GASTROENTEROLOGY 1997;113:543-549
How Does Helicobacter pylori Cause Mucosal Damage?
Its Effect on Acid and Gastrin Physiology
JOHN CALAM, ANITA GIBBONS, ZOE V. HEALEY, PHILIP BLISS, and NAILA AREBI
Department of Gastroenterology, Imperial College School of Medicine, Hammersmith Hospital, London, England
Helicobacter pylori infection increases gastric acid
secretion in patients with duodenal ulcers but dimin-
ishes acid output in patients with gastric cancer and
their relatives. Investigation of the basic mechanisms
may show how H. pylori causes different diseases in
different persons. Infection of the gastric antrum in-
creases gastrin release. Certain cytokines released in
H. pylori gastritis, such as tumor necrosis factor a and
specific products of H. pylori, such as ammonia,
release gastrin from G cells and might be responsible.
The infection also diminishes mucosal expression of
somatostatin. Exposure of canine 0 cells to tumor
necrosis factor a in vitro reproduces this effect. These
changes in gastrin and somatostatin increase acid
secretion and lead to duodenal ulceration. But the acid
response depends on the state of the gastric corpus
mucosa. The net effect of corpus gastritis is to de-
crease acid secretion. Specific products of H. pylori
inhibit parietal cells. Also, interleukin 113, which is
overexpressed in H. pylori gastritis, inhibits both pari-
etal cells and histamine release from enterochromaffin-
like cells. H. pylori also promotes gastric atrophy,
leading to loss of parietal cells. Factors such as a
high-salt diet and a lack of dietary antioxidants, which
also increase corpus gastritis and atrophy, may protect
against duodenal ulcers by decreasing acid output.
However, the resulting increase of intragastric pH may
predispose to gastric cancer by allowing other bacteria
to persist and produce carcinogens in the stomach.
B
efore Helicobacter pylori was discovered, thoughts on
the etiology and treatment of gastroduodenal disor-
ders were dominated by gastric acid. Now it is clear that
H. pylori plays a major causative role in gastric and
duodenal ulcers (DDs) as well as gastric cancer of the
intestinal type. Studies of gastric physiology in patients
are revealing complex interactions between the bacterium
and gastric acid that seem to predict the clinical outcome.
For example, among infected patients, acid secretion
tends to be high in patients with DDs but low in those
with gastric cancer and their close relatives. Therefore,
examining the mechanisms responsible for these various
changes in physiology should illuminate the pathways
that lead to the different clinical outcomes of this
infection.
Effects of H. pylori on Gastric
Endocrine and Exocrine Cells
The effects of H. pylori infection on the gastric
endocrine and exocrine cells that determine acid secretion
are described below. Some research is defining the effects
of the infection on gastric physiology and differences
between patients. Other studies are identifying factors
that reproduce these effects in model systems and might
therefore be responsible (Figure 1). Then we will need to
determine which of these determines the physiological
response of patients and the relationship to clinical
outcome.
Gastrin Cells
Gastrin pep tides I are released from G cells in the
gastric antrum and duodenum and act via the circulation
to stimulate acid secretion. They stimulate parietal cells
directly2 and by releasing histamine from adjacent entero-
chromaffin-like (ECl) cells. 3 H. pylori infection has been
found to consistently elevate plasma gastrin concentra-
tions. This occurs in the fasting state, after meals, and
during infusion of gastrin-releasing peptide (GRP).4-6
The excess of gastrin during stimulation with GRP4 or
food 7 is largely gastrin 17, which is the smaller of the
major forms of gastrin. This might be because this is the
predominant form in the gastric anttum where the
infection is most abundant. 8 Alternatively, H. pylori
might increase cleavage of gastrin 34 to produce gastrin
17. Eradication of H. pylori restores normal control of
gastrin release, including the inhibitory effect of cholecys-
tokinin (CCK).9 This reflex is believed to involve CCK-
stimulated release of somatostatin from D cells,lO
G cells may be affected by products of H. pylori itself or
Abbreviations used in this paper: DU, duodenal ulcer; Eel, entero-
chromaffin-like; GRP, gastrin-releasing peptide; IFN--y, interferon
gamma; Il, interleukin; MAO, maximal acid output; PAF, platelet-
activating factor; TNF, tumor necrosis factor.
© 1997 by the American Gastroenterological Association
0016-5085/97/$3.00
S44 CALAM ET AL.
Corpus
X H. pylori
o
o
o
Anlrum
ILS +
Figure 1. Diagram of gastric physiology and the effects of H. pylori.
Gastrin released from antral G cells (G) acts via the circulation to
stimulate ECl cells to release histamine, which stimulates parietal
cells (P) to secrete acid. These three types of cells are restrained by
somatostatin (SMS) released from local 0 cells (D). Products of H.
pylori stimulate G cells, inhibit parietal cells, and recruit inflamma-
tory cells by stimulating release of chemokines such as Il-8. Of the
cytokines released, TNF-a inhibits 0 cells and parietal cells but
stimulates G cells, whereas Il-1[3 inhibits Eel cells and parietal
cells. IFN--y and Il-8 both stimulate G cells to release gastrin. H.
pylori infection increases gastrin release and diminishes mucosal
somatostatin, but the net effect on acid secretion depends on
whether the patient has corpus gastritis, because this inhibits ECl
and parietal cell function.
by inflammatory factors released in the associated gastri-
tis. In terms of bacterial products, luminal acid inhibits
gastrin release; therefore, we have suggested that the
alkali generated by the urease of H. pylori may be
responsible. l l Measurements of the pH in the antral
mucous layer, however, only showed differences of 0.3-
O.S of a pH point between infected and uninfected
persons. 5 Ammonium ions from urease may also contrib-
ute, irrespective of any effect on pH. Lichtenberger et
al. 12 found that diets supplemented with ammonium
acetate elevated plasma gastrin concentrations in rats, but
the salt caused gastritis, which might have been involved.
The bacterium produces N-a-methylhistamine, 13 an ago-
nist of histamine H3 receptors, and another agonist of this
receptor released gastrin from preparations of antral
cells. 14
Inflammatory mediators released in H. pylori gastritis
may also be responsible for increasing gastrin release. The
infection increases mucosal expression of many cytokines
including interleukins (Il)-ll3, 6, and S, tumor necrosis
factor (TNF) a, interferon gamma (lFN--y), and platelet-
activating factor (PAF).15 Weigert et aP6 found that
TNF-a and Il-ll3 release gastrin from rabbit G cells. We
found that TNF-a and IFN--y release gastrin from canine
GASTROENTEROLOGY Vol. 113, No. 6
antral endocrine cells in primary cultureY TNF-a also
increased gastrin release from slices of human antral
biopsy specimens in organ culture. 18 Both TNF-a and
the presence of H. pylori infection attenuated the inhibi-
tory effect of CCK on gastrin release from biopsy slices.
This effect of CCK is probably mediated by release of
somatostatin lO ; therefore, these findings support the idea
that D-cell function is impaired. Another study showed
the importance of synergism between stimuli; H. pylori
sonicates did not release gastrin from canine antral cells
when given alone but strongly released gastrin from
Il-S-primed cells. 19 Interestingly, this response varied
between strains of H. pylori.
Somatostatin Cells
Somatostatin peptides 20 are released from D cells
and play a major inhibitory role within the gastric
mucosa. D cells present in both the antrum and corpus
mediate the major reflexes that inhibit gastrin release and
acid secretion, respectively.2o,21 Factors that stimulate D
cells include luminal acid,22 fasting,23 GRP,24 and certain
small intestinal peptides such as CCK.IO Expression of
somatostatin is diminished in H. pylori-infected mucosa.
Srudies show less somatostatin peptide,25-28 less somato-
statin messenger RNA (mRNA),27,29 and fewer D
cells. 29 ,30 This is important because a lack of somatostatin
could explain increased gastrin release and acid secretion
in infected subjects. More specifically, the lack of somato-
statin might explain the defective reflex inhibition of
gastric secretion in H. pylori infection (see below).
It is difficult to measure responses of gastric D cells in
patients because somatostatin is released in many organs
and acts locally. We found that 3-hour infusions of GRP
significantly elevated somatostatin mRNA content of
antral biopsy specimens from patients infected with
H. pylori, showing that the cells are at least capable of
responding. However, the amounts of somatostatin mRNA
after stimulation remained well below those present in
uninfected persons,31 The mechanism responsible for
diminished expression of somatostatin remains unclear,
but a recent srudy suggests that the cytokine TNF-a
might be involved. Incubation ofD cells with TNF-a for
24 hours resulted in a 40% diminurion in somatostatin
release in response to CCK. This was partly caused by a
decrease in intracellular somatostatin and partly by a
decrease in the percent of somatostatin released by
CCK.32
ECl Cells
Histamine is produced from histidine by histidine
decarboxylase in gastric ECl cells and perhaps also in
gastric mast cells. Histamine stimulates acid secretion via
December Supplement 1997
H2 receptors on parietal cells. Gastrin stimulates acid
secretion by stimulating Eel cells as well as by a direct
effect on parietal cells. 2 Mucosal concentrations of hista-
mine are diminished in H. pylori-induced gastritis,33
which probably reflects diminished synthesis because
mucosal levels of histidine decarboxylase are also dimin-
ished. 13
Prinz et aP4 recently reported that Il-ll3 first stimu-
lates, then profoundly inhibits histamine release from
Eel cells and postulated that this effect' might cause
suppression of Eel-cells in H. pylori-induced gastritis.
Stimulation of histamine H3 receptors on Eel cells also
inhibits histamine release 35 ; therefore, production of the
H3 agonist N-a-methylhistamine by H. pylori 13 might
contribute to suppression of these cells.
Parietal Cells
Of course the main interest in the preceding cell
types arises from their effects on parietal cells, which
secrete the acid. Emerging studies show that the net
effect of H. pylori infection on parietal cells varies from
time to time and from patient to patient (see below).
Increased circulating gastrin and diminished mucosal
expression of somatostatin tend to increase acid secretion.
Whether this occurs depends on factors that affect the
parietal cells themselves. The bacterium releases various
factors capable of inhibiting parietal cells. Huang et aP6
have identified two factors, one of which resembles
nigericin. The other is a dimer of 46-kilodalton subunits
that has been cloned. Beil et alY found that H. pylori
produces unusual fatty acids that can also inhibit parietal
cells. In addition, the cytokines TNF-a and Il-ll3, which
are released in H. pylori gastritis, inhibit parietal cell
function. 38 One feature of these results is that the
cytokines decrease the response of maximally stimulated
parietal cells, which may lead to acute changes in a
patient's maximal acid output. H. pylori is now recog-
nized to be a major cause of gastric atrophy,39 which is a
loss of specialized cells, including parietal cells, from the
gastric mucosa. Thus, the infection can decrease acid
secretion by changing gastric histology, independent of
the physiology of parietal cells. H. pylori products might
also stimulate parietal cells. For example, N-a-methylhis-
tamine, which is produced by H. pylori, is an agonist of
H2 receptors and stimulates acid secretion from parietal
cells as strongly as histamine itself. 4o H. pylori also
apparently produce PAF from its precursor lysoPAF,41
which is of interest because PAF stimulates parietal cells
in vitro. 42 Overall, however, clinical studies suggest that
the net effect of corpus gastritis is to inhibit acid
secretion.
H. PYLORI: EFFECTS ON ACID AND GASTRIN S45
Effects of H. pylori Infection
on Gastric Acid Secretion
The effects of H. pylori on acid secretion depend on
several variables. Differences between patients are impor-
tant; for example, H. pylori infection elevates acid secre-
tion in patients with DUs but decreases it in patients
with gastric cancer. The response also varies with time.
Acid diminishes on first infection, then returns. 43 Acid
secretion also depends on the physiological conditions at
the time of measurement. H. pylori had no effect on
meal-stimulated acid secretion when the intragastric pH
was high but elevated acid secretion when the intragastric
pH was low. 44
One way to disentangle the subject is to divide acid
secretion into maximal acid output (MAO) and the actual
rate of acid secretion. MAO reflects the rate of acid
secretion produced by maximal stimulation with agents
such as pentagastrin or histamine, whereas the actual rate
is determined by physiological control mechanisms under
the conditions of study, which will fall within the range
from zero to the MAO.
MAO
Low acid secretion. In infected persons without
ulcers, MAO tends to be normal or slightly dimin-
ished. 45 -48 MAO is markedly abnormal in certain groups
of patients. It is decreased in patients who develop gastric
cancer49 and greatly diminished for weeks or months after
first infection. 43 Gastric atrophy probably contributes to
diminished acid secretion in the former. The latter is
reversible, suggesting temporary suppression of parietal
cells by H. pylori products or inflammatory mediators.
Such factors may also contribute to the chronically low
acid secretion found in a minority of patients with
chronic gastritis. This is supported by normalization of
acid secretion in these subjects after eradication of
H. pylori. 5o
High acid secretion. Infected patients with DUs
tend to have an increased MAO and parietal cell mass.
Until recently, the increased MAO in these patients was
regarded as being more or less fixed because early studies
showed no change 1 month after eradication of H.
pylori. 51 ,52 However, two recent studies have shown that
MAO eventually decreases when H. pylori is eradicated
from patients with DU disease. 53 ,54 The mechanism of
this effect is currently unknown, but withdrawal of
stimulatory factors such as gastrin and N-a-methylhista-
mine could be involved. On the other hand, if it does take
6 or 12 months for MAO to decrease, a slower process
might be involved, such as withdrawal of a trophic effect
S46 CALAM ET AL.
of gastrin 55 or some other growth factor or cytokine on
parietal cells.
Physiological Control of Acid Secretion
H. pylori infection causes defects in the reflex
inhibition of acid secretion, which were previously
observed in patients with DU disease. This is probably
related to the paucity of mucosal somatostatin. We and
other investigators have observed a significant decrease in
basal acid secretion after eradication of H. pylori from
patients with DUs,56,57 consistent with the decrease in
plasma gastrin levels. The same change is not observed in
nonulcer patients. 58,59 It is possible that an improvement
in corpus gastritis led to an opposing increase in acid
secretion. We also found that H. pylori impairs inhibition
of peptone-stimulated acid secretion by a low intragastric
pH. The low pH suppressed acid secretion by more than
80% in uninfected persons but by less than 50% in
infected volunteers. 44 Acid secretion stimulated by neu-
tral peprone was similar in the infected and uninfected
groups, indicating that the abnormality lies in the
inhibitory pathway. Antral distention normally inhibits
pentagastrin-stimulated acid secretion, and this reflex is
also attenuated by H. pylori infection. 6o Infusions of GRP
may exert a mixture of stimulatory and inhibitory effects
on acid secretion. GRP directly activates G cells but also
indirectly stimulates D cells via gastrin release in the
gastric antrum and through neural reflexes in the gastric
corpus. 24 D cells may also be stimulated by small
intestinal hormones, such as CCK, which GRP also
releases. Acid secretion stimulated by GRP is elevated
about three times in H. pylori infection and about six
times in patients with DUs compared with uninfected
controls. 61 The more marked elevation of acid secretion in
patients with DUs may be a result of their greater parietal
cell mass. Elevated GRP-stimulated acid secretion disap-
pears slowly during the first year after successful eradica-
tion.
Effect on Duodenal pH
One important question relating to variations of
gastric pH is whether the changes produced by H. pylori
are sufficient to affect the pH in the duodenum. Hamlet
et al. 62 found that infected persons did indeed have a
lower intraduodenal pH during the second hour after
neutral and acidic meals than healthy controls. However,
this was at least partly due to rapid gastric emptying, as
well as greater acid secretion.
GASTROENTEROLOGY Vol. 113, No. 6
Different Reactions to the
Same Infection
It is unclear why the same infection produces
different patterns of acid secretion in different individu-
als. Several possibilities exist.
Bacterial strain. There is currently no evidence
to link any particular strain of bacteria to high or low acid
secretion. The presence of antibodies to the cagA protein
has been linked with mucosal atroph y63 and gastric
carcinoma,64 both of which are associated with low acid
secretion, and with DU disease,65 which is associated
with high acid secretion.
Effect of the distribution of gastritis on acid
secretion. It is possible that the distribution of gastritis
within the stomach determines acid secretion. Clinical
observations indicate that patients with DUs tend to
have gastritis restricted to the antrum 66 ; the predomi-
nant effect of H. pylori on acid secretion might be gastrin-
mediated stimulation. On the other hand, patients with
gastric cancer have a pangastritis67 ; their parietal cells
may therefore be mostly influenced by the inhibitory
effects of H. pylori ptoducts and inflammatory cytokines.
Effect of acid secretion on the distribution of
gastritis. Suppression of acid secretion with proton
pump inhibitors limits growth of H. pylori in the gas-
tric antrum, but it either has no effect or increases
colonization and gastritis in the gastric corpus. 68 There-
fore, one may envisage a vicious circle whereby low acid
secretion becomes self-perpetuating through low acid
secretion.
The development of gastric atrophy. H. pylori
infection favors the development of atrophy,39 and suppres-
sion of acid secretion with proton pump inhibitors seems
to accelerate this process. 69 Environmental factors associ-
ated with atrophy include a lack of antioxidant vita-
mins 70 and a high-salt diet. 71 In addition, we found
HLA-DQ5 to be overrepresented in infected patients
with atrophy.72
Eel cell density. It was recently reported that
patients with DUs who were all infected with H. pylori
had approximately three times as many ECL cells in their
gastric mucosa than either infected nonulcer or unin-
fected controls.?3 This raises the possibility that elevated
acid secretion in patients with DUs may be caused by
excessive histamine release from ECL cells in the gastric
mucosa.
Conclusions
Current evidence suggests that H. pylori infection
affects gastric endocrine and exocrine cells through direct
December Supplement 1997
effects of its products and through inflammatory media-
tors released in H. pylori-induced gastritis. The net effect
may be determined by aspects of the bacterium, the host,
and the environment. Interestingly, the resulting rates of
acid secretion correlate with the clinical outcome of
H. pylori infection. Therefore, knowledge of the processes
determining acid secretion may throw light on the
pathways that lead to the important clinical outcomes of
this common infection.
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Received June 30,1997. Accepted July 22,1997.
Address requests for reprints to: John Calam, M.D., Department of
Gastroenterology, Imperial College School of Medicine, Hammer-
smith Hospital, London W12 ONN, England. Fax: (44) 181-749-
3436; e-mail: jcalam@rpms.ac.uk.
The authors thank the following for funding: Astra Foundation (to
Z.V.H.), the British Digestive Foundation (to P.B.), and the
Wellcome Trust (to A.G.).