically significant added value compared to the recognised triple therapy. The authors also dealt with questions of antibiotic resistance. S-14, S-10 and T-14 were all affected by clarithromycin resistances, with S-14 and S-10 metronidazole resistances playing a role. In Germany, the S3 guideline Helicobacter pylori and gastroduodenal peptic ulcer disease of the DGVS advises to first determine resistance after treatment failures. Doctors could however, according to the Taiwanese researchers, query whether patients had previously been taking macrolide antibiotics. In cases of frequent use, a quadruple therapy would be indicated, indeed as the first step.
Vaccine for the stomach
All medication strategies take effect only after an infection. Also, despite successful eradication, patients are not immune to being infected again. What could be more fitting than an immunisation? Despite years of research, this has until today not been a success. Our immune system is responsive to pathogens – but too weakly and ineffectively. Gene products such as γ-glutamyl and vacuolising cytotoxin (VacA) keep dendritic cells in check. Inflammations become chronic and the germ remains. One possibility with vaccines would be to directly approach Peyer’s patches (Folliculi lymphatici aggregati). These structures consist of up to 50 lymphoid follicles and are to be found throughout the digestive tract. Via the use of M-cells, they take up antigens such as superoxide dismutase and thiolperoxidase. Both enzymes are expressed by H. pylori and are essential in securing the bacteria’s survival.
Cholera toxin and the heat-labile enterotoxin from Escherichia coli have proven themselves in mouse models as mucosal adjuvants. These lead to severe diarrhoea in humans: a sign of failure. For this reason, researchers are now experimenting with ISCOMATRIX (an adjuvant from saponins), cholesterol as well as phospholipids. For scientists there is still much work ahead; triple and quadruple therapies will not disappear so soon in the clinic.