(Hp) is now considered
as the primary etiological factor of acute, chronic active and finally atrophic
gastritis leading to gastro-duodenal ulcerations, gastric MALT lymphoma or cancer
(1-5). Hp infection is widespread and involves about 50% of human population.
In general, Hp prevalence increases with age and is universally related to socio-economic
and hygienic status and living conditions, suggesting that Hp might be transmitted
from person to person and possibly also from infected animals to persons, both
probably by the fecal-oral route (6-10). Several studies have demonstrated a
higher prevalence of Hp in certain professions with direct contact with Hp-infected
animals and patients including veterinarians, butchers, abattoir workers as
well as gastroenterologists and dentists (8-10). Isolation of Hp from domestic
cats, dogs and sheep implies the possibility that Hp may be transmitted from
these domestic animals to humans (or vice-versa) (11-13). Goodman at al
(14) observed an excessive Hp infection rate among children having contact with
sheep in the Colombian Andes. Studies on Sardinian shepherds with close contact
with sheep (15) and school children in rural areas of Sardinia contacting both
sheep and sheep dogs revealed that contact with these domestic animals might
be a powerful and independent risk factor for Hp infection and accompanied dyspepsia
in this Sardinian subpopulation (16). Our previous study on shepherds from the
Polish Tatra Mountains based on modified 13
breath testing (UBT) (17) and serology revealed a very high active Hp infection
rate and high incidence of cytotoxic CagA seropositivity, as well as increased
pro-inflammatory serum cytokine levels compared to control subjects without
sheep contact (18).
Hp infection is not only the major pathogen of the gastrointestinal tract but may also be responsible for the growth retardation, dyspeptic symptoms and reduced appetite, possibly due to inhibition of the expression and release of ghrelin, identified in the oxyntic gland area of the stomach as an endogenous ligand of growth hormone secretagogue receptor. In addition to its potent growth hormone releasing activity, ghrelin influences also appetite, energy balance, gastric motility and acid secretion (19-20).
Our preliminary findings of a higher prevalence of Hp infection and higher incidence of dyspeptic symptoms in shepherd children, as well as retardation in growth (18-22) prompted us to conduct the present study to determine the relationship between Hp infection and the serum release of appetite-affecting gastric hormones such as ghrelin, leptin and gastrin in children and adults.
MATERIAL AND METHODS
We studied healthy adult subjects and school children from the same residential (Cracow) area of similar socio-economic status. Enrollment criteria for the adult group included subjects without history of malignancy, peptic ulcer, past treatment with antibiotics and bismuth salts as well as the use of non-steroidal anti-inflammatory agents or immunosuppressive therapy. Total number of 120 male healthy subjects aged from 23 to 48 yr (mean 41.5; SEM 3.2 yr) was included and divided at random into two subgroups, one with positive and another with negative UBT. We also studied 60 children (28 male and 32 female) from the same region, aged from 6 to 17 yr (mean 10.2 yr ± 2.2 yr) and divided into two subgroups, one with positive and another negative UBT. None of children had history of peptic ulcer, gastrointestinal malignancy or past treatment with antibiotics, antisecretory agents and immunosuppressive therapy. All subjects completed a detailed questionnaire under supervision of gastroenterologists regarding their demographic data, childhood and present socio-economic status, number of persons in the household, parents’ occupation, and past and present history of dyspeptic symptoms such as pain and/or discomfort in the upper abdomen, fullness, nausea and appetitive behavior as specified by Falley et al. (23).
Serum and UBT samples were collected from year 2002 to 2005. The study was reviewed, approved and supervised by the Institutional Ethical Committee for Human Research at the Medical College, Cracow, Poland.
Determination of Hp status
Hp status was assessed using our modification of the 13
breath test (UBT) by placing urea, an Hp urease substrate, in special capsules
(to avoid contact with oral urease containing oral bacteria) that disintegrate
in the gastric lumen within about 1-2 min after swallowing. This low-dose capsulated
UBT has been effectively used in over 20,000 subjects from 1994 and was found
to exhibit over 95% and 97% sensitivity and specificity, as described previously
(24). Briefly, two baseline breath samples were collected after an overnight
fast followed by administration of capsulated 13
(~ 40 mg). Post-dose breath samples were collected 10 and 20 min later. All
samples were analyzed using a mass spectrometer (Heliview, Medichems, South
Korea). A delta value of 2.5 over baseline was considered as positive result
Blood samples were withdrawn after an overnight fast, and serum samples were separated and immediately frozen at –80 °C until determination of serum anti-Hp and anti-Cag IgG using a commercial ELISA kit (EIAGEN HP IgG, Clone Systems). As indicated by the manufacturer, the results of anti-Hp IgG > 15 AU/mL (arbitrary units) and anti-CagA > 0.3 OD (optical density) were considered seropositive, as reported previously (24,25).
Measurement of serum ghrelin, leptin and gastrin
Ghrelin concentrations were determined in serum samples using a human radioimmunoassay
kit (Peninsula Lab., Inc., Bachem, San Carlos, CA) according to the manufacturer’s
instruction (25-27). Serum leptin was determined using a human leptin radioimmunoassay
kit (R/D Systems Inc, Minneapolis, NM) as described previously (28). Serum gastrin
concentration was measured by specific RIA using highly specific antiserum (No
4562, kindly supplied by Professor Jens Rehfeld from Copenhagen University,
Denmark). This antiserum recognized alpha
gastrin-17 (G-17) and G-34 equally, as described previously, and has been employed
in our laboratory for the last two decades at a final dilution of 1:500.000,
with normal values established in healthy fasting subjects below 60 pmol/L (29).
Plasma IL-8 and TNFalpha
also measured in all tested subjects by ELISA using commercially available kits
(Biosource Europe SA, Belgium) in accordance with the manufacturer’s instructions
Hp infection was considered present when positive results were obtained for
the UBT and the anti-IgG or anti-CagA ELISA tests. The data were expressed as
means ± standard error of the mean. Statistical analyses were performed using
the Student t test or Tukey test after analysis of variance. A P
of less than 0.05 was considered statistically significant.
Based on UBT and anti-Hp IgG tests two groups of school children and two groups of adults were included in this study, one with negative UBT and serology Hp tests and another with positive Hp tests. Anti-CagA antibodies occurred in 58% of Hp positive adults and in 52% of Hp positive school children, but were not detectable in Hp negative subjects.
Mean basal serum ghrelin concentration in Hp positive adults was 550 ± 80 pg/ml
compared to 1040 ± 100 pg/ml in age-matched Hp-negative controls, and this difference
was highly statistically significant (Fig. 1
). Serum basal leptin levels
in Hp positive adults were significantly higher than those in Hp-negative controls.
Serum basal gastrin concentrations in Hp positive adults averaged 53.6 ± 6.2
pmol/l and were significantly higher than those in the Hp-negative controls
(31 ± 4.2 pmol/l). Serum ghrelin levels in Hp-infected children were about 650
± 40 pg/ml and were markedly lower than those in Hp-negative children (1150
± 94 pg/ml). Serum leptin was 4.3 ± 0.6 ng/ml in Hp-infected children, significantly
higher than that in children without Hp infection (Fig. 1
). Plasma gastrin
was 47 ± 16 pmol/l in Hp-infected children and this was, significantly higher
than that in Hp-negative children (28.3 ± 3.2 pmol/l).
Serum ghrelin and leptin concentrations in fasted school children and
adults with and without Hp infection Asterisk indicates significant (P
< 0.05) change as compared to the values recorded in in Hp positive children
shows the day-time alterations in serum ghrelin and leptin in
5 Hp positive and 5 Hp negative adults. Serum ghrelin concentrations showed
a marked increase after an overnight fast and also before lunch and dinner,
but immediately after ingestion of meal the hormone level dramatically declined.
These increments in serum ghrelin were significantly more pronounced in Hp negative
than in Hp positive subjects. In contrast, serum levels of leptin showed a tendency
to increase with the decline of serum ghrelin, but failed to demonstrate the
meal-related alterations. The overall levels of serum leptin were significantly
higher in Hp positive than in Hp negative subjects. (Fig. 2
The daily alterations in serum levels of ghrelin and leptin in adult subjects
at 2 h intervals before and after breakfast, lunch and dinner with and
without Hp infection. Mean of 5 determinations in 5 adult subjects. Asterisk
indicates significant increase as compared to the values recorded in Hp
In Hp positive adults, basal serum levels of TNF-a (36.6 ± 7.2 pg/ml) and IL-8 (38.2 ± 5.1 pg/ml) were 2-5 times higher than those in Hp-negative controls. Similarly, cytokine concentrations were significantly lower in Hp-negative than in Hp-positive children. Dyspeptic symptoms (23), including mainly discomfort centered in the upper abdomen accompanied by the lost or reduced appetite, were reported by majority (65%) of Hp-positive children, but only by 15% of Hp-negative children.
The results of this study show that Hp infection has pronounced influence on serum levels of gastric hormones involved in appetitive behavior, particularly on the serum concentrations of ghrelin and gastrin. Ghrelin exhibits marked fluctuations during the day time, reaching the peak value just before the meal and then shows the sudden decline to the nadir followed by subsequent slow increase before the next meal. These ghrelin fluctuations were more pronounced in Hp negative than in Hp positive subjects. Such a day-time alterations in serum ghrelin were tested only in adults so further studies are needed to find out whether they occur also in children. It is of interest that reduced serum levels of ghrelin were accompanied by the dyspeptic symptoms including the suppression of the appetite, observed in majority of examined Hp infected children.
The control of food intake and body weight actually concerns the control of
adipose tissue with the key role of hypothalamus, possessing several neuronal
centers such as that in lateral hypothalamic nuclei considered to be “hunger”
center and in ventromedial nuclei serving as the “satiety” center (Fig. 3
In addition, hypothalamic paraventricular and arcuate nuclei (ARC) are the sites
of action of multiple hormones released from the gut and adipose tissue that
regulate food intake and energy expenditure (Fig. 4
). There are two distinct
types of neurons in ARC that are important in control of food intake; (1) proopiomelanocortin
(POMC) and cocaine-amphetamine-related constructs (CART) neurons activated by
peripheral anorexigenic hormones and releasing a-melanocyte-stimulating hormone
-MSH) in satiety center and (2) neurons
activated by orexigenic peptides such as ghrelin and orexins that release the
substances including neuropeptide Y (NPY), orexins and Agouti-related Peptide
(AgrP) in hunger center. Arcuate nucleus integrates also afferent neural (mostly
vagal) and humoral inputs such as enteropeptides including orexigenic (ghrelin
and orexins) and anorexigenic peptides (cholecystokinin, polypeptide YY, glucagon-like
peptide-1, oxyntomodulin, leptin and others) that exert a physiological role
in governing appetite and satiety. The peripherally (gut, adipose tissue) and
centrally expressed modulators of appetitive behavior act through specific receptors
in the afferent (mostly vagal) nerves and hypothalamic neurons implicated in
adiposity signaling and regulation of food intake (Fig. 5
Enteropeptides and neurotrasmitters involved in the suppression (anorexigenic
peptides) and stimulation of appetitive behavior resulting, respectively,
in cahexia and obesity.
Hypothalamic centers and peripheral adiposity, satiety and hunger signals
as well as vagal afferents involved in the control of satiety and hunger
in medial and lateral hypothalamic area, respectively.
Peripheral signals originating from the adipose tissue (leptin), pancreas
(insulin), the stomach (ghrelin) and intestines (PYY3-36,
oxyntomodulin (OXM), GLP-1, PP and GI affectine appetitive behavior through
the action on the hypothalamuc or vagal nerves.
The major gastrointestinal hormone with known orexigenic properties is ghrelin
(29) which has been identified in gastric ghrelin X/A cells, now called Gr cells,
characterized by large eletrodense granules of P/D type in man and A-like type
in rats (31). Ghrelin is a 28 amino acid peptide, primarily released by these
endocrine cells in empty stomach (Fig. 6
). As shown previously and demonstrated
in this report, plasma concentrations of ghrelin peak under fasting conditions
before the meal and then level off after meal to a nadir to increase again after
gastric emptying before next meal (32). The mechanisms of ghrelin action on
appetite and food intake is believed to be primarily mediated through peripheral
input at the arcuate nucleus (ARC) and further spread to the nucleus tracti
solitari (NTS). Ghrelin exerts growth hormone (GH)-releasing properties (33)
and is involved in the hypothalamic regulation of metabolic control and energy
balance. Ghrelin serves as a ligand for growth hormone secretagogue receptors
(GHS-R). The primary hypothalamic target for ghrelin are neurons in ARC that
contain and release NPY and AgRP in the lateral hypothalamus and in PVN to mediate
orexigenic effect in the brain (34, 35). It may also inhibit the neurons in
the ARC that contain POMC-derivative a-MSH that mediate the anorexigenic effect
in the ventromedial hypothalamus (36). An appetite stimulating action of ghrelin
has been proven in humans (37). Clinical implications of this have been forwarded
as patients with Prader-Willi syndrome exhibit greatly increased circulating
levels of ghrelin accompanied by marked enhancement of appetite and obesity
(38, 39). Furthermore, gastric bypass surgery for morbid obesity leads to the
considerable weight loss and reduction in appetite (40, 41), pointing at a ghrelin
as mediator of altered energy balance and appetitive behaviour. Peripherally
in the gut, ghrelin was shown by us to stimulate gastric acid secretion and
gastrin release (43) and to exhibit the gastro- and pancreato-protective activities
against various irritants (43). In addition, ghrelin was reported to exert a
prokinetic effect on the small bowel, where it stimulates activity front of
the migrating motor complex (MMC) through cholinergic mechanisms (44). It is
of interest that food desire combined with an increase of gastric acid secretion
occurs after intake of ethanol at low concentration (“coctail”), which appears
to enhance the overexpression of ghrelin in the oxyntic mucosa and an increase
in plasma levels of this peptide, gastric motility and gastric acid secretion
(45). Thus, ghrelin appears to contribute to the initiation of food intake,
body mass index (BMI) and stimulation in motilin-like fashion of gastrointestinal
Ghrelin and leptin, their sites of origin and way of action on hypothalamic
centers to affect food intake and BMI. The inhibitory influence of Hp
infection on the release of ghrelin and stimulatory action on leptin release
are also marked.
In addition to the initiation of food intake, exogenous ghrelin decreases the
release and action of leptin and vice-versa
exogenous leptin reduces
the plasma level of ghrelin (46). It has been proposed that leptin exerts a
negative regulatory effect on the release and action of ghrelin and that increase
in ghrelin induced by fasting or weight loss arises because of the diminished
inhibitory input from leptin and probably also from PYY. This may implay that
weight- and appetite-reducing effects of leptin are mediated not only by its
direct central action on hypothalamus but also through its peripheral inhibitory
effect on the release and action of ghrelin. According to our experience in
rats (47), the parenteral administration of ghrelin at a dose that raised plasma
hormone to the level observed under fasting conditions, significantly attenuated
plasma levels of leptin, while markedly increasing food intake. Immuno-neutralization
of circulating plasma ghrelin with specific IgG anti-ghrelin antibodies, caused
a marked increase in plasma leptin and decreased food intake. In contrast, exogenous
leptin, at the dose (10 µg/kg ip) that raised plasma leptin to the level occurring
postprandially, reduced markedly plasma levels of ghrelin and attenuated food
intake and these effects were reversed by the administration of specific IgG
anti-leptin antibodies (47). These results clearly support the hypothesis that
ghrelin negatively controls plasma release of leptin and vice-versa that leptin
has a counter-regulatory influence on ghrelin release and action, though the
former effect appears to be much stronger than the later. This interaction between
ghrelin and leptin in control of food intake has been called “ghrelin-leptin
In addition to ghrelin, orexins A (OXA) and B (OXB), the novel neuropeptides were found to play the role in the stimulation of food intake and energy homeostasis (48). OXA has been detected in the mucosa and neuronal plexuses of the gastrointestinal tract and in the central nervous system, especially in lateral hypothalamus, the area involved in the stimulation of food intake (49, 50). Plasma levels of OXA are increased during fasting in humans (51) and are lower in obese subjects than normal-weight people (52), suggesting that peripheral OXA modulate food intake as an orexigenic peptide (53). However, intravenous infusion of OXA in humans does not appear to induce any hunger-stimulating drive in humans but increases gastric emptying.
In the present study, we attempted to determine the relationship between Hp
infection and two crucial peptides, ghrelin and leptin, which are known to play
an important role in the regulation of appetite, body mass index (BMI) and food
intake (47), in the groups of healthy school children and healthy adults. We
were particularly interested in the influence of Hp infection on ghrelin release
into the circulation both under basal and postprandial conditions, since previous
studies showed that stomach is the major source of circulating ghrelin (45,
46). It was reported that plasma ghrelin concentration is markedly decreased
following gastrectomy (54), but evidence to date shows conflicting results for
the influence of Hp infection with or without eradication therapy on gastric
ghrelin, and, in overall, the subject remains controversial (55, 56). For instance,
Nwokolo et al.
(55) reported that the plasma ghrelin level increased
after Hp eradication, suggesting a possible link between Hp infection and ghrelin
secretion in the post-treatment stomach. In contrast, another study revealed
a lack of significant difference in plasma ghrelin levels between Hp-positive
and Hp-negative patients of similar age and body mass index (BMI) (56). Recent
reports by Isomoto et al.
(57) and Ozawa et al.
that Hp infection actually inhibited the release of gastric ghrelin into the
circulation, but again, Hp eradication in their studies had no effect on plasma
ghrelin levels in subjects that underwent anti-Hp therapy and were successfully
cured. Reduced expression of mRNA for preproghrelin and a concurrent fall in
plasma ghrelin levels were also observed in Hp-infected Mongolian gerbils, the
most appropriate experimental model for studying various aspects of Hp-associated
gastric cancer pathogenesis (59).
Our previous study in the Polish shepherd population of the Tatra Mountains
documented for the first time that serum ghrelin concentration is significantly
decreased in Hp-positive shepherds and their children as compared to that in
Hp-negative counterparts (60). Moreover, we found that Hp eradication in the
same shepherds resulted in a profound increase in plasma ghrelin levels, indicating
that Hp, in fact, exhibits an inhibitory effect on ghrelin release into the
circulation and that removal of this bacteria from the stomach using triple
eradication therapy based on a proton pump inhibitor results in an enhancement
of circulating plasma ghrelin (60). The importance of the inhibitory influence
of Hp infection on circulating ghrelin is supported by our recent finding (60)
that ghrelin content in the gastric corpus mucosa, a major source of this hormone
in the stomach, was significantly higher than that in gastric antrum and that
this corpus ghrelin concentration was markedly suppressed in Hp-infected shepherds
before eradication therapy, whereas anti Hp-eradication therapy counteracted
the inhibitory effect of Hp on gastric ghrelin content. Our present comparative
results obtained from age-matched children and adults without or with Hp infection
confirm and extent the above mentioned data obtained from shepherds and their
children and strongly support the conclusion that Hp infection strongly suppresses
plasma ghrelin secretion while enhancing the plasma leptin response. Our findings
are in keeping with previous reports by Nwokolo et al.
(57) and Tatsagouchi et al.
(61) that Hp suppresses gastric
ghrelin, as reflected in their studies by a marked decrease in the number of
immunoreactive ghrelin neuroendocrine cells in gastric corpus and by a subsequent
fall in plasma ghrelin levels observed in Hp-infected subjects. Moreover, our
present study as well as Hp-eradicated patients in other reports (55, 57, 60
- 62) demonstrate an increase in gastric ghrelin, which may contribute to the
ghrelin-induced increase in appetite and weight gain observed following successful
bacteria eradication. This notion is supported by the observation that Hp infection,
which negatively influenced plasma ghrelin dynamics, was shown to correlate
in a positive manner with the BMI of Hp infected patients (57). It is of interest,
however, that leptin levels were not significantly affected in Hp-infected adults,
confirming the observation by Isomoto et al.
(57) that leptin levels
exhibit a positive correlation with BMI irrespective of Hp status as the primary
contributor of circulating leptin is the adipose tissue. In another report,
plasma leptin concentration was increased in Hp-positive subjects (63). In agreement
with this latter report, we found that in Hp-infected children and adults, serum
leptin concentrations were significantly increased, suggesting that the stimulatory
effects of Hp on leptin release is independent on the age of examined subjects.
This increase in leptin release in Hp-infected children and adults were, however,
not paralleled by a decrease in plasma ghrelin concentration. The question remains
what is the possible mechanism of the alterations of ghrelin release by Hp infection.
Hp may act directly or through its cytotoxins on the secretory activity of the
Gr cells. The fact that prolong Hp infection and accompanying atrophic gastritis
results in the decrease in the number of the Gr cells that is paralleled by
the decrease in plasma levels of pepsinogen I, which is considered as biomarker
of the integrity of the oxyntic mucosa, suggests that Hp may indeed interfere
directly with the Gr-cells and ghrelin release but this requires further studies
(59). Hp infection seems to enhance the release of leptin, which originates
predominantly from the adipocytes and less from the gastric glands, and it is
not clear how the Hp in the stomach could affect the release of this peptide.
Although we found that Hp infection alters serum levels of ghrelin and leptin,
further studies are needed to determine whether the alterations in serum ghrelin
and leptin in Hp infection play any important role in appetite control energy
homeostasis in Hp infected children and adults.
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