Comparison of culture and histological finding of
Abstract
Studies on gastric microbiota find several bacterial families and species in the stomach using molecular-based techniques. When biopsies are cultured, there may be growth of bacteria, pure culture of Helicobacter pylori, or no growth. When looking at the histological sections of corresponding biopsies no bacteria may be seen, except curved rods (H. pylori) adherent to the gastric epithelial cells. In a number of biopsies, several different bacteria are cultured with or without H. pylori. The non–H. pylori bacteria cultured are like the normal oral flora and may be contamination of the samples during endoscopy. In histological sections, these bacteria are seen above the mucin layer and not adherent to the epithelial cells confirming that it is contamination of the samples and can thus not be regarded as gastric microbiota. Therefore, the susceptibility of H. pylori to antibiotics is independent of coexisting bacterial flora. A review of H. pylori susceptibility to antibiotics in untreated and previous treated patients will be given including meta-analyses of H. pylori susceptibility to metronidazole (MTZ), clarithromycin, and levofloxacin. These data indicate that these antibiotics become more doubtful to use for primary therapy and should be banned for secondary therapy without susceptibility testing.
Keywords
- gastric microbiota
- H. pylori
- histology
- susceptibility testing
- resistant rates
1. Introduction
Microbiota and microbiome are not always clearly defined or distinguished. The human microbiota comprises the population of microbial species that live on or in the human body. This is the resident flora of the body and does not include the transient flora (sampling contamination, etc.). The microbiome is constituted by all the genes inside these microbial cells and is thus restricted to detection by molecular methods (sequencing, polymerase chain reactions [PCR]) [1].
By molecular methods, bacteria are usually identified to family and genera level [2]. Bacterial families and genera may include species and types of bacteria that may have completely opposite actions in the human body [3]. It is, therefore, doubtful if molecular methods alone are sensitive enough to predict the effect of the composition of microbiota. The limited original literature on gastric microbiota has mainly focused on gastric cancer and contains conflicting results [4, 5, 6, 7]. There are many difficulties in investigating the gastric microbiota. One thing many authors are not aware of is the difficulty of getting samples without contaminating bacterial flora (Figure 1) [8]. In animal models, the whole stomach can be removed, and contamination of the stomach can be avoided, but in most animal species, physiology, acidity, etc. of the stomach are very different from the human stomach. Samples from the human stomach are usually taken as biopsies during gastroscopy. Even though the endoscope and the forceps are sterilized or decontaminated, it will be contaminated with oral bacterial flora during gastroscopy and thereby will the samples be contaminated by oral flora mainly of the phyla
Bacterial resistance to antibiotics can occur either if the bacteria obtain plasmids containing resistance genes from other bacteria in the microbiota (conjugation); they can take up free DNA with resistance genes from the environment (transcription) or DNA can be transferred by bacteriophages (transduction). Furthermore, mutations can occur in the bacterial genome which may result in resistance if the mutation occurs in the part of the genome that codes for a structure on which the antibiotics act; this action may be interfered, and the bacteria becomes resistant to the antibiotic [10, 11, 12]. The conjugation of plasmids increases with the number of different bacteria in the microbiota and depends on a close contact between the bacteria. Uptake of free DNA does not demand a direct contact with other bacteria, but bacteria should probably be present in the close environment [3]. Mutations occur in all bacteria with a certain time because of natural replication errors [12]. Some bacteria mutate more often than others; but because of the short generation time for bacteria, each bacterial clone will have several mutations. If the mutation occurs in a part of the genome, which is target for the antibiotics, resistance to the antibiotic may occur.
2. Study on gastric microbiota
In a previous unpublished study that included 411 biopsies from patients undergoing upper gastrointestinal endoscopy were investigated both by microaerobic culture and by histology (Table 1). From 249 (60%) biopsies other bacteria than
No. of biopsies | Culture | Histology | ||
---|---|---|---|---|
Other bacteria | Other bacteria | |||
411 | 106 | 249 | 83 | 20 |
All known mechanisms for
Resistance to | Mutation |
---|---|
Amoxicillin | PBP1 |
Clarithromycin | InfB |
rp1V | |
A2142C | |
A2142G | |
A2143G | |
Metronidazole | rdxA |
frxA | |
fdxB | |
Fluoroquinolones | gyrA |
gyrB | |
Tetracycline | AGA925-967TTC |
Rifampicin | RNA polymerase subunit beta/beta |
3. Diagnosis of H. pylori
The detection of
Culture of
Histology is an invasive method which requires a least one antral biopsy and preferably two antral and two corpus biopsies. The biopsy is stained with hematoxylin and eosin, Giemsa, or silver staining.
Stool antigen test is another noninvasive method. It was first successfully described in 1997 using polyclonal antibodies [18]. Today monoclonal antibodies are used, and the sensitivity and the specificity are at the same levels as for UBT, but are preferred in special patients like children and patients with bleeding ulcers. This test can be done within ½ hour and is good for screening a patient for an infection with
The humoral antibody response to
Gastrin and pepsinogen are compounds produced in the stomach that depend on the changes in the gastric mucosa, and the serum levels of pepsinogens are a marker of atrophic gastritis [22]. This can be combined with the
Molecular methods have been of increasing interest in the field of microbiology and for detection of
4. H. pylori susceptibility to antibiotics
During the last decade, an increased number of
The susceptibility testing of
The dilution method is regarded to be the golden standard for susceptibility testing. A two-fold dilution row of the test antibiotic is made. A standard number of bacteria (McFarland 3) are added to each tube with antibiotics. The bacterial growth is inhibited by high concentrations of antibiotics. The first tube with bacterial growth is called the minimal inhibitory concentration (MIC).
The disk diffusion test requires a small tablet of an antibiotic. The tablet is placed on the agar plate and is incubated for 3 days. After 3 days, there will be a zone around the tablet with no growth of
The E-test is a stripe with a concentration gradient of an antibiotic. The stripe is placed on the agar plate and is incubated for 3 days. After 3 days, there will be a droplet shape around the stripe with no growth of
5. Treatment of H. pylori infection
Group | Preparation |
---|---|
Antibiotics | Amoxicillin |
Clarithromycin | |
Metronidazole | |
Tetracycline | |
Levofloxacin | |
Ciprofloxacin | |
Rifampicin | |
Nonantibiotics | PPI |
Bismuth nitrate | |
Bismuth citrate | |
Bismuth subsalicylate | |
H2 blocker |
PPI in standard doses do not have antibacterial effect on
6. Prevalence of H. pylori resistance to antibiotics
When analyzing different studies around the world, the primary resistance rate for
The high rate of metronidazole resistance seen in developing countries may be due to the high use of metronidazole for treatment of parasites and gynecological infections [62, 68]. It is therefore likely that the patients who are treated for
The high resistance rates for clarithromycin and levofloxacin in South America, Africa, and Asia can be due to the use of huge amounts of antibiotics in general [69]. Typically, the diagnostics are not precise, and the patients are treated with more a broad spectrum of antibiotics for a longer period. This can lead to a faster development of resistance in
A large multinational study tested
The prevalence of
6.1. Effect of antibiotic treatment on H. pylori resistance rates
International guidelines recommend first line of treatment of
The primary and secondary resistance rate for
The meta-analysis shows a high increasing resistance rate for all three antibiotics when the patient had been treated for
6.2. Vaccine
Another way to overcome
Appropriate bacterial antigens, safe and effective adjuvants, and a route of delivery are required for developing a vaccine. For the bacterial antigen, most studies use urease, but other antigens are investigated for example Cag L. The CagL is a protein essential for the pathogenesis of
The use of heat shock proteins in a vaccine introduced protective immunity without requiring the addition of an adjuvant. The protection, however, is not optimal because sterilizing immunity is not obtained, which is shown in a study from 2014 [77].
A derivate of the cholera toxin (CTA1-DD) and safe nontoxic mutants of
The routes of delivery that have been tested are sublingual, intranasal, respiratory, and oral [79]. A study on humans from China (2015) tested a vaccine based on a urease B subunit and heat-labile enterotoxin B subunit (gene derived from
7. Discussion
The human gastric microbiota may be difficult to estimate since samples for microbiome investigations often are contaminated with oral bacterial flora during gastroscopy. And the studies in these fields do not make any attempt to remove the oral contamination prior to sequencing. Histological examination of biopsies reveals
Thus, in noncancer patients,
An increasing resistance to antibiotics in
Due to the high resistant rates, it is necessary to perform a susceptibility test before starting the treatment. The advantages would be a better and maybe quicker eradication of the
When detecting
Due to the enormous amount of mutations leading to antibiotic resistant, the culture and susceptibility testing done by E-test is still the best and most economical way.
The increasing resistant rates to the most commonly used antibiotics raises the question of whether other antibiotics or combinations of antibiotic and nonantibiotic should be used for primary treatment of
8. Conclusion
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