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Dig Dis 2011;29:592–599

DOI: 10.1159/000333260

Bacterial Load and Degree of Gastric


Mucosal Inflammation in Helicobacter
pylori Infection
M. Varbanova P. Malfertheiner
Department of Gastroenterology, Hepatology and Infectious Diseases, Otto von Guericke University,
Magdeburg, Germany

Key Words Introduction


Helicobacter pylori infection ⴢ Bacterial load ⴢ
13C-urease breath test Helicobacter pylori-infected individuals develop
chronic gastritis, and a proportion of these individuals
develop dyspeptic symptoms or severe clinical manifesta-
Abstract tions such as peptic ulcer, adenocarcinoma, and mucosa-
Helicobacter pylori induces an inflammatory immune re- associated lymphoid tissue lymphoma [1, 2]. The degree
sponse in the gastric mucosa. The degree of gastric mucosal of gastric mucosal inflammation as well as the topo-
inflammation and its topographic distribution are key factors graphic expression is a key for the diversity of H. pylori-
in the diversity of H. pylori-related complications. Here we related complications.
summarize substantial evidence reported in the literature H. pylori represents a potent immunogenic agent in
concerning the impact of H. pylori density on gastric inflam- the gastric mucosa. But are these effects dependent on
mation, the development of severe complications, and its re- bacterial load? To date, there is a paucity of methods for
lation to H. pylori suppression therapy. Most studies demon- bacterial density assessment. These include some indirect
strate a significant correlation between H. pylori density and semi-quantitative methods, e.g. histology, 13C-urease
the grade of acute and chronic inflammation, taking into ac- breath test (13C-UBT), and PCR, and the direct quantita-
count the limitations of each method for density assessment. tive bacterial density assessment by culture of H. pylori
Overall, high bacterial loads are associated with increased measured in colony-forming units (CFU). Results ob-
acute mucosal damage and long-term changes in the gastric tained by each of these methods will be discussed sepa-
mucosa. The influence of H. pylori density reduction on the rately in this review. This study aims at evaluating the
improvement of gastric mucosal changes was observed in density of H. pylori colonization per se as a significant
studies using ‘clearance’ therapies. Mucosal agents provoke determinant of the grade of inflammation in gastritis and
a significant, but not persistent, reduction in gastritis activity. associated lesions.
Treatments suppressing the density and virulence of H. py-
lori could become strategies to prevent H. pylori-associated
disease in the future. Copyright © 2011 S. Karger AG, Basel
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© 2011 S. Karger AG, Basel Prof. Dr. med. Peter Malfertheiner


0257–2753/11/0296–0592$38.00/0 Department of Gastroenterology, Hepatology and Infectious Diseases
Fax +41 61 306 12 34 Otto von Guericke University
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E-Mail karger@karger.ch Accessible online at: Leipziger Str. 44, DE–39120 Magdeburg (Germany)
www.karger.com www.karger.com/ddi Tel. +49 391 671 3100, E-Mail peter.malfertheiner @ med.ovgu.de
Table 1. H. pylori density measured in number of CFU and correlation with the grade of gastric inflammation

Reference n H. pylori Clinical manifestation of disease Correlation of H. pylori density with parameters of inflammation
strain
antrum corpus
PNC MNC PNC MNC

Khulusi et al. [3] 1995 110 undetermined gastritis (50%) and DU (50%) rs = 0.53 rs = 0.51 rs = 0.50 rs = 0.53
Atherton et al. [4] 1996 29 undetermined gastritis p < 0.01 p < 0.01 n.s. n.s.
Tummala et al. [5] 2007 19 undetermined gastritis r2 = 0.22 n.s. n.s. n.s.
Yamaoka et al. [7] 1999 100 CagA+ gastritis (50%) rs = 0.83 rs = 0.8 rs < 0.2 (n.s.) rs < 0.2 (n.s.)
DU (50%) rs = 0.67 rs = 0.79 rs < 0.2 (n.s.) rs < 0.2 (n.s.)
Dzierzanowska-Fangrat 41 CagA+ gastritis (76%) and peptic ulcer (24%) r = 0.27 (n.s.) r = 0.22 (n.s.) – –
et al. [8] 2002*

PNC = Polymorphonuclear cell infiltration; MNC = mononuclear cell infiltration; DU = duodenal ulcer; rs = Spearman’s rank correlation coefficient;
r2 = correlation coefficient (regression analysis); r = Pearson’s correlation coefficient. * This study was conducted in patients <18 years of age.

Number of CFU and Grade of Gastric Inflammation gastritis cases, H. pylori density was significantly higher
than in DU cases (5.7 vs. 4.3 ! 105 CFU/mg protein, p !
The first reports on the correlation of high bacteria 0.05), but did not correlate with either PNC or mono-
count with both activity and severity of inflammation ap- nuclear cell infiltration (MNC) in both gastritis and DU.
peared in the 1990s (table 1). Khulusi et al. [3] and Ather- Inadequate cellular inflammatory response in the cor-
ton et al. [4] showed that higher H. pylori density is asso- pus in cases of antral predominant gastritis have been
ciated with an increase of activity and severity of gastritis commonly observed and explained by host factors, espe-
in both the antrum and corpus. In addition, bacterial cially high acid secretion [10]. On the other hand, in both
load in the antrum of duodenal ulcer (DU) patients sig- the antrum and corpus, the relation between the number
nificantly exceeds that in non-DU gastritis, suggesting of CFU and IL-1␤ and IL-8 expression describes a dose-
that the grade of colonization may influence the clinical response curve [IL-1␤: PNC and MNC each p ! 0.0001
representation of disease. In a small study of 19 asymp- (antrum) and p ! 0.0005 (corpus); IL-8: PNC and MNC
tomatic H. pylori-infected volunteers, the number of CFU each p ! 0.0001 for antrum and corpus]. All cited authors
correlated significantly with polymorphonuclear cell in- also reported consistent results for H. pylori density
filtration (PNC) infiltration only in the greater curva- when determined by quantitative culture or histological
ture, although bacterial counts were surprisingly similar grading.
at all biopsy sites [5]. This discrepancy can be due to the
small sample size of the study and other variables such as
patient age and duration of infection, which are likely to Histological Determination of Bacterial Density and
modulate the severity of gastritis and bacterial density [6]. Grade of Gastric Inflammation
The number of H. pylori CFU also correlates with the
urease activity (Berthelot reaction) per biopsy, but not per The Sydney Classification established a standardized,
organism. international, and reproducible system for the histologi-
Other studies, which take bacterial virulence factors cal grading of gastritis and H. pylori density using an an-
into account, presented partially different results. CagA+ alogue visual scale [11–13]. PNC and MNC are assessed
H. pylori strains influenced the grade of inflammation separately indicating continuing acute inflammation and
depending on bacterial density in gastritis and DU pa- chronic inflammation, respectively. The density of in-
tients only in the antrum. However, H. pylori density was traepithelial neutrophils represents mucosal damage and
not directly related to the CagA status (CagA+ vs. CagA– is a sensitive predictor of the presence of H. pylori [14].
antrum: 5.1 vs. 5.2 ! 105 CFU/mg protein, p = 0.65; cor- Altogether, significant correlation between bacterial
pus 5.7 vs. 5.0 ! 105 CFU/mg protein, p = 0.22) [7–9]. count and PNC as well as MNC has been repeatedly ob-
Interestingly, they reported that in the corpus of CagA+ served in numerous studies from different continents
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Table 2. H. pylori density assessed by histology and correlation with the grade of gastric inflammation

Reference Country n Biopsy Correlation of H. pylori density with parameters of inflammation


sites
antrum corpus
PNC MNC PNC MNC

Stolte et al. [17] 1995 Germany 240 2 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001
Sepulveda et al. [18] 2002 USA 188 12 p < 0.01 – p < 0.01 –
Misra et al. [23] 2000 India 50 11 p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001
Yamamura et al. [16] 1999 Japan 81 2 rs = 0.61 rs = 0.57 rs = 0.61 rs = 0.57
Fareed et al. [29] 2000 Pakistan 150 3 rs = 0.54 rs = 0.17 (n.s.) rs = 0.64 rs = 0.245
Alam et al. [19] 1992 USA 903 1 p < 0.001 p < 0.001 – –

rs = Spearman’s rank correlation coefficient.

[15–22]. Table 2 shows an overview of several selected re- H. pylori Density Assessed by PCR and Grade of
ports. Inflammation
A comprehensive topographic study on H. pylori den-
sity distribution in 11 biopsy sites and associated inflam- After the nucleotide sequences of the H. pylori ge-
mation was conducted on 50 H. pylori-infected individ- nome were determined [61], a number of PCR techniques
uals with chronic gastritis in India [23]. The correlation were proposed for detection and quantification of H. py-
between the occurrence and grading of gastritis at the lori in gastric biopsies and other specimens [16, 30].
site of maximum density (proximal antral lesser curva- Compared to histology, quantitative PCR is generally
ture) was highly significant (r = 0.7096, p ! 0.0001). The equally (or more) sensitive, but has a poorer specificity.
minimum of both H. pylori density and inflammatory Different amplification targets as well as different PCR
changes was observed in the most distal part of the cor- methods (conventional PCR, real-time PCR, nested
pus at the greater curvature [23, 24]. A positive correla- PCR) hinder the analysis and comparability of PCR-
tion between high histological gastritis score and high based studies. Here we focus on some recent reports in-
density of H. pylori was also demonstrated in cases of vestigating the grade of gastritis assessed by histology
nodular gastritis in adults as well as in children, where with H. pylori density measured by quantitative PCR (ta-
this typical endoscopic representation of disease is more ble 3). Kobayashi et al. [31] showed a strong correlation
common [25, 26]. Marked CD4 (Th cell marker) and between histological grade of gastritis and H. pylori ge-
CD19 (B cell marker) positive inflammatory cell infiltra- nomes/pg of human DNA, and a sensitivity and specific-
tion is concomitant in cases with a high histological ity of 100% of a TaqMan PCR amplifying fragments of
grade of gastritis and high density of H. pylori, suggest- 16S ribosomal DNA. Molnar et al. [32] showed increased
ing predominance of a humoral type immune response H. pylori density (urease A target gene) in antral ero-
rather than a cytotoxic response. Significantly increased sions. Interestingly, they found similar bacterial density
IL-8, IL-10, IFN-␥, and MIP-1␣ levels confirm this ob- levels in gastritis and intestinal metaplasia with atrophy,
servation as these chemokines are known to promote whereas numerous histological observations stress the
migration of neutrophils and mononuclear cells, espe- lack of H. pylori colonization in this type of lesion. Such
cially activated CD4 cells, to the inflammatory focus. discrepancies raise the question of the clinical signifi-
Interestingly, the anti-inflammatory cytokine IL-10 is cance of H. pylori detection via PCR. The use of real-time
also found increased in gastric mucosal biopsies from H. PCR targeting the H. pylori SSA gene did not permit the
pylori-positive patients, indicating a dual role for H. py- demonstration of a significant correlation between num-
lori in induction and regulation of inflammatory reac- ber of copies and degree of gastritis [33]. Zsikla et al. [34]
tions [27–29]. also noted a lack of correlation between H. pylori DNA
molecules (urease C gene)/DNA equivalent of 105 cells
and inflammation score in biopsies of chronic gastritis.
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594 Dig Dis 2011;29:592–599 Varbanova/Malfertheiner


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Table 3. H. pylori density assessed by quantitative PVR and correlation with the grade of gastric inflammation

Reference n Target PCR Primer pairs Inflammation Correlation of


sequence marker H. pylori
density with
parameters of
inflammation

Kobayashi 72 16S ribosomal RNA TaqMan F 5ⴕ-CTCATTGCGAAGGCGACCT-3ⴕ histological grading p < 0.001
et al. [31] R 5ⴕ-TCTAATCCTGTTTGCTCCCCA-3ⴕ
2002 P 5ⴕ-ATTACTGACGCTGATTGC-3ⴕ
Molnar 53 urease A gene LightCycler F 5ⴕ-GCCAATGGTAAATTAGTT-3ⴕ erosive gastritis p < 0.01
et al. [32] R 5ⴕ-CTC CTT AAT TGT TTT TAC-3ⴕ
2008
Ladeira 108 26-kDa SSA gene real-time PCR F 5ⴕ-TGGCGTGTCTATTGACAGCGAGC-3ⴕ histological grading n.s.
et al. [33] R 5ⴕ-CCTGCTGGGCATACTTCACCAG-3ⴕ
2008 P not reported
Zsikla 126 urease C qPCR F 5ⴕ-GGATCTGGGCTTTGCTTTTG-3ⴕ histological grading n.s.
et al. [34] R 5ⴕ-CCCATGCACGATATTCCCTAAA-3ⴕ
2006 P 5ⴕ-Fam-TGGCGATGCGGATAGGCTAGTGGT-Tamra-3ⴕ

Interestingly, they also reported a weak insignificant High H. pylori Density in Complications of Gastritis
correlation of the cumulative grade of inflammation
with histologically assessed density. However, urease C High H. pylori density has been attributed to a clinical
gene PCR scored best in comparison with the other four representation of disease in the form of peptic ulcer [18].
mentioned primer pairs in terms of sensitivity and spec- In a group of 113 patients requiring surgical intervention
ificity, as well as positive predictive value (100%) and due to ulcer disease, bacterial load was found to be close-
negative predictive value (96%) [35]. ly associated with ulcer perforation, rather than with
hemorrhagic or stenotic ulceration [48]. Additionally,
heavy bacterial loads indicate an increased tendency and
13C-Urease Breath Test Result in Relation to H. pylori frequency of bleeding in preformed DUs, but do not pre-
Density and Grade of Inflammation dict the severity of a bleeding episode [49]. Hydrophobic-
ity of gastric mucus is reduced in DU patients as com-
The 13C-urease breath test (13C-UBT) is undoubtedly pared to gastritis cases, and is related to the density of
the most widely used noninvasive test for detection of H. pylori colonization [50]. It is interesting to note that
H. pylori infection in clinical practice and scientific tri- increased epithelial cell proliferation (measured by bro-
als. But the accuracy of 13C-UBT for assessment of bacte- modeoxyuridine and Ki-67 labeling) as well as an in-
rial load in the stomach is a matter of ongoing contro- creased apoptotic count of up to 17% of epithelial cells
versy, originating to a certain extent in the variety of ap- were found to be depending on H. pylori density in in-
plied protocols. A large number of studies have reported fected biopsy specimens [51, 52]. The correlation with
a significant correlation between delta 13CO2 excretion MNC in the examined specimen was stronger than with
and the histologically determined bacterial density [36– that of PNC, suggesting a possible link to gastric carcino-
43]. Additionally, some authors have shown a significant genesis.
correlation of 13C-UBT values with activity of gastritis
[37–40] and pepsinogen I/II ratio [40]. However, other
reports suggest that 13C-UBT is not an appropriate tool Mucosal Agents in the Relationship of H. pylori
for assessment of bacterial load [44–47]. Given the broad Suppression with Gastric Inflammation
variety of protocols and varying sensitivity and specific-
ity of the method, this discrepancy can be explained by Eradication of H. pylori leads to the disappearance of
the lack of comparability standards among the studies gastric mucosal inflammation and complete restoration
(table 4). of normal mucosa unless preneoplastic changes, i.e. atro-
phy and intestinal metaplasia, have already occurred [53].
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Inflammation in H. pylori Infection
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Table 4. H. pylori density assessed by 13C-UBT and correlation with H. pylori density and the grade of gastric inflammation

13
Reference n C-UBT Reference method Mean delta Correlation of Correlation of
protocol 13CO 13C-UBT value 13C-UBT values
2
with H. pylori with parameters
time cutoff
density of inflammation

Chen et al. [40] 2000 135 20 min 2.5‰ histology, serology 30.0822.44‰ p < 0.01 PNC, p < 0.01
Zagari et al. [37] 2005 192 30 min 5‰ histology, rapid urease test 32.0819.7‰ p < 0.05 PNC, p < 0.05
Chang et al. [38] 2003 100 30 min 4‰ histology 48.6827.5‰ p < 0.001 PNC, p < 0.001
Cho et al. [36] 2008 123 20 min 2‰ histology – rs = 0.674 n.s.
Perri et al. [42] 1998 172 30 min 3.3‰ histology, culture, serology – p < 0.001 erosions, p = 0.03*
Machado et al. [44] 2006 44 60 min 4‰ histology 29.1‰ n.s. n.s.
Logan et al. [45] 1991 50 40 min 4–5‰ histology, culture, serology – n.s. PNC, p < 0.001
MNC, p < 0.07
Auroux et al. [46] 1998 37 20 min – quantitative culture – n.s. –

rs = Spearman’s rank correlation coefficient. * Pearson’s ␹2 = 4.36.

Table 5. Effect of H. pylori suppression therapies on bacterial load and the grade of gastric inflammation

Reference n Substance Disease Duration H. pylori colonization Gastritis score


of therapy density decrease improvement

Banerjee et al. [59] 1996 11 sucralfate DU 4 weeks p < 0.01 n.s.


Barbara et al. [58] 1990 89 sucralfate vs. sulglycotide nonulcer dyspepsia 6 weeks n.s. p < 0.05 vs. p < 0.01
Berstad et al. [57] 1988 89 Alu-Mg antacid or pirenzepine nonulcer dyspepsia 4 weeks p < 0.001 or n.s. vs. n.s. increase p < 0.01 or n.s.
vs. placebo vs. n.s.
Wagner et al. [54] 1991 25 bismuth subsalicylate (BSS) nonulcer dyspepsia 4 weeks 50% vs. 38% clearance p < 0.001
vs. BSS + omeprazole
Miyake et al. [55] 2004 68 teprenone or H2-RA or sucralfate nonulcer dyspepsia 12 weeks p* = 0.035 or n.s. or n.s. p* = 0.009 or n.s. or n.s.
or peptic ulcer scars
Goh et al. [56] 1991 71 bismuth vs. placebo nonulcer dyspepsia 4 weeks 80% vs. 0 71.4% vs. n.s.

p* = Fisher’s projected least significant difference (PLSD) test.

The influence of H. pylori density reduction on improve- load reduction on sucralfate therapy which was not paral-
ment of gastric mucosal changes was observed with the leled by decreases in gastritis activity scores after 4 weeks
first therapeutic attempts. Substances like bismuth, su- of treatment in 11 DU patients. Berstad et al. [57] even
cralfate, antacids, and proton pump inhibitors were used demonstrated worsening of antral histopathological gas-
in various combinations or as monotherapies, leading in tritis scores and symptoms as compared with placebo,
most of the cases to a reduction of the bacterial load, despite a strong decrease in H. pylori colonization in 10
which resulted in a rapid and significant, but not persis- H. pylori-positive nonulcer dyspepsia patients after treat-
tent, reduction of gastritis activity [54–56]. Nevertheless, ment with antacids. Miyake et al. [55] accurately de-
some authors reported dissociation between H. pylori scribed the close relationship between H. pylori density
density and gastritis scores before and after treatment (ta- reduction and inflammation decrease after 3 months of
ble 5) [57–59]. Using a mucoprotective agent, Barbara et therapy with the mucoprotective drug teprenone. In fact,
al. [58] reported improvement of gastritis score despite teprenone was shown to have a strong effect on corpus
unchanged H. pylori density after therapy with sucral- gastritis with the concomitant reduction of H. pylori den-
fate. In contrast, Banerjee et al. [59] described H. pylori sity and neutrophil infiltration. None of the studies con-
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596 Dig Dis 2011;29:592–599 Varbanova/Malfertheiner


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sidered virulence and host-related factors which could density in the biopsy to enable growth after standardized
explain some of the contradicting findings. After H. py- tissue dilution, histological examination is restricted in
lori suppression therapy, in most cases the favorable ef- its accuracy by the patchy colonization pattern of the bac-
fects on gastric inflammation did not endure longer than terium, and PCR amplification lacks specificity and may
a few weeks after end-treatment [54]. This suggests an be too sensitive for clinical questions.
immediate beneficial effect of H. pylori suppressive agents The complexity of coexistent acute and ongoing
on gastric inflammation, but also an impermanent im- chronic immune response reflects the immunogenic and
pact after agents’ withdrawal. carcinogenic potential of a lifelong H. pylori infection.
Overall, high bacterial loads are associated with increased
acute mucosal damage and long-term changes in epithe-
Conclusion lial proliferation and mucus balance in the course of
adaptive reparative and defense mechanisms, leading to
Helicobacter pylori infection inevitably leads to a the development of complications of gastritis, i.e. peptic
chronic inflammation of gastric mucosa according to the ulcer disease, and preneoplastic conditions of gastric mu-
current clinical observations and pathophysiological cosa.
concepts. Here we summarized substantial evidence re- Eradication of H. pylori is certainly the most effective
ported in the literature on the impact of H. pylori density way to avoid H. pylori-related complications; neverthe-
on gastric inflammation, its implication on developing a less, with the loss of efficacy of eradication therapy [60]
severe complication, and its relation to eradication ther- and limitation to offer eradication therapy on a global
apy. We found a significant correlation between H. pylori level to the world population, the development of sub-
density and grade of inflammation whatever the method stances that suppress density and virulence of H. pylori
used to measure H. pylori load. Partially varying results could become instruments for other valuable strategies to
of correlation strength and significance can be explained prevent H. pylori-associated diseases in the future.
by other factors influencing the severity of gastric in-
flammation such as H. pylori strain-specific virulence
factors, host genetic factors, duration of infection, and
Disclosure Statement
subject age. Moreover, limitations of each method for
density assessment should be taken into account, i.e. The authors declare that no financial or other conflict of inter-
quantitative culture requires a minimum of colonization est exists in relation to the content of the article.

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