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Institute of Stomatology, 2Department of Clinical Physiology, , 3Department of Medicine,
Jagiellonian University Medical College, Cracow, Poland
Helicobacter pylori (H. pylori) is an important gastrointestinal pathogen associated
with gastritis as well as gastric or duodenal ulcers and gastric cancer. The oral cavity
has been considered as a potential reservoir for the gastric infection and reinfection.
The objective of our studies was to evaluate the influence of oral H. pylori for the
stomach infection and the release of gut hormones affecting food intake such as
ghrelin and gastric secretion such as gastrin. Additionally, the contribution of H.
pylori in the periodontal disease has been examined. H. pylori infection in stomach
was assessed by 13C- Urease Breath Test and presence of the bacteria in oral cavity by
culture. The periodontal status was measured by pockets depth with the periodontal
probe. We estimated the serum level of IgG anti-H. pylori, anti-VacA, anti-CagA,
ghrelin, gastrin, TNF-α and IL-8 in blood and the level of IgA anti-H. pylori in saliva.
The presence of H. pylori in oral cavity was detected in 54.1% of examined
individuals, whereas the H. pylori gastric infection in tested group was found in 51%
cases. However, the correlation analysis between those two groups of patients
involving together about 100 subjects showed that within the group of patients with
positive gastric H. pylori infection only 45.1% did not show the presence of H. pylori
in saliva and 43.1% showed no H. pylori in supragingival plaque. In line of these
findings patients who did not have gastric H. pylori infection, 53.2 % showed
presence of H. pylori in saliva and 42.9% in supragingival plaques. Serum level of
ghrelin and gastrin in subjects with oral H. pylori inoculation but without gastric H.
pylori infection were not significantly different from those without the presence of
this germ in oral cavity. In contrast, gastric H. pylori infection resulted in significant
reduction in serum ghrelin levels and significant elevation of gastrin as compared to
those who were gastric H. pylori negative. We concluded that oral H. pylori alone
does not seem to serve as bacterium sanctuary for gastric H. pylori infection and,
unlike gastric infection, it fails to affect serum levels of hormones stimulating
appetitive behaviour such as ghrelin and gastric acid secretion such as gastrin.
K e y w o r d s : Helicobacter pylori, oral cavity Helicobacter inocculaion, gastric infection,
gastrin, food intake
Helicobacter pylori (H. pylori) is a well-recognized pathogen associated
primarily with type B gastritis and peptic ulcers (1) usually associated with
dyspepsia and disorders of food intake (2, 3). It has been also designated as a type
I carcinogen, predisposing to gastric cancer or gastric mucosa associated
lymphoid tissue (MALT) lymphoma (4). The occurrence of H. pylori gastric
infection is high all over the world and reaches 80% and 40% in developing and
developed countries, respectively (5). Despite of numerous investigations, the
modes of its transmission in the population remains still unclear. It has been
shown that both oral-oral and fecal-oral transmission occurs in humans (6).
Humans appear to be the main reservoir of H. pylori in nature. Therefore, the
transfer of H. pylori between individuals via infected saliva or contaminated food
and eating devices appear to be the major routes of spreading of the bacteria (7,
8). Taking all these into account it could be reasonable to assume that the oral
cavity should plays a critical role in the process of H. pylori transmission and
infection in humans. However, the exact role of oral cavity in this transmission as
well as eating disorders remains under discussion and the subject of controversy.
It is likely that oral cavity may represent an important reservoir of H. pylori
infection for gastric infections and contributes to alteration in food intake and its
controlling mechanisms originating in the upper gastrointestinal tract (GI) due to
the activation of various oral receptors and afferent nerves signaling to the
feeding centers in hypothalamus involved in the control of food intake (9).
The contribution of H. pylori in the pathogenesis of periodontal disease,
recurrent aphthous stomatitis, glossitis, burning mouth syndrome and mucosa
lesions remains unclear. It is, however, possible, that H. pylori is transiently
present in oral cavity and leads to a disbalance of the residual flora of oral cavity.
Furthermore, there is the possibility that the bacteria is a part of normal oral
microenvironment and belongs to a normal bacteria-film that is not pathogenic
reservoir of H. pylori for the stomach, remaining in normal immunological
balance with the host or even protecting host against dangerous pathogens. In
addition, the numbers of H. pylori colonizing the oral cavity could be too small
to cause the gastric infection provided that the host immunity remains
appropriate. However, when host immunological defense becomes impaired,
bacteria’s role as commensal is changed and it becomes pathogen.
The occurrence of oral colonization by H. pylori, its relation to oral health and
food intake or dyspeptic symptoms as well as its relationships to gastric H. pylori
infection remain unclear. Accordingly, the objectives of the present study were to
evaluate the presence of H. pylori in the oral cavity and to investigate its
environmental niche. Additionally, we aimed to determine if the presence of H.
pylori in oral cavity is reflected in the change of the selected parameters of the
immune system including IgG anti-Hp, IgG anti-CagA, anti-VacA in blood and
IgA anti-H. pylori in saliva as well as plasma levels of cytokines like TNF-α, and
IL-8. We also decided to analyze the relationship between the occurrence of H.
pylori in the oral cavity and the presence of gingivitis and priodontitis in
examined individuals. Eventually, we investigated the prevalence of gastric H.
pylori in oral cavity of H. pylori positive and negative patients and the serum
levels of ghrelin (major appetite stimulating hormone) and gastrin (the major
gastric acid secretagogue) in all these subjects tested with confirmed by 13C-urea
breath test (UBT) to detect gastric H. pylori infection of accompanied by
dyspeptic symptoms and alterations in feeding behavior.
Study population
One hundred female subjects aged 20-52 (mean 41 ± 16 were included into a study. Detailed oral
clinical examination and collection of saliva (2 ml) and supragingival dental plaque samples, as well
as UBT and blood collection were performed. Study was approved by the Institutional Research Ethics
Committee of the Jagiellonian University and informed consent was obtained from all individuals
before the study. Patients who had taken antisecretory drugs or antibiotics, bismuth salts or
antisecretory agents within previous 2 months, were excluded from the study. Oral clinical parameters
including probing depth, bleeding on probing and clinical attachment level were collected by the same
investigator. Patients presenting ≤3 probing depth within at least four sites and exhibiting bleeding on
probing were diagnozed as gingivitis and the patients presenting ≥5 probing depth at least four teeth
and bleeding were allocated to periodontitis group. The rest of individuals were considered as healthy
oral cavity status subjects. The samples of the supragingival plaques were collected with a periodontal
curette from two different front teeth, or in the case of tooth loss, from premolars and molars.
Determination of H. pylori status in stomach
The infection of the stomach was estimated using UBT as described before (10). After obtaining 2
baseline breath samples for registering baseline 13CO2 /12CO2 level, gelatin capsule containing 38 mg of
13C-urea was swallowed with 25 ml of water by each subject. Then, breath samples were collected into
testing vials after 10 and 20 minutes following 13C-urea administration. Final results of 13CO2/ 12CO2
ratios were measured with the use of isotope ratio mass-spectometry (IRMS, Heliview, Medichems
Seoul, Korea) and were expressed as δ 13CO2 (per mil) values. A change of mean δ 13CO2 value over
baseline (DOB) after urea capsule administration, of more than 2.5 was considered as positive result.
Detection of oral H. pylori
The presence of H. pylori in the oral cavity was determined using microbiological culture. The
samples of saliva and supragingival dental plaque were obtained into sterile vials. Aliquots (100 µl)
of the samples were cultured on solid selective, enriched medium (H. pylori agar, Becton Dicinson)
containing 5% horse blood and incubated microaerophilically at 37°C for 5-7 days. Colonies were
confirmed as Helicobacter pylori by Gram staining to show the presence of gram-negative spiral
bacteria and by using the tests for bacterial urease, catalase and oxidase. The API-Campy test
(BioMerieux) was performed to confirm diagnosis.
Serological tests
Five ml of vein blood was obtained from each subject. The blood was centrifuged for 10 min at
2000g and serum was saved for the further investigation. To measure the level of anti-Hp IgG, we
used Captia TM H. pylori IgG (Trinity Biotech) test based on enzyme linked immunosorbent assay.
Levels of TNF-α, IL-8 were determined using EASIA test (Biosource) based on solid phase enzyme
amplified sensitivity immunoassay. We detected the presence of anti-CagA IgG and anti-VacA IgG
using MarDx H. pylori Marblot strip System. The level of gastrin and progastrin in serum was
studied by specific radioimmunoassay (RIA) described previously. Salivary anti-Hp IgA was
determined using ELISA kit (EIAGEN HP, Clone System) as described before (11). Levels of antiHp IgA> 1.0 OD were considered positive, based on previous population study (12, 13).
Patients were asked about their appetite behavior and dyspeptic symptoms such as upper
abdominal pain and discomfort in the abdomen that are considered as dyspeptic symptoms (14).
Statistical analysis
The data were expressed as means ± standard error of the mean (SEM). Statistical analysis was
performed using Student t or Tukey test after analysis of variance. A P value of less than 0.05 was
condired statistically significant.
H. pylori in the oral cavity
H. pylori was found in saliva in 54.1 % and in dental pockets in 48.3%
examined individuals. Simultaneously IgA anti-H. pylori IgA antibodies were
detectable at high levels in saliva of 84.5% indicating significantly higher
exposure to H. pylori (Fig. 1).
Environmental niche for H. pylori in the oral cavity
We also investigated, the relationships between environmental niches of H.
pylori and its presence was detected in the oral cavity, namely supragingival
plaques and saliva. H. pylori presence was detected in supragingival plaques in
70% of individuals who showed the H. pylori in saliva, while 69% of saliva of H.
pylori negative patients were negative in supragingival plaque too (Table 1).
These results indicate that these two environmental niches: saliva and dental
plaque are connected and H. pylori does not seem to have a preferential niche for
the oral cavity habituation. Moreover, we observed that H. pylori was present in
saliva in 63.7% of toothless subjects indicating that the presence of teeth and
gingival pockets are not critical for oral H. pylori colonization.
Age and oral H. pylori
As propensity to certain infections may be related to the age of patient, we
have analyzed the relationship between the occurrence of H. pylori in the oral
cavity in relation to subject’s age. Interestingly, no significant difference in age
was found in relation to oral H. pylori occurrence in oral cavity (Fig. 2).
Relationship of selected immunological parameters with oral H. pylori
The mean level of TNF-α was 27.3±30.7 pg/ml. Anti-Hp IgG and anti-CagA
IgG in plasma were elevated in 50.5% and in 20% of subjects, respectively. We
compared levels of anti-Hp IgG (plasma), TNF-α, IL-8 and presence of antiCagA, anti-VacA IgG in plasma and anti-Hp IgA in saliva between individuals
who showed presence of H. pylori in the oral cavity (namely who were positive
in saliva and/or dental plaque) with individuals who were Hp negative in culture
from oral cavity (Fig. 3). We did not observe any significant differences in
immunological parameters studied between these two groups.
Relationships between serum ghrelin and gastrin levels with and without oral
and gastric H. pylori
Serum ghrelin and gastrin levels were measured as indices of the association
of H. pylori in oral cavity and in the stomach with appetitive behaviour and
gastric secretion. The comparison of ghrelin and gastrin levels between H. pylori
inoculation of oral cavity or gastric H. pylori infection shows that patients with
the presence of H. pylori in the oral cavity but without gastric infection, showed
no statistically significant difference in serum hormones as compared to those
without gastric H. pylori infection (healthy controls) (Figs 4 and 5).
% of patients
Hp positive
Fig. 1. The comparison
between the presence of
H. pylori in saliva and
supragingival (sg) plaque
with amount of the patients
with elevated anti-H. pylori
IgA in saliva.
Fig. 2. The levels of the cytokines (TNF-α and IL8) in the patients with and without presence of
H. pylori in saliva (panel A) and with and without presence of this bacteria in supragingival (sg)
plaque (panel B). The immunoreactive status ratio (ISR) estimated from the levels of anti-H.pylori
IgA, IgA and CagA in saliva and material from supragingival plaque in oral cavity
H. pylori positive and negative patients.
Relationships between oral H. pylori and gastric infection
The presence of H. pylori in oral cavity was detected in 54.1% of examined
individuals, whereas the gastric H. pylori infection was found in 51% of these
cases. However, the correlation analysis between those two showed that within in
the group of patients with positive UBT (gastric infection) - 45.1% did not show
the presence of H. pylori in saliva and 43.1% showed no H. pylori in supragingival
plaque. In line with these findings patients, who did not have H. pylori gastric
infection (UBT negative) 53.2 % showed presence of H. pylori in saliva and 42.9%
in supragingival plaque. The overall X2 analysis showed no relationship between
oral and gastric H. pylori in studied group (X2= 0.029; p>0.05).
Relationships between oral H. pylori and appetitive behavior and dyspeptic
Among patients without and with H. pylori colonization of the oral cavity, the
appetite disorders and dyspeptic symptoms were similar and averaged about 25%
and 36%, respectively. In patients with gastric H. pylori infection the reduction or
loss of appetite and dyspeptic symptoms, mostly in the form of upper abdominal
H.p. (-)
Supragingival plaque
H.p. (-)
Fig. 3. The mean age of the
patients with and without H.
pylori (H.p.) in saliva (panel
A) and in supragingival
plaque (panel B).
pain or discomfort was recorded in 45% and 63%, respectively, and the
occurrence of these symptoms were found statistically significant in higher
number of patients as when significant higher number of patients compared to
those recorded in patients without gastric H. pylori infection, who showed the
alterations in appetite in about 30% and 31%, respectively (Fig. 6).
The results of this study revealed that H. pylori is relatively commonly present
in the oral cavity, although the character of this oral colonization remains unclear
and its relation to appetite behavior and dyspeptic symptoms is uncertain. Our
results indicate that the presence of H. pylori in oral cavity does not seem to be
significantly associated with either gastric infections or periodontal health status
or to serum levels of ghrelin and gastrin. In addition, the comparisons shows that
oral H. pylori does not seem to evoke significant changes in major inflammatory
Serum hormones
Ghrelin (pg/ml)
Gastrin (pmol/L)
300 10
Hp – positive
Hp – negative
Fig. 4. Serum ghrelin and
gastrin levels in patients
with and without the
presence of H. pylori (H.p.)
in oral cavity in patients
without gastric H. pylori
Serum hormones
Serum hormones
Ghrelin (pg/ml)
Gastrin (pmol/L)
Hp – positive
Hp – negative
Fig. 5. Serum ghrelin and
gastrin levels in patients
with and without gastric
H. pylori (H.p.) infection but
without the presence of the
bacteria in oral cavity.
Asterisk indicates significant
change as compared to the
levels recorded in patients
without gastric H. pylori
Effects of H. pylori
G- cells
A/X cells
Ghrelin in
gut and
dystributor pancreas
Local effects;
Blood flow
of H.p.
Food intake
Energy expenditure
Gastric blood flow
Gastric secretion
Fig. 6. Schematic presentation of H. pylori (H.p.) infection and its effects on serum gastrin and
ghrelin release. This infection enhances gastrin release while reduced ghrelin release and results in
appetite disorders and dyspeptic symptoms.
cytokine production or in specific antibodies directed against H. pylori proteins,
apart from salivary IgA. Moreover, much higher occurrence of the latter
antibodies than the presence of bacteria itself may suggest that H. pylori in the
oral cavity is transient, possibly dependent on other regulatory factors.
Numerous conflicting studies regarding oral localization of H. pylori have been
reported. Some authors showed that the occurrence of H. pylori is relatively low
and equals about 38% (15), while others find it in nearly 90% (16) or even in 100%
of subjects (17, 18). The major differences in study populations, sample collection
and laboratory procedure for bacteria detection between studies described above
make it difficult to compare results obtained in these studies. There are two main
methods currently accepted for the H. pylori detection in oral cavity that is culture
and PCR (19, 20), but each of them has disadvantages. Culture is not that sensitive
as PCR and H. pylori, because a microaerophilic bacteria, may not be able in some
cases to survive the sampling process before being transferred into the medium.
This could particularly refer to cases in which numbers of colonizing bacteria are
low. PCR detection in turn, although highly sensitive, could result in false positive
results. More importantly, PCR detects bacteria’s DNA, which is not a viable
organism but potentially just a part of dead bacteria genome. Finally, PCR allows
to detect very small numbers of bacteria which may have no significant influence
on oral cavity and stomach infection. Therefore, while accepting the limitations of
culture as a method for H. pylori identification, we assumed that it reflects the
presence of clinically relevant inoculation.
The major question which is related to the presence of H. pylori in the oral
cavity is whether this is a residual bacteria, composing part of biofilm of the oral
cavity, or whether it plays a pathogenic role. Some investigators suggested that H.
pylori can contribute to the etiology of recurrent aphthous stomatitis (21). Our
study was limited to analyzing the presence of periodontitis and gingivitis and did
not find an evidence linking H. pylori to either of these clinical conditions and
this is in keeping with Okuda et al. (22) who concluded that H. pylori has only a
transient presence in oral cavity.
Fritscher et al. (23) who examined 105 individuals with recurrent aphthous
stomatitis did not find significant difference in H. pylori PCR detection between
stomatitis and control groups. Some other authors postulated that H. pylori may
be important in atrophic glossitis or cancer lesions (22, 24). Despite, H. pylori
being found in a few samples, it was only a minority of the examined individuals.
These authors concluded that H. pylori does not contribute to lesions, but,
conversely, it is mucosal lesion that makes mucosa more prone for H. pylori
colonization (22, 24). The role of H. pylori in periodontal diseases and upper
gastrointestinal symptoms in gastrin and ghrelin release is still unclear. Some
authors show evident association of H. pylori presence in supra- and sub-gingival
plaques and periodontal disease (25-27), while others (28, 29), similarly to us,
were unable to confirm this relationship (30). Okuda et al. (22) discovered that
Porphyromonas gingivalis and Fusobacterium nucleatum, both periodontal
disease bacteria, are able to adhere to H. pylori bacteria and to trap them. It is
possible, that although H. pylori may not directly contribute to periodontal
disease, it may accompany the pathogenic bacteria causing periodontal diseases.
This could explain why H. pylori is often detected in periodontal disease patients.
Okuda et al. (22) established also that bacteria composing normal biofilm like
Streptococcus mutans and Prevotella intermedia, may produce bacteriocin-like
inhibitory protein, thus inhibiting growth of H. pylori strains. This fact supports
the idea that H. pylori occurs transiently in the oral cavity, because it could be
quickly removed by other bacteria within a biofilm (22). Moreover, it is possible,
that despite of H. pylori being directly harmless for gingival tissue, may also
contribute to periodontal disease indirectly. It has been found H. pylori antibody
that is cross-reactive with antibody of Campylobacter rectus. H. pylori stomach
infection can create complexes of antigen-antibody, which infiltrate gingival
tissue and initiates inflammation. We did not, however, find features of systemic
inflammation in relation to the presence of oral H. pylori.
According to our experience, the presence of H. pylori in oral cavity by itself
does not induce important appetite alteration or dyspeptic symptoms or
significant alterations in serum levels of ghrelin, representing a major, stomach
originating hormone responsible for the appetitive behavior or that of gastrin
known to act as the major gastric acid secretagogue. It seems reasonable to
conclude, therefore, that highly complicated hormonal mechanisms involved in
the control of appetitive behavior or gastric acid secretion may not be affected by
the merely presence of H. pylori in oral cavity.
Similarly, despite of the claim of some investigators that oral H. pylori is the
reservoir for stomach infection or reinfection, we did not find such a relationship in
the studied population. Almost the same number individuals with and without H.
pylori in oral cavity among those with gastric infection indicates that these bacteria
in oral cavity may not represent the sanctuary of this germ for the stomach. This is
confirmed by our finding that only about 53% of the patients, with confirmed by
UBT gastric H. pylori infection, revealed the presence of bacteria in the oral cavity
and these observations are consistent with findings of others (29, 30).
Our results appear to indicate that H. pylori could be as a transient microbe,
which comes in oral cavity with food and vanishes after some time depending on
some host factors as well as its interactions with the residual microflora of oral
biofilm (22). We showed in our study that H. pylori in saliva and dental plaque is
present in about 54% and 48%, respectively, while the elevation of IgA anti-Hp
in saliva was registered in 84,5% cases. This indicates, that significantly more
subjects have had contact with this bacterium in past and have eliminated it
without recent antibiotic treatment, as patients who received antibiotics during 2
months prior to the study were excluded. This could also, at least in part, explain
the fact of very varying occurrence of oral H. pylori in different studies.
On the other hand, it is possible that bacteria is constantly present in oral
cavity in a small numbers, and its detection depends on sensitivity of the used
method, reaching sufficient numbers to be detected by microbiological
techniques in relation to some changes of oral and general health. Additionally,
we did not notice the elevation of the markers of immunology defense like IgG
anti-H. pylori, TNF-α, IL-8 and presence of IgG anti-CagA, anti-VacA in
plasma. It would support the idea that oral bacterium is causing rathed
negbligible immune reaction in the host.
In summary; the presence of H. pylori in oral cavity seems to be transient and
it remains without causing any marked alterations in appetite and dyspeptic
symptoms or hormonal changes that appear to be associated with gastric H. pylori
infection. This does not exclude the possibility that the bacteria could still
contribute to oral mucosal lesions and periodontal disease. It appears that oral
cavity H. pylori in balanced immunological status of the host, may not be
sufficient to be a source of infection and reinfection for the stomach. However, in
changing environmental conditions, which would promote bacteria’s growth such
as immunodeficiency or disturbed oral biofilm balance, like in patients with
denture, the number of bacteria can increase and could possibly be sufficient for
gastric infection. These problems require further investigation in those groups of
patients. It seems obvious, however, that gastric H. pylori infection with chronic
active gastritis is accompanied by enhanced serum gastrin release possibly related
to the suppression of this germ of the D-cells and release of somatostatin (31, 32).
As oral cavity is equipped with myriad of various mechano- and
chemoreceptors playing crucial role in the short-term control of food intake,
further studies would be required to establish whether oral infection with more
toxic H. pylori expressing various cytotoxins (CagA or VagA), especially in the
mucosal area with histopathological changes and erosions could activate
afferent cephalic pathways causing alteration in the neuronal mechanisms
controlling of food intake.
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Author’s address: Prof. Stanislaw Konturek, M.D. Department of Physiology CMUJ, 31-531
Krakow, Grzegorzecka 16, Poland. E-mail: [email protected]