Clinical Research Report

Journal of International Medical Research

2019, Vol. 47(2) 875–883
Effects of periodontal therapy ! The Author(s) 2019
Article reuse guidelines:
on eradication and recurrence [Link]/journals-permissions
DOI: 10.1177/0300060518816158
of Helicobacter pylori infection [Link]/home/imr

after successful treatment

Taweesak Tongtawee1,2,
Wareeporn Wattanawongdon1 and
Theeraya Simawaranon1

Abstract
Objectives: This study aimed to evaluate the effects of periodontal therapy on the efficacy of
Helicobacter pylori eradication and on the recurrence of infection after eradication.
Methods: We conducted a prospective randomized trial on 698 gastric H. pylori-infected
patients, of whom 347 received gastric H. pylori treatment alone and 342 received gastric
H. pylori treatment plus periodontal therapy. The presence of H. pylori and associated virulence
genes were detected by real-time polymerase chain reaction.
Results: After eradication of gastric H. pylori infection, the recurrence of gastric H. pylori was
significantly lower in the gastric H. pylori treatment plus periodontal therapy group than in the
group receiving gastric H. pylori treatment alone (OR 0.67; 95% CI 0.45 to 0.99), whereas the
eradication rate was not significantly different (OR 0.87; 95% CI 0.68 to 0.98). There was a close
relationship between the presence of H. pylori in saliva and its presence in the stomach.
Conclusions: The oral cavity is an important reservoir for gastric H. pylori infection. Adjunctive
periodontal therapy could enhance the efficiency of H. pylori treatment and reduce the recurrence
of gastric H. pylori infection.

Keywords
Periodontal therapy, gastric eradication, Helicobacter pylori, oral cavity, recurrent infection,
virulence, adjunctive therapy, gastrointestinal disease
Date received: 21 June 2018; accepted: 5 November 2018

Corresponding author:
1
Department of Surgery, Institute of Medicine, Suranaree Taweesak Tongtawee, Department of Surgery, Institute of
University of Technology, Nakhon Ratchasima, Thailand Medicine, Suranaree University of Technology, Nakhon
2
Suranaree University of Technology Hospital, Nakhon Ratchasima 30000, Thailand.
Ratchasima, Thailand Email: taweesak.t@[Link]

Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative
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permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is
attributed as specified on the SAGE and Open Access pages ([Link]
876 Journal of International Medical Research 47(2)

Introduction gastrointestinal diseases are not clear.

There is a high prevalence of H. pylori
Helicobacter pylori infection is an impor-
DNA in dental plaque and saliva; notably,
tant gastrointestinal disease associated
the oral cavity may constitute a reservoir
with the onset of gastritis, as well as gastric
for gastric infection and transmission.18–22
or duodenal ulcer disease and gastric
Therefore, failed H. pylori eradication may
cancer. Chronic gastritis-associated
be linked to the presence of oral H. pylori.
H. pylori infection has been found in
To determine whether eradication thera-
approximately 50% of the global popula-
py alone or eradication therapy plus peri-
tion and is etiologically linked to gastric
odontal therapy contribute to reduced
cancers, comprising 25% of cancers related
recurrence, it is necessary to identify factors
to this etiology of infection; therefore, it involved in the recurrence of H. pylori in
constitutes a primary public health prob- gastric mucosa. This study evaluated the
lem.1–4 In Thailand, the infection rate association between the presence of
ranges from 54.1% to 76.1%;5 however, H. pylori in saliva and its presence in the
the age-standardized incidence rate of gas- stomach, and investigated possible
tric cancer is relatively low in Asian coun- H. pylori treatment in Thailand. The find-
tries.6 The progression of disease depends ings of this study may improve treatment
on multiple factors, which contribute to efficacy and reduce the risk of H. pylori
the onset of associated gastric diseases.7 recurrence in this region.
Cytotoxin-associated antigen (cagA) and
vacuolating cytotoxin (vacA) are the major
virulence factors of H. pylori,8 and are most Patients and methods
closely associated with clinical outcomes of
H. pylori infection.9 The cag pathogenicity Patients and sampling
island (cag PAI) is a cluster of genes found Samples were obtained from patients
in strains exhibiting enhanced interactions diagnosed with H. pylori-associated gastric
with gastric tissue.9 This cluster encodes a diseases who underwent esophagogastro-
bacterial type IV secretion system that duodenoscopy (EGD) at Suranaree
translocates cagA into host gastric epithelial University of Technology Hospital in the
cells, and has been associated with the pro- northeast region of Thailand from March
duction of vacA, which causes cytoplasmic 2017 to December 2017. Full-mouth peri-
vacuolization in gastric epithelial cells;9,10 odontal examination was performed in all
moreover, it has been associated with cases. The plaque index (PI) score was clas-
delayed healing of gastric ulcers, inhibition sified as follows: 0 ¼ no plaque; 1 ¼ a film of
of re-epithelialization, and worsening of the plaque adheres to the gingival margin,
quality of mucosal scarring.11 H. pylori assessed by passing a probe across the
strains harboring cagA and vacA are more tooth surface; 2 ¼ moderate accumulation
frequent among patients with peptic ulcers, of plaque visible to the naked eye within
gastric mucosa-associated lymphoid tissue the gingival pocket, and/or at the gingival
(MALT) lymphoma, and gastric can- margin and tooth surface; and
cers.12–14 3 ¼ abundant accumulation (1- to 2-mm
Although standard triple therapy regimens thick) of plaque visible to the naked eye
achieve successful eradication in H. pylori- within the gingival pocket, and/or at the
positive gastritis patients, the recurrence gingival margin and tooth surface. The gin-
rate is relatively high (13%).16–18 Causes of gival index (GI) score was recorded as fol-
gastric H. pylori recurrence-associated lows: 0 ¼ normal gingiva; 1 ¼ mild
Tongtawee et al. 877

inflammation, slight change in color, slight professional tooth cleaning or any other
edema, and no bleeding on probing (BOP); periodontal treatment within the past
2 ¼ moderate inflammation, edema, redness 6 months. We recruited a total of 689
and glazing, and BOP present; and H. pylori-associated gastritis patients who
3 ¼ severe inflammation, marked redness underwent EGD at Suranaree University
and ulceration, spontaneous bleeding, and of Technology Hospital (Figure 1).
edema. Probing depth (PD) and relative Demographic and clinical data, including
attachment level (RAL) were measured at sex, age, oral health status (dental caries,
six locations per tooth (mesial, distal, lin- dental plaque, aphthous stomatitis, peri-
gual/palatal, and buccal/labial) using a odontitis, and dental caries þ periodontitis)
periodontal probe.23–25 After baseline were collected for the enrolled patients.
recording of clinical parameters, saliva Written informed consent was obtained
was collected into a polypropylene tube,
from all patients, and the study protocol
via the passive drool technique, until 2 mL
was approved by the Ethics Committee
of saliva was collected per patient; this
for Research Involving Human Subjects,
saliva (2 mL) was mixed with DNAgard
Suranaree University of Technology (EC
saliva stabilizer (1.5 mL; Biomatrica, San
13-2560) and Thai Clinical Trials Registry
Diego, CA, USA), in accordance with the
manufacturers’ instructions. After oral clin- (Study ID: TCTR20170324001). The meth-
ical examination in accordance with the ods were performed in accordance with the
World Health Organization criteria, the principles of good clinical practice and the
patients were subjected to esophagogastro- Declaration of Helsinki guidelines.
duodenoscopy (EGD), which was per-
formed using an upper GI video Study groups
endoscope (Olympus EVIS EXERA III, Six hundred eighty-nine H. pylori-associat-
CV-190). First, the whole stomach was ed gastritis patients were randomly divided
examined by conventional endoscopy; into two groups using a random number
then, biopsies were conducted using the generator from SPSS for Windows (ver-
site-specific biopsy technique.26 Gastric sion 16.0; SPSS Inc., Chicago, IL, USA)
biopsy specimens for histological determi-
(Figure 1). Among these patients, 347
nations were subsequently examined by
(168 female and 179 male; mean age of
the pathologist. Hematoxylin and eosin
46  2 years; range, 17–80 years) were
(H&E) and giemsa stains were used for
randomized to 1-week triple therapy
H. pylori identification. All samples were
(esomeprazole 20 mg twice per day,
stored at 20 C until further processing
by molecular methods. clarithromycin 500 mg twice per day, or
H. pylori-associated gastritis patients, as metronidazole 400 mg three times per day
determined by stool antigen, rapid urease (if clarithromycin-resistant), and amoxicil-
test, or histological examination, were lin 1000 mg twice per day (group 1)), and
included in the study. The exclusion criteria 342 patients (173 female and 169 male;
were as follows: treatment for H. pylori mean age of 49  3 years; range, 17–80
infection during the previous 2 months; years) were randomized to triple therapy
presence of metabolic disorders; immuno- plus periodontal therapy (group 2). There
suppression; use of antibiotics or gastroin- were no significant differences between
testinal medications, such as proton pomp group 1 and group 2 in terms of numbers
inhibitors, within the previous 2 months; of patients, age, sex, or periodon-
previous gastric surgery; and a history of tal diseases.
878 Journal of International Medical Research 47(2)

Patients enrolled and

randomized, n = 700

ITT analysis, n = 700

11 cases excluded:
2 wrong enrollment
6 follow-up losses
3 discontinued therapies
PP analysis, n = 689

Group 1, n = 347 Group 2, n = 342

Figure 1. Flow diagram showing numbers of patients enrolled and missed for per-protocol and intention-
to-treat analyses. ITT: intention-to-treat; PP: per-protocol; ATB: antibiotic. Group 1: ATB alone, group 2:
ATB plus periodontal therapy.

Follow-up statement following SRP to confirm the therapeu-

tic results.
Patient follow-up was scheduled 4 weeks
after the completion of therapy. Stool anti-
gen tests, rapid urease tests, and histopatho- DNA extraction
logical examinations were performed as per Genomic DNA was extracted from saliva
routine practice, with polymerase chain reac- and fresh frozen gastric biopsies using the
tion (PCR) for validation. Those who were QIAampVR DNA Microme Kit (Qiagen,
negative for H. pylori underwent further Duesseldorf, Germany) and QIamp DNA
examination after 1 year to establish the mini kit (Qiagen), respectively, in accor-
recurrence rate. Both invasive tests (gastric dance with the manufacturer’s protocol.
biopsy and PCR) and non-invasive tests The extracted DNA concentration and
(rapid urease test and histopathological purity were evaluated using a DS-11þ spec-
examination) were used for diagnosis of
trophotometer (Denovix, Wilmington, DE,
reinfection with H. pylori.
USA) and stored at 20 C.
Periodontal therapy
Real-time polymerase chain
Scaling and root planning (SRP) is the gold reaction (PCR)
standard in periodontal therapy. Treatment
included hand instrumentation of the teeth To determine the presence of H. pylori and
to remove dental plaque and calculus from its virulence genes, real-time PCR was per-
affected enamel and cementum, ultrasonic formed. DNA extracted from saliva and
scaling therapy, flossing, irrigation with gastric biopsies samples was used as tem-
0.12% chlorhexidine mouth rinse for 45 plate in the amplification reactions. Real-
seconds, and oral hygiene instruction.27 time PCR was performed in accordance
All patients were examined at 3 months with the manufacturer’s protocol in a final
Tongtawee et al. 879

Table 1. Primer sequences used for real-time polymerase chain reaction.

Gene Forward Reverse

0 0
CagA 5 -GAGTCATAATGGCATAGAACCTGAA-3 50 -TTGTGCAAGAAATTCCATGAAA-30
VacA 50 -CTCCAGAAGGCACACCAATAA-30 50 -TGGCTTCCACTTCCCCATTAA-30
UreA 50 -CGTGGCAAGCATGATCCAT-30 50 -GGGTATGCACGGTTACGAGTTT-30
16s 50 -GGAGTACGGTCGCAAGATTAAA-30 50 -CTAGCGGATTCTCTCAATGTCAA-30

volume of 20 ml, containing cDNA tem- Results

plate, 2X SYBR Green PCR Master Mix
(Roche Applied Science, Mannheim, Presence of H. pylori and virulence genes
Germany), and 5 pmol of each primer in saliva and stomach and their
using a LightCyclerVR 480 Instrument associations
(Roche Diagnostics, Neuilly sur Seine,
France). The PCR primers for 16s RNA, Two H. pylori-specific genes, the 16S rRNA
cagA, vacA, and ureA (Integrated DNA and ureA genes, were included for H. pylori
Technologies, Coralville, IA, USA) are detection; these genes were detected in all
shown in Table 1. The PCR conditions 689 (100%) gastric biopsy samples, and
were as follows: 95 C for 10 minutes, then were detected in 549/689 (79.7%) saliva
40 cycles of 95 C for 15 s and 60 C for samples. An association was observed
1 minute. All data were analyzed using between saliva H. pylori and gastric
LightCycler 480 software, version 1.5 biopsy H. pylori (p ¼ 0.007). Among the
(Roche Diagnostics). 549 H. pylori-positive cases, 231 were posi-
tive for the cagA gene (42%) and 223 were
Statistical analysis positive for the vacA gene (41%) in saliva.
On gastric biopsy, 605 H. pylori-positive
All statistical analyses were performed cases were positive for the cagA gene
using SPSS for Windows, version 16.0 (87.8%) and 532 cases were positive for
(SPSS Inc., Chicago, IL, USA). the vacA gene (77.2%). There were no sig-
Comparisons between groups were per- nificant associations between the virulence
formed using ANOVA for patient demo- genes of H. pylori in saliva and gastric
graphic data. Statistical significance of the biopsy samples.
correlations of the presence of H. pylori
between saliva and gastric biopsies was
evaluated using the v2 and Pearson’s corre-
H. pylori eradication
lation tests. The eradication rates of We subsequently examined the potential
H. pylori were evaluated by intention-to- therapy for gastric H. pylori eradication
treat (ITT) and per-protocol (PP) analysis. and its recurrence in patients with gastric
All patients were subjected to the ITT anal- H. pylori treatment alone and in those
ysis; however, patients with incorrect with gastric H. pylori treatment plus peri-
enrollment, or who were lost to follow-up, odontal therapy. We found that gastric
were subjected to PP analysis. The associa- H. pylori treatment plus periodontal thera-
tion between treatment with H. pylori py produced a significantly lower recur-
eradication therapy alone and H. pylori rence rate of H. pylori infection than
eradication therapy plus periodontal thera- did gastric H. pylori treatment alone (OR
py was analyzed using a logistic regression 0.69; 95% CI 0.52 to 0.99; p ¼ 0.001) by
model, with significance set at p < 0.05. PP analysis; however, the eradication rates
880 Journal of International Medical Research 47(2)

Table 2. Outcomes of treatment with triple therapy alone and treatment with triple therapy plus peri-
odontal therapy.

Treatment

Variable ATB alone ATB þ periodontal therapy OR (95% CI) p-value

ITT
Cure rate 304/350 (86.85) 331/350 (94.57) 0.87 (0.68–0.98) 0.076
Recurrence 53/350 (15.14) 7/350 (2) 0.67 (0.45–0.99) 0.001*
PP
Cure rate 304/347 (87.60) 331/342 (96.78) 0.77 (0.58–0.97) 0.078
Recurrence 53/347 (15.27) 7/342 (2.04) 0.69 (0.52–0.99) 0.001*
ATB: antibiotic OR: odds ratio; CI: confidence interval; ITT: intention-to-treat; PP: per-protocol.

were not significantly different (OR 0.77; promising approach for reducing the risk of
95% CI 0.58 to 0.97) (Table 2). ITT analy- recurrent H. pylori infection. Moreover, we
sis showed that the recurrence rates were observed a significant association between
significantly different between the groups H. pylori in saliva and gastric biopsy.
(OR 0.67; 95% CI 0.45 to 0.99; p ¼ 0.001), Avcu et al.31 found that the recurrence of
while the eradication rates were not signif- gastric H. pylori infection after triple thera-
icantly different (OR 0.87; 95% CI 0.68 to py was more frequent among patients with
0.98) (Table 2). poor oral hygiene than among patients with
good oral hygiene. Furthermore, Adler
et al.32 demonstrated that the oral cavity
Discussion
was an initial extra-gastric reservoir for
H. pylori infection has been associated with H. pylori; they found a strong relationship
chronic gastritis, peptic ulcers, gastric between H. pylori infections in the mouth
MALT lymphomas, and gastric adenocar- and stomach. This observation may explain
cinomas.28 Reported annual H. pylori the consistently high recurrence rates of
recurrence rates after eradication therapy H. pylori infection in the stomach. Several
in developed and developing countries studies have demonstrated that bacterial
were 2.67% and 13.00%, respectively;18 eradication in the oral cavity should be con-
notably, the organism has been observed sidered as an important aspect in the elim-
in various niches in the oral cavity, includ- ination of H. pylori-associated diseases,
ing the tongue, saliva, and dental because the oral cavity may serve as a
plaque.9,29 In Thailand, the reported potential reservoir.3,28,33–37 Our results
annual recurrence rate of H. pylori infection agree with these observations, in that,
after successful eradication was 2.9%.30 To after treatment for H pylori infection,
the best of our knowledge, this study is the patients treated with periodontal therapy
first to determine the effect of periodontal plus triple therapy had a significantly
therapy on gastric H. pylori eradication, as lower recurrence rate of H. pylori infection,
well as to evaluate the association between relative to the rate observed in patients who
the presence of H. pylori in saliva and in the received only triple therapy. There was no
stomach in Thailand. We found that peri- significant difference in the eradication
odontal therapy plus gastric H. pylori treat- rates between the groups. Nevertheless,
ment reduced the recurrence of gastric periodontal therapy plus triple therapy
H. pylori infections. This result suggests a appears to have a better effect on
Tongtawee et al. 881

H. pylori eradication. We suspect that peri- comprise the same strains. Therefore, geno-
odontal treatments may be useful adjuncts typing of H. pylori strains isolated from
to triple therapy for H. pylori eradication. stomach and saliva should be prioritized in
Some authors have proposed that no future research.
living H. pylori can be found in the oral Although our findings revealed an asso-
cavity and that the positive response on ciation between the presence of H. pylori in
PCR may therefore result from regurgita- saliva and that in the stomach, the complete
tion, vomiting, or reflux from the stomach; genomes of H. pylori strains in both sites
however, in the present study, we found should be sequenced, because this is the
H. pylori in the saliva and stomach of only method to assess genetic identity.
79.7% and 100% of enrolled patients, Furthermore, additional multicenter studies
respectively (p ¼ 0.007). We speculate that and large-scale randomized controlled trials
the oral cavity is a potential reservoir for
are required to provide a better representa-
H. pylori and may be the source of gastric
tion of the actual data and evaluate
infection (and re-infection) and bacterial
the hypothesis.
transmission. Currently, it remains unclear
whether H. pylori strains in the oral cavity
are the same strains that cause gastritis. Conclusions
Nevertheless, genotyping of H. pylori
strains isolated from the stomach and the To the best of our knowledge, this is the
oral cavity have demonstrated that strains first study to assess the prevalence of
from these two sites appear to be identical, saliva H. pylori strains in the northeast
although different strains are harbored by region of Thailand, where there is a high
different individuals.9,38 Additionally, some prevalence of H. pylori infection. An asso-
studies have shown 98% agreement ciation was observed between H. pylori in
between DNA sequences of H. pylori in saliva and in gastric biopsies, suggesting
the stomach and corresponding strains in that the oral cavity might constitute a res-
dental plaque or saliva,9 suggesting that at ervoir for gastric H. pylori infection and re-
least some individuals harbor the same infection. We further observed that
strain in both the stomach and the H. pylori eradication plus periodontal ther-
mouth.9,28 There have been many reports apy reduced the recurrence of gastric
that H. pylori strains carrying cagA and H. pylori infection in both PP and ITT anal-
vacA are closely associated with the incidence yses. Therefore, periodontal therapy should
of severe gastroduodenal diseases.12–14 be applied to reduce the risk of recurrence
Therefore, H. pylori strains in the oral of H. pylori re-infection-associated gastritis.
cavity that produce cagA and vacA may be
considered highly virulent. We observed a
high rate of detection of H. pylori cagA-pro- Declaration of conflicting interest
ducing virulent strains in saliva (42% posi- The authors declare that there is no conflict
tive), while 41% of strains produced vacA in of interest.
saliva. This finding suggests that salivary
H. pylori might be a risk factor for gastroin-
Funding
testinal reinfection. Interestingly, we
observed no significant association between This research was supported by a grant from
the virulence genes of H. pylori in saliva and Suranaree University of Technology and by the
those in gastric biopsy. It is possible that Office of the Higher Education Commission
H. pylori from two different places may under the NRU project of Thailand.
882 Journal of International Medical Research 47(2)

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