Failure of understanding of anatomy and physiology
of the digestive system prevented any progress in gastroenterology for thousand
years of antiquity and medieval time, when major remedies for digestive problems
involved diverse prayers to gods, sacrifices and, at best, herbal medicine.
The
alpha and
omega of medicine were dogmas coined by ancient
Galen and Hippocrates, who believed that food in the digestive system undergoes
ordinary boiling before assimilation by the body. Modern gastroenterology started
with the discovery by W. Prout (1) in 1823 of the presence of inorganic hydrochloric
acid (HCl) in the stomach and with ingenious observations by W. Beaumont (2)
in 1822 of gastric secretory functions in Alexis St. Martin, a French Canadian
traveler, with the permanent post-shot-gastric fistula that served to Beaumont
as a precious “human guinea pig” for experimentation on gastric secretion. Since
then it became generally accepted that gastric HCl (and pepsin) secretion is
present in the stomach to contribute to food digestion as proposed for the first
time by Spallanzani (3). Further studies on animals and humans, confirmed that
gastric acid secretion is required for normal digestion and that it results
from the interplay of stimulatory and inhibitory influences on the gastric parietal
cells as suggested before by Beaumont (2).
Gastric acid secretion in healthy stomach and infected by Helicobacter pylori (H. pylori)
The first impressive basic research related to the physiology of gastric HCl
secretion originated at the end of 19
th and beginning
of 20
th century from the experiments performed
in St-Petersburg by I. P. Pavlov’s team on “sham-fed” dogs prepared with special
vagally innervated gastric pouches or gastric fistulas and with esophageal fistulas
(4). Pavlov demonstrated that gastric HCl secretion starts almost immediately
after presentation to hungry animal of appetizing food or feeding such animals
without allowing the food to enter the stomach (“sham-feeding”). Pavlov proposed
the concept of
nervism or entirely neural control of gastric secretion
(as well as salivary and pancreatic) and this raised wide interest including
Nobel Foundation at the Karoliska Institute, which offered financial support
for Pavlov (and closely collaborating with him Polish chemist M. Nencki) and
then awarded Pavlov first in gastroenterology Nobel Prize in 1904 (
Fig. 1).
|
Fig. 1.
Historical background of major discoveries in gastrology without and with
(stars) Nobel prize awards |
The importance of vagal nerves in sham-feeding induced secretion documented
by showing that vagotomy in dogs eliminated such neurally stimulated gastric
acid secretion and, later on, by L. Dragstedt (5), who pioneered in using
vagus
section in humans to treat acid-pepsin disorders in peptic ulcer. The K. Schwarz’s
(1910)
dictum “no acid no ulcer” initiated gastric resections to treat
peptic ulcer starting in 1881 with first gastrectomy carried out by Polish surgeon
from Chelmo, L. Rydygier, then professor of
Alma Mater Jagiellonica,
and almost concomitantly by Austrian surgeon from Vienna, T. Billroth. With
discovery by J.S. Edkins in 1906 of antral hormone, gastrin (6), confirmed about
half century later by isolation and synthesis of gastrin peptides (17-aminoacid
“little gastrin” and 34-aminoacid “big gastrin”) by R. Gregory and H. Tracy
(7), the novel neuro-hormonal concept of gastric secretory mechanism was formulated,
indicating that, in addition to vagal nerves, also gastric hormones are involved
in stimulation of gastric HCl secretion. The discovery in 1916 by L. Popielski,
Polish pharmacologist at the Lvov University, a former assistant of Pavlov and
fervent supporter of his
nervism, that histamine (8), a non-nervous factor,
produced the most powerful gastric acid stimulation opened an alternative, humoral,
concept of oxyntic cell stimulation and became an important contribution to
the development of gastric physiology, apparently depreciating the role of nerves
and hormones, but favoring histamine as natural gastric secretagogue, the concept
championed later on by C.F. Code (9). Further studies (10, 11) revealed that
vagal excitation by sham feeding increased not only gastric HCl secretion but
also enhanced release of gastrin (9,10) as well as histamine (12, 13), the former
being released, at least in part due to the activation of the neuronal gastrin-releasing
peptide (GRP), acting on the G-cells and the latter due to the excitation of
enterchromaffin-like (ECL)-cells situated in close vicinity of parietal cells
to stimulate in paracrine fashion histamine-2 receptors (H
2-R)
of parietal cells (
Fig. 2).
|
Fig. 2.
Interaction of gastrin, released from the G-cells, acetylcholine originating
from the cholinergic neurons of intramural plexus in gastric mucosa and
histamine released from the ECL-cells and acting on parietal cells via
H2-receptors. Somatostatin (SST), released
from the D cells, inhibits the ECL-cell and parietal cell activity, acting
via specific SSTR2 receptors (modified
from 36) |
It is of interest that
H. pylori infected
stomach contains unusual form of histamine such as N-alpha-methyl histamine,
produced by N-methyl transferase expressed in such
H. pylori-infected
stomach and being a potent stimulant of gastrin release from antral G-cells
(14), thus, there is a complex vagus-gastrin-histamine interaction, a self-stimulating
loop, acting in positive feedback mechanisms to stimulate gastric acid secretion,
particularly excessive in subjects with chronic
H. pylori infected antral
portion of the stomach. An important role in maintenance of the balance between
the release of gastrin from G-cells and histamine from ECL-cells is played by
somatostatin (SST), released from the D-cells, present in close vicinity of
the G-cells in antral mucosa to exert a tonic inhibitory influence on gastrin
release. Whenever the intraluminal; pH drops below 4.0, the H
+
ions activate the D-cells to release of somatostatin, that in turn reduces gastrin
release via SST receptors2 (SSTR2) on D-, ECL and parietal cells (15) (
Fig.
3).
|
Fig. 3.
Relation between the activity of vagal nerves and enteric cholinergic
and GRP-releasing neurons and gastrin released from the G-cells (A) in
intact and H. pylori infected mucosa. Meal and IV injection of
gastrin-releasing peptide (GRP) induces gastric acid secretion via
releasing gastrin and subsequent stimulation of the parietal cells to
secrete acid that in turn inhibits further release of antral hormone by
stimulating the D-cells and releasing somatostatin (SST). The latter peptide
inhibits gastrin release via SST receptors (SSTR2)
and thus attenuates gastric acid secretion (modified from 36) |
This complex mechanism controlling gastrin and histamine release involving
SST, normally released by D cells in close vicinity of G cells, effectively
prevents excessive histamine release and subsequently gastric acid secretion.
This mechanism is deeply impaired by
H. pylori infection, that suppresses
the D cell activity leading to hypergastrinemia and subsequently increases gastric
acid secretion observed in
H. pylori-infected patients with
antrum-predominant
gastritis.
H. pylori may, also act directly on the ECL-cells to release
histamine that increases the secretory activity of the parietal cells. When,
however,
H. pylori infection involves oxyntic gland area and so called
corpus-predominant gastritis develops, the bacteria acts directly on
the oxyntic cells to down-regulate the expression of the subunits of the proton
pumps or H
+/Na
+-ATPase,
resulting in hypochlorhydria characteristic for acute
H. pylori infection
and for chronic
corpus-predominant gastritis. The overall changes in
gastric secretory activity regarding gastrin–histamine–somatostatin interaction
on parietal cells in intact and
H. pylori-infected stomach are presented
on
Fig. 4. Thus, usual localization of
H. pylori infection in
gastric
antrum leads to gastric acid hypersecretion due to hypergastrinemia,
eventually resulting in duodenal ulcer, particularly when islets of gastric
metaplasia appear in the
duodenum, whereas
corpus-predominant
H. pylori infection, leading to atrophic gastritis, is accompanied by
low acid secretion and high plasma gastrin due to lack of normal acid-dependent
inhibition of the G-cells and stimulation of D-cells. Under such conditions,
the atrophic gastritis without or with intestinal metaplasia may develop and
the risk of gastric neoplasia becomes very high so such
H. pylori-infected
patients require periodical checking (gastroscopy and biopsy) to detect the
possible progression towards the cancerogenesis (
Fig. 5).
|
Fig.
4. Interrelationship between gastrin, histamine and somatostatin in
control of gastric acid secretion. Luminal acid directly inhibits the
G-cells and gastrin release but stimulates the D-cells to release somatostatin
which by paracrine pathway inhibits gastrin release from the G-cells and
indirectly reduces gastric acid secretion. The H. pylori infection
of antral mucosa increases gastrin release by acting on the G-cells through
Nalpha-methyl-histamine produced by infected
mucosa and increase the release of proinflammatory cytokines that stimulate
the G-cells to release gastrin and ECL-cells to release histamine, both
leading to increased gastric acid secretion. |
|
Fig. 5.
Chronic gastric Helicobacter pylori infection results either in
antral predominant gastritis with hypergastrinemia and hyperchlohydria
leading to duodenal or gastric peptic ulceration, while corpus predominant
H. pylori-induced atrophic gastritis leads to hypochlohydria and
increased gastrin release, resulting in the cancerogenesis. Most of infected
patients (~80%) show only mild mixed gastritis and normal gastric acid
secretion without significant gastric diseases (modified from 36). |
Pharmacological control of gastric acid secretion and ulcer healing
One of the first agents used in the pharmacotherapy of gastritis and peptic
ulcers were extracts of
Atropa belladonna, which eventually resulted
in the isolation at the end of 19
th century of
active principle, atropine. The extracts of
belladonna and atropine are
known to inhibit gastric acid secretion, especially when induced by vagal stimulation
(4, 15) but, unfortunately it is accompanied by unpleasant side-effects such
as dry mouth, blurred vision or bladder dysfunction. Novel highly specific muscarinic
M
1-receptor antagonists (M
1-RA)
such as pirenzepine and telenzepine became available for treatment of acid-pepsin
disorders but their clinical usefulness was later found rather limited, particularly
that the target parietal cells are equipped with M
3-R,
rather than M
1-R and that they fail to affect
histamine-induced gastric acid secretion. Pharmacological studies initiated
by J.W. Black
et al. (16), who modulating chemically the structure of
histamine, succeeded in development of specific H
2R
antagonists, which were found to cause not only potent and side-effect free
gastric acid inhibition, but also to be effective in acceleration of ulcer healing
that brought to their inventor, Black, a second Nobel prize in gastrology within
last century. It should be noticed that Black’s pioneering studies were carried
on the assumption, originally proposed by L. Popielski (8, 9) that histamine
plays a key role in gastric acid secretory mechanism, the concept that was challenged
by Johnson’s (17), stating in 1971, few month before synthesis of H
2-R
antagonists that there is “no room for histamine” in gastric secretory mechanisms,
presumably because of ubiquity of this amine in various organs of the body and
failure of inhibiting gastric secretion by suppressing histidine decarboxylase
(HDC) activity in rats. Interestingly, these new agents, H
2-R
antagonists, such as burimamide, metiamide and then cimetidine or ranitidine,
were found to inhibit gastric secretion not only induced by histamine, but also
by other stimulants of parietal cells including ordinary meal and even vagal
excitation (17, 18). These results were initially explained by the interaction
of H
2R with others such as M
3-R
and gastrinic (CCK
2-R) receptors at the oxyntic
cell membrane and this was supported, at least in part, by
in vitro studies
on isolated oxyntic cells by Lloyd and Soll (19). The discovery of H
2-R
and their specific antagonists should be considered as the major breakthrough
in the physiology of gastric secretion, reinforcing previous Popielski’s and
Code’s assumption concerning significant role of histamine in the regulation
of gastric secretion as the “final common chemostimulator” of oxyntic cells
(9,17) (see
Fig. 4). More recent achievements in pharmacological research
led to discovery by G. Sachs and his associates (20) of Na
+/K
+-ATPase
(proton pump) existing in inactive form in cytoplasmic tubulo-vesicles that
following excitation of oxyntic cells and an increase of intracellular mediators
such as cyclic AMP (histamine) or Ca
2+ ions (acetylcholine
or gastrin) and subsequent increase in protein kinase activity, are incorporated
into the membrane of intracellular cannaliculi of oxyntic cells resulting in
the stimulation of gastric acid secretion. The discovery of specific proton
pump inhibitors (PPI), such as omeprazole, polprazole, lanzoprazole, pantoprazole,
esoprazole and others that were found to be the most powerful inhibitors of
gastric acid secretion, acting independently of the mode of oxyntic cell stimulation
and clinically extremely useful in controlling of gastric acid secretion due
to higher gastric acid inhibitory efficacy than that of H
2-R
antagonists (20-22). Moreover, their biological (gastric inhibitory) half life
was found to be remarkable longer, ranging from 14 h for lanzoprazole to 46
h for pantoprazole, when compared to that for histamine H
2-R
antagonists. These discoveries apparently undermined, at least from practical
point of view, the significance of both vagal nerves, as well as gastrin in
the in the concepts of the gastric secretory stimulation (
Fig. 5).
Secretion of gastric acid, constituting major “parietal” component of gastric juice (17) results from the interaction of numerous stimulatory and inhibitory neuro-hormonal factors, acting on parietal cells after ingestion of food. It should be mentioned at this point that already A. Vesalius in 1543 (23) identified the unusually “wandering” (vagal) nerves among various intra-abdominal structures. The question was then raised what functions could be attributed to these “wandering” nerves in gastric secretion and food digestion. Pavlov (4) showed experimentally that vagally stimulated gastric acid secretion induced by e.g. sham feeding (cephalic phase) or provoked by ordinary feeding can be, at least in part, reduced by vagotomy introduced later on into clinical practice by Dragstedt (5). With the use of microscopy, it was demonstrated that the gastric glands comprise the parietal (oxyntic – acid producing) as well as peptic (pepsinogen producing) cells. R. Heidenhain (24) of Breslav University, characterized a “third” type of cells, which adhere to the external surface of epithelial cells, later identified as ECL-cells and found to express the histidine decarboxylase (HDC), the important enzyme responsible for the biosynthesis in the oxyntic mucosa of histamine, the major stimulus of parietal cells. Naturally, in addition to vagus and histamine, gastrin was considered as major player in the mechanism of gastric acid secretion.
All the above mentioned gastric secretagogues stimulate “parietal” component of gastric juice secreted by parietal cells, which are exposed to extremely high acid concentration, reaching within intracellular cannaliculi, about 170 mmol/L. The possible cell damage by this highly concentrated acid is prevented by locally released prostaglandins (PG) released due to constitutively expressed COX-2 in these cells (25). Non-parietal secretion originating from other than parietal cells of gastric mucosa contributes to the mucus-alkaline secretion, protecting surface epithelium that appears to be mediated by COX-1-PG system existing in normal mucosa to exert gastroprotection and to maintain mucosal integrity (25-32).
The role of H. pylori infection in the development of gastro-duodenal ulcers
The spiral
bacterium, has been identified for the first time in gastric
sediment and depicted under microscope in humans with various gastric diseases
by W. Jaworski, professor of Cracow Academy in his Handbook of Gastric Diseases
(in Polish) over 100 years ago and due to their curved forms named by him
Vibrio
rugula (33) (
Fig. 6).
|
Fig. 6.
Nobel laureates in physiology and medicine in 2005. B.J. Marshall and
J.R. Warren receiving prize for the discovery of Helicobacter pylori
and its role in gastritis and peptic ulcer disease. W. Jaworski (upper
panel), who described spiral bacteria in the human stomach 100 years before
Marshall and Warren should be considered a real discoverer of these bacteria. |
Definitive microbiological characterization of this spiral bacteria named initially
by mistake
Campylobacter pylori, but then properly identified as
H.
pylori should be attributed to Australian clinical researchers, R. J. Warren,
pathomorphologist, and B. J. Marshall, gastroenterologist (34), who in early
1980s proved that
bacterium is pathogenic by fulfilling all three Koch’s
criteria (isolation of germ, its culture and demonstration of it pathogenicity).
Marshall used his own stomach to prove pathogeneicity of bacteria by drinking
their pure culture and documenting endoscopically and histologically the development
of acute gastritis cured with antibiotics and bismuth salts. Numerous studies
in various countries showed that the stomach of more than 50% of world adult
population contains
H. pylori (35, 36) that exhibits an ability to induce
gastritis in all infected subjects and peptic ulcers in about 10-15% of them.
H. pylori is mobile germ due to the presence of flagella and easily moves
within thick mucus layer covering the gastric mucosa to reach the apical membrane
of surface epithelial cells and to bind by its adhesin molecules to mucosal
glycolipid receptors at this membrane (
Fig. 7). Bacterial genome is now
well-studied structure and shown to contain about 1300 genes. More toxic bacteria
are capable of expressing the cytotoxins such as CagA encoded by cagA and VacA
encoded by
vacA. The
bacterium adhering to mucous cell membrane,
is capable to “inject” into cytoplasm of mucosal cells its cytotoxins acting
there like “Trojan horse” to induce inflammation (CagA) or to damage its mucosal
cell surface and causing its vacuolization (VacA) (36, 37). Furthermore, the
cytotoxins turn on the mucosal immunological system, resulting in enhanced expression
and release of proinflammatory cytokines, including interleukin-8 (IL-8), interleukin-1ß
(IL-1ß) and tumor necrosis factor-
alpha
(TNF-
alpha) (
Fig. 8). It is of interest
that
H. pylori infection interferes with ghrelin releasing cells (Gr-cells),
present mainly in oxyntic mucosa to decrease usual fasting rise in plasma ghrelin
and the appetite as well as to retard the growth of infected children (38,39).
Following eradication of
H. pylori the plasma and gastric corpus mucosa
content of ghrelin were restored accompanied by the improvement of appetite
and reduction in dyspeptic symptoms.
|
Fig. 7.
Schematic presentation of the H. pylori, its colonization of the
stomach, induction of immune gastric response (gastritis) and development
of gastric or duodenal ulcers without or with complication such as bleeding. |
|
Fig. 8.
The activation and expression of Helicobacter pylori cytotoxins
(CagA and VacA) and expression of other genes (oipA, dupA
an babA) result in mucosal cell damage and proinflammatory cytokine
formation. |
The infection strongly affects gastric acid secretion by altering the gastrin-somatostatin
ratio as well as damaging the mucus-alkaline coat at the mucous surface and
the quality of adherent mucus gel, resulting in acute and then chronic gastritis
and ulcerations (
Fig. 9). The induction of COX-2-PG system by this
bacterium
may limit the mucosal cell damage due to released PG, but the
H. pylori
infection results also in the generation of proinflammatory substances, including
reactive oxygen species (ROS), that, unlike PG belong to damaging proinflammatory
“team”. It becomes evident that the eradication of the
bacterium restores,
at least in part, the disturbed mucosal integrity and reverses the course of
gastritis. Administration of mucosal barrier breaker such as aspirin or ethanol
usually results in bleeding erosions or exacerbation of chronic gastric ulcerations
(30,32). Considering duodenal mucus-alkaline secretion in response to topical
H
+, delivered into duodenal bulb by
H. pylori
infected stomach, it should be emphasized that the duodenal mucosa behaves somehow
differently than gastric mucosa in response to topical acid. Isenberg and his
colleagues (31, 40) and Kaunitz and Akiba (26) using chambered human or animal
duodenum, confirmed earlier proposal that, unlike gastric mucosa, where tight
epithelial cells constitute the main component of gastric mucosal barrier against
H
+, in the duodenum, H
+
easily penetrates the duodenocytes, but does not damage them, though transiently
decreases their intracellular pH (pH). This strongly activates the basolateral
Na
+-HCO
3-
cotransporters, allowing for massive inward movement through baso-lateral membrane
of HCO
3- from
the extracellular space, leading to activation of the HCO
3/Cl
exchangers in apical membrane of duodenocytes and resulting in a marked stimulation
of HCO
3- secretion
together with mucus gel that is capable of neutralization of H
+
ions entering the duodenal lumen, thereby securing duodenal mucosal neutrality
and integrity (
Fig. 10).
|
Fig. 9.
The possible long-term effects of H. pylori infection of the stomach
and the percentage of various pathologies resulting from this infection. |
|
Fig. 10.
Mechanisms controlling the duodenal alkaline secretion. |
Sjoblom and Flemstrom (41) provided evidence that, neurally released melatonin
and neuronal VIP, participate in the mechanism of the stimulation of duodenal
mucus-alkaline secretion by topical H+-activating the vago-vagal reflexes and
their brainstem centers, also essential for the control of gastric, duodenal
or pancreatic secretion (32, 42). The neuronal pathway involved in activation
of gastro-duodenal mucus-alkaline secretion with the contribution of melatonin
was confirmed by Reiter
et al. (43), just reinforcing Sjoblom and Flemstrom
(41) idea implicating melatonin in gastro-duodenal protective system. As shown
by Isenberg
et al (40), the
H. pylori infection reduces duodenal
HCO
3- mucus secretion
(despite of increasing mucosal PGE
2 generation)
and this allows for excessive penetration of gastric H
+
and other irritants into the mucosa, causing damage of duodenocytes with subsequent
formation of gastric metaplastic islets in duodenum. This mechanism leads to
the formation of the “
locus minoris resistentiae” for duodenal
H.
pylori infection and, finally, to the ulcer development in duodenum. This
occurs when
duodenitis, combined with disorders of duodenal mucus-alkaline
secretion caused by
H. pylori infection, takes place and when complex
mechanism controlling this secretion is deeply altered by this infection (
Fig.
10).
As shown on Figs 11, the prevalence of
H. pylori infection estimated by W. £aszewicz (35) on about 18 000 subjects and Bielanski’s studies including about 20 000 subjects of southern part of Poland (46-48), reached similar values. The infection rate shows similar trends regarding the influence of the age, but in Bielanski’s studies extending up to 80 years of age, some tendency of the infection rate to decline at age above 50 years and this could be due either to the development in these patients of atrophic gastritis and/or the translocation of the bacteria from the gastric surface into the mucosal cells without showing
H. pylori positivity in UBT or CLO (46).
|
Fig. 11.
Mean H. pylori infection rate in various countries of the world
and in Poland, in which the infection rate averages 58.29% for the entire
adult Polish population (35). |
It is of interest that the prevalence of
H. pylori infection in Poland
decreased by about 30% during last 10 years when the eradication procedure has
been widely applied in ulcer therapy. At the same time, the incidence of ulcers
without
H. pylori infection or the use of non-steroidal anti-inflammatory
drugs (NSAID) also tended to increase so that the ratio of these “idiopathic”
ulcers to total number of ulcer significantly increased (47, 48). Despite of
the decline in
H. pylori prevalence, the rate of ulcer complications
such as bleeding and perforation did not change dramatically as compared to
the period when no eradication therapy has been applied. According to the opinion
of Blaser (49) the fall in
H. pylori prevalence occurs all over the world
due to improvement of living standard levels, but it is accompanied by the increase
in the occurrence of gastro-esophageal reflux disease (GERD), Barrett’s esophagus
and esophageal carcinoma (
Fig. 12).
|
Fig. 12.
During last decades the H. pylori prevalence and the occurrence
of distal gastric cancer are declining, while there is an increase in
the gastro-duodenal reflux disease (GERD), esophagitis and cancer of the
proximal part of the stomach. |
The
H. pylori infection appears to interfere with the expression and
release from the oxyntic mucosa of ghrelin, and this may result in the decrease
of appetite and retardation of the growth in children (38, 39). Following the
eradication of the
H. pylori the release of ghrelin has been restored
and this was accompanied by the improvement of appetite and decrease of dyspeptic
symptoms (
Fig. 13).
|
Fig. 13.
The gastric infection with H. pylori results in the decrease in
the expression and the release of ghrelin, gastric hormone stimulating
appetite and enhancing the body growth. |
Concerning the risk of
H. pylori infection, numerous conditions increase such risk including the low socio-economic status, poor sanitary conditions, unclean water and smoking as well as the direct exposure nurses to endoscopic instruments or gastric contents (51).
Brain-gut axis in gastroduodenal mucosal damage caused by H. pylori, NSAID and other irritants
The question remains whether
H. pylori-induced gastric and duodenal mucosal
damage is merely a local phenomenon or whether it also involves the extragastric,
namely neuro-hormonal mechanisms. To answer this question, several tools were
employed in experimental animals; 1) inactivation of sensory afferent nerves
that serve to signal the brain the changes occurring in the gastrointestinal
tract by using animals injected with large neurotoxic dose of capsaicin; 2)
surgical vagotomy to eliminate the transmission of signals from the GI tract
to central nervous system (CNS) through the sensory vagal fibers, which constitute
over 90% of total vagal fibers, and which supply the gastro-duodenal area that
is crucial for the
H. pylori-induced inflammatory changes and ulcerogenesis;
3) intracerebral application of various hormonal substances to determine whether
the CNS centers can influence the gastric H
+-secretory
pattern and gastro-duodenal mucus-HCO
3-
responses to topical irritant application such as
H. pylori or aspirin
and 4) determination of expression of cFOS in intrinsic and extrinsic neurons
involved in the transmission of gut-brain-gut signals (30). Using such wide
spectrum of physiological and pharmacological tools, several researchers, including
our group, were able to reveal that the gastro-duodenal mucosa is equipped with
a variety of neuronal sensors that respond to the action of luminal irritants
such as
H. pylori produced cytotoxic substances, especially cytotoxin
CagA, VacA and ammonia, luminal acid, ethanol, various drugs e.g. NSAID or even
physiological changes such as chemical ingredients of food, its osmolarity and
pH as well as motility and tension of the GI tract wall. Through activation
of chemo-, osmo-, mechano- and noci-receptors of gastroduodenal mucosa, the
afferent nerves may mediate short local or intramural and long, vago-vagal or
extramural (axonal and spinal or cerebral) reflexes triggered by luminal H
+
or
H. pylori and affecting, among others, also the mucus-HCO
3-
secretion, the gastro-duodenal mucosal barriers, and mucosal integrity as well
as mucosal microcirculation (30). The space limitation of this review does not
allow for the detailed presentation of the evidence, obtained, in part, from
animal experimentations, supporting the involvement of extragastric neuro-reflexes
in the maintenance of gastro-duodenal mucosal integrity but it is of interest
that e.g. experimental chronic gastric ulcers in rats infected with
H. pylori
or with gastric mucosal damage by acidified aspirin or ethanol are greatly augmented
following capsaicin-induced inactivation of afferent sensory nerves or vagotomy.
This could be interpreted that both sensory afferent and vagal efferent nerves
are involved not only in the pathogenesis of gastro-duodenal mucosal lesions
but also are required for normal course of their healing and for the maintenance
of mucosal integrity (30). In humans with
H. pylori infected stomach,
the course of post-eradication ulcer healing probably also involves the long
vago-vagal reflexes initiated by activation of gastric mucosal sensors by
H.
pylori-released cytotoxins and inflammatory products such as the reactive
oxygen species (ROS) as well as various growth factors including EGF, TGF
alpha,
bFGF, VEGF generated in gastric mucosa under the influence of
H. pylori
infection but enhancing mucosal regeneration and ulcer healing. Also the clot
filling the ulcer niche is rich source of various growth factors produced by
platelets as well as by microphages and interacting with the damage by ulcer
mucosa to enhance its regeneration and ulcer healing (
Fig. 14). Also
the development and subsequent repair of aspirin- and ethanol-induced gastric
mucosal lesions may involve the brain-gut axis, starting with the irritation
of mucosal chemo-receptors by noxious chemicals and their mucosal toxic products
such as ROS (32). This is supported by experimental evidence that inactivation
of sensory afferent fibers with capsaicin or subdiaphragmatic vagotomy, eliminating
the activity of both afferent and efferent vagal pathways, greatly delays ulcer
healing and worsens the lesion induced by various local irritants (30-32). Mucosal
lesions and ulcerations induced either by
H. pylori infection and aspirin,
ethanol or ischemia-reperfusion, have been thought to involve predominantly
local mechanism related to the activation of COX-2-PG system and various growth
factors assuring spontaneous healing of gastric lesions (
Fig. 14). However,
based on studies with ulcer healing after inactivation of afferent sensory fibers
with neurotoxic dose of capsaicin or by vagotomy, it is tempting to assume that
brain-gut axis is involved in pathogenesis of
H. pylori induced ulcer
formation and in healing of these ulcers
via neural mediation of local
mucosal changes including gastric blood flow at ulcer area (30). This does not
to exclude the contribution in mucosal repair processes of local anti-ulcer
and protective humorals such as COX-2-PG, growth factors, gastrin, somatostatin,
ghrelin, melatonin etc., that may modify the final outcome of
H. pylori-induced
ulcer healing, and repair processes involving both local factors and neural
brain-gut axis (32).
|
Fig. 14.
The healing process of acute or chronic gastric ulcerations induced by
the H. pylori infection involves a variety of growth factors and
the products of cyclooxygenase (COX) or nitric oxide synthase (NOS) products
that counteract the deleterious effects of this infection. |
Concluding remarks
- H. pylori infection interferes with the release and action on parietal
cells of basic secretagogues such as histamine, gastrin and somatostatin,
resulting in gastric acid hypersecretion, when the infection is localized
in gastric antrum, or in hypochlorhydria when such infection involves
gastric corpus, resulting in corpus-predominant chronic gastritis.
- Duodenal ulcer, which is causally related to the H. pylori infection
in antral mucosa, is usually accompanied by hyperchlorhydria caused by an
excessive release of gastrin from the G-cells due to deficient somatostatin
release from the antral D-cells as well as due to excessive histamine release
from the ECL-cells caused by their stimulation by endogenous gastrin induced
by the action on Nalpha-methyl histamine,
present in H. pylori infected stomach.
- Gastric ulcer is usually accompanied by reduced corpus mucosal integrity
and altered mucosal barrier as well as reduced gastric acid secretion caused
by down-regulation of the expression of compound units of the proton pumps
and reduced acid secretory activity of oxyntic cells. Following H. pylori
eradication, gastric acid tends to increase depending upon the improvement
of the mucosal integrity and secretory activity of oxyntic cells.
- Neuro-hormonal pharmacology of the stomach and duodenum succeeded in discovery
and clinical use of potent inhibitors of gastric acid secretion such as
H2-R antagonists and PPI, that abolish all
modes of gastric secretory stimulation but, concomitantly, result in hypergastrinemia
that stimulates the growth of H. pylori promoting spreading the infection
towards the proximal part of the stomach with subsequent development of
corpus-predominant atrophic gastritis and cancerogenesis.
- The eradication of H. pylori abolishes hyperchlorhydria and hypergastrinemia in duodenal ulcer patients and is successful in healing and prevention of ulcer recurrence as well as in prevention of the H. pylori-related gastric cancerogenesis.
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