Research in Veterinary Science 81 (2006) 225–230

www.elsevier.com/locate/rvsc

Abomasal contents of parasitised sheep contain an inhibitor

of gastrin secretion in vitro
D.C. Simcock a, I. Scott b, S.M.C. Przemeck c, H.V. Simpson a,*

a
Institute of Food, Nutrition and Human Health, Massey University, Private Bag 11-222, Palmerston North, New Zealand
b
Institute of Veterinary, Animal and Biomedical Sciences, Massey University, Private Bag 11-222, Palmerston North, New Zealand
c
Department of Medicine, University of Liverpool, Liverpool L69 3BX, UK

Accepted 12 January 2006

Abstract

Serum gastrin concentrations are typically elevated in parasitised sheep; however, in some animals serum gastrin concentrations may
fall abruptly despite a very high abomasal pH. Although proliferating abomasal bacteria in culture generate a potent inhibitor of in vitro
gastrin secretion, this inhibitor has not been detected in abomasal contents of unparasitised sheep. In sheep parasitised by O. circum-
cincta, all abomasal fluid samples of pH 5 and above were inhibitory to gastrin release in vitro. Inhibitory activity and abomasal pH
were correlated in two separate experiments; the model best fitting the data being sigmoidal in each case, with zero activity at pH 3.6
and 4.6, respectively. There was no clear evidence that the presence of a gastrin inhibitor in the abomasal contents reduced the serum
gastrin concentration in parasitised sheep. Serum gastrin was correlated with abomasal pH (log10 serum gastrin concentrations con-
formed to log-linear sigmoidal models).
Ó 2006 Elsevier Ltd. All rights reserved.

Keywords: Ostertagia (Teladorsagia) circumcincta; Gastrin; Abomasal bacteria; Abomasal pH

1. Introduction tion of abomasal contents in unparasitised animals (Rey-

Elevated serum gastrin and pepsinogen concentrations
are typical of parasitism of sheep by Ostertagia (Teladorsa-
gia) circumcincta (Anderson et al., 1976, 1981; Lawton
et al., 1996) or Haemonchus contortus (Fox et al., 1988;
Simpson et al., 1997) and of cattle by Ostertagia ostertagi
(Fox et al., 1993) and can be used to diagnose abomasal
parasitism (Fox et al., 1988; Hilderson et al., 1992). The
removal of negative feedback from gastric acidity is
believed to be an important cause of the hypergastrina-
emia, since abomasal pH usually rises in parallel with
serum gastrin concentration during the initial period of
infection (Fox et al., 1987, 1993; Nicholls et al., 1988; Law-
ton et al., 1996). Frequently serum gastrin concentrations
in parasitised sheep far exceed those caused by neutralisa-
*
Corresponding author. Tel.: +64 6 350 4479; fax: +64 6 350 5753.
E-mail address: H.V.Simpson@massey.ac.nz (H.V. Simpson).
nolds et al., 1991) and hypergastrinaemia persists after
abomasal pH has dropped to normal levels (Lawton
et al., 1996), suggesting other known stimulants of the G-
cells, such as the inflammatory mediators histamine (Bado
et al., 1994), TNF-a (Lehmann et al., 1996; Weigert et al.,
1996) or IL-1b (Weigert et al., 1996) are involved. Parasite
excretory/secretory (ES) products do not seem to stimulate
gastrin release directly (Lawton et al., 2002; Haag et al.,
2005).
In some parasitised sheep, the opposite happens: after
an initial increase, serum gastrin concentrations may fall
abruptly despite a very high abomasal pH (Lawton et al.,
1996; Simcock et al., 1999) or occasionally there may be
no increase in serum gastrin concentration (Simcock
et al., 1999). The depletion of tissue gastrin stores reported
by Purewal et al. (1997), Scott et al. (1998) in parasitised
animals may be responsible for some sudden decreases in
hormone secretion, however, this is unlikely when these

0034-5288/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.rvsc.2006.01.005
226 D.C. Simcock et al. / Research in Veterinary Science 81 (2006) 225–230
events occur very early in the infection. Alternatively, large
numbers of larvae developing in the gastric antrum can
cause marked inflammation, which may damage G-cells
directly or indirectly (Simcock et al., 1999).
An additional factor to be considered is possible bacte-
rial inhibition of gastrin secretion. In vitro studies on gas-
trin release by ES products of O. circumcincta (Lawton
et al., 2002) or H. contortus (Haag et al., 2005) have shown
the presence of a gastrin inhibitor in occasional parasite
incubates. In the absence of antibiotics, similar inhibitory
activity develops in aerobic cultures of abomasal fluid, in
parallel with increasing bacterial numbers in the culture
fluid (Simcock et al., 2006). Abomasal bacterial popula-
tions increase in parasitised animals (Jennings et al.,
1966; Nicholls et al., 1987; Simcock et al., 1999) dependent
upon increasing abomasal pH (Simcock et al., 1999), rais-
ing the possibility that unexplained decreases in circulating
gastrin levels may be associated with the release of prod-
ucts from microbes surviving in the less acidic abomasum.
The present experiments examined the relationship in
parasitised sheep between serum gastrin concentration,
abomasal pH and in vitro effects of abomasal contents
on gastrin release. Since cultures of abomasal fluid may
contain in vitro gastrin inhibitors and stimulants and occa-
sionally also apparent proteolytic activity (Simcock et al.,
2006), in the first experiment only the net effect in vitro
of abomasal contents from parasitised sheep was related
to abomasal pH, but in the second group of sheep, proteo-
lytic activity was also estimated.
2. Materials and methods
2.1. Animals
All animals were reared indoors in helminth-free condi-
tions from birth and at approximately 5 months of age
were fitted surgically with abomasal cannulae (Lawton
et al., 1996). During the experiments, they were housed
individually, provided with water ad libitum and fed once
daily with 800 g lucerne nuts and aged hay. Sheep were
of both sexes, Poll Dorset in Expt. 1 and Romney cross
in Expt. 2.
Expt. 1: (1) Controls (CTR): four parasite-naı̈ve sheep;
(2) larval parasite-infected (LPI): four sheep infected
intraruminally by tube with 40,000 L3; (3) adult parasite-
infected (API): six sheep infected with approximately
20,000 adult worms via indwelling abomasal cannulae
and treated with oral ivermectin (Merial, 400 mg/kg) on
day 12 p.i. The adult worms were obtained 28 days after
infection of donor sheep whose abomasal contents were
pooled, concentrated by sedimentation, and divided into
seven aliquots, including one to estimate worm numbers.
The full experimental details and histopathology of muco-
sal biopsies collected on 12 days in LPI and control animals
and 11 times in API animals, as well as the serum gastrin
concentrations and abomasal pH for each animal, have
been reported by Scott et al. (2000).
Expt. 2: Eight sheep were infected with 50,000 L3
intraruminally by tube, followed by 10,000 L3 weekly for
6 weeks starting on day 35.
2.2. Sample collection
For Expt. 1, abomasal fluid was collected for in vitro
studies just before infection and on days 1, 4, 5, 7, 13,
15, 18 and 20 p.i. from API and LPI sheep and also on days
25 and 27 from LPI sheep and on days 4, 5, 7, 13, 15 and 18
from CTR sheep. Jugular blood and abomasal fluid for pH
measurement were collected on additional days over this
period. For Expt. 2, blood and abomasal fluid were
collected on days 13, 14 and 43 p.i.
Blood was collected into plain evacuated tubes, the
serum separated and stored at 20 °C for gastrin assay.
The pH of abomasal fluid pH was measured with a
PHM82 Standard pH meter (Radiometer).
2.3. In vitro gastrin secretion
Abomasal samples were tested at 10% final concentra-
tion for effects on the rate of gastrin release by an ovine
antral mucosal preparation (Lawton et al., 2000). Each
sample was tested in two plates, each containing eight rep-
licate tissue pieces incubated at 37 °C, first for three 10 min
periods in control medium, followed by three periods in the
test solution. The response to test agents was compared
with that of reference tissue incubated in control medium
for 60 min. The incubation medium was HBSS (Hank’s
balanced salt solution) without NaHCO3 (GIBCO), with
added 0.35 g/l NaHCO3, 0.25% bovine serum albumin
(Fraktion V, Boehringer Mannheim), 0.1% D-glucose
(Sigma) and 10 mM HEPES (GIBCO) adjusted to pH
7.4. Solutions were gassed with oxygen and maintained at
4 °C under a 100% oxygen atmosphere until warmed to
37 °C for testing. After the incubation, the contents of
the wells were aspirated, pooled for each replicate test solu-
tion and stored at 20 °C.
To test whether abomasal fluid affected the gastrin con-
centration measured in the test system, samples (10% final
volume) were incubated at 37 °C for 30 min with a series of
gastrin standards (50 pM, two of 100 pM, 200 pM) to
mimic exposure of secreted gastrin to test solutions. After
the incubation period, the solutions were stored at 4 °C
for 2–3 h, then at 18 °C before being assayed for gastrin
concentration.
2.4. Gastrin assay
Gastrin concentrations were determined in triplicate by
a radio-immunoassay (RIA) (Simpson et al., 1993) based
on the method of Hansky and Cain (1969). The antiserum
used was Hansky’s Ab74 and human synthetic nsG17 (Pen-
insular Laboratories) was used to prepare radioactive label
and standards. To test whether abomasal fluid affected the
assay of gastrin, fluid was added to make 10% final volume
 D.C. Simcock et al. / Research in Veterinary Science 81 (2006) 225–230 227

to blank (non-specific binding) and zero tubes (gastrin-like moidal (r2 = 0.68; SEM at V50 = 0.19, where V50 is the
substances present). midpoint between top and bottom), with zero effect on
in vitro gastrin release at pH 3.6 (Fig. 2). There was a sim-
2.5. Data presentation and statistics ilar relationship between abomasal pH and in vitro inhibi-
tory activity in the abomasal contents of the eight
Effects on gastrin release in vitro were expressed as per- parasitised sheep in Expt. 2 (Table 1); the data also fitted
centage change from basal (mean ± SEM), determined a sigmoidal model (r2 = 0.85; SEM at V50 = 0.07) with zero
from the ratio of the gastrin concentration in the presence activity at pH 4.6.
of the test agent to that in control medium, adjusted for the
slow decline in secretion of the reference tissue pieces in 3.2. Effect of abomasal contents on gastrin standards
control medium for the whole 60 min (Lawton et al.,
2000). Gastrin responses in different samples were com- To test for effects of abomasal contents on the stability
pared by UNIANOVA or by paired t-tests using SPSS ver- and subsequent assay of gastrin, known gastrin standards
sion 9.0.
For abomasal pH and serum gastrin concentration, the
upper limit of the normal range was established for each
animal and for the group as two SD above the mean of
all pre-infection values. Models relating abomasal pH to
serum gastrin concentration or to in vitro gastrin responses
were developed using nonlinear regression with Graphpad
Prism 4.

3. Results

3.1. Effect of abomasal contents on in vitro gastrin secretion

Abomasal contents of parasitised sheep (Expt. 1) were

inhibitory in the in vitro test system when the abomasal
pH was elevated above normal (calculated as pH 3.20), in
contrast to uninfected animals, either CTR sheep or other
groups before infection, in which no inhibitory activity
developed. All abomasal fluid samples of pH 5 and above
contained some inhibitory activity, whereas samples with
a low pH were often stimulatory (Fig. 1). The model best
fitting the pooled data from API and LPI sheep was sig-
Fig. 2. Plot of the change in gastrin release (% basal) by antral mucosa
in vitro in the presence of abomasal contents against pH of samples
collected from sheep infected with 20,000 adult (API) or 40,000 L3 (LPI)
O. circumcincta. The mean ± SEM of all values from uninfected control
animals are indicated by the shaded box. The sigmoidal model shown is
the best fit of the pooled from API and LPI sheep (r2 = 0.68; SEM at
V50 = 0.19, where V50 is the midpoint between top and bottom).

Fig. 1. Change in gastrin release (% basal) by antral mucosa in vitro in the presence of abomasal contents (top) and abomasal pH (bottom). Abomasal
samples of individual sheep were collected from cannulae in sheep infected with 20,000 adult (API) or 40,000 L3 (LPI) O. circumcincta or maintained as
uninfected controls (CTR). Times of infection of API and LPI sheep and drenching of API sheep with ivermectin are indicated.
228 D.C. Simcock et al. / Research in Veterinary Science 81 (2006) 225–230

Table 1
Abomasal pH and change in gastrin secretion in vitro (% basal; mean ± SEM) and percentage change in gastrin standards (mean ± SEM) after exposure
to abomasal contents collected from three parasitised sheep on days 13, 14 and 43 after infection with 50,000 L3 O. circumcincta intraruminally by tube,
followed by 10,000 L3 weekly from day 35
Sheep Day 13 Day 14 Day 43
pH In vitro Stand pH In vitro Stand pH In vitro Stand
1 4.58 32 ± 8 18 ± 1 3.65 2 ± 12 12 ± 7 – – –
2 5.14 66 ± 4*** 13 ± 5 5.14 77 ± 1*** 12 ± 7 6.67 77 ± 3** 4±9
3 4.60 34 ± 4 7 ± 11 3.80 23 ± 15 13 ± 3 – – –
4 6.47 85 ± 3*** 7 ± 14 6.20 87 ± 2*** 1 ± 10 2.34 25 ± 16 11 ± 8
5 4.81 51 ± 6** 10 ± 8 4.62 26 ± 24 44 ± 7 3.65 22 ± 9 14 ± 15
6 4.93 55 ± 4** 35 ± 6 3.28 10 ± 10 4±5 2.90 8 ± 15 11 ± 11
7 6.51 85 ± 1*** 20 ± 8 6.79 58 ± 6*** 8±4 3.00 77 ± 10*** 10 ± 7
8 3.82 4±8 7±4 3.91 10 ± 10 0±9 2.84 19 ± 15 9±6
Significant effects on in vitro gastrin secretion are indicated.
**
p < 0.01.
***
p < 0.001.

were incubated under the same conditions as the in vitro
release system with all samples of abomasal contents from
the parasitised sheep in Expt. 2 (Table 1). Only two of the
22 samples tested had large effects on the stability and
assay of gastrin ( 35% and 44%), the latter, however,
when the overall activity of the sample on antral tissue
was stimulatory. The presence of abomasal contents did
not interfere in the RIA itself (radioligand (zero) or non-
specific (blank) gastrin binding).
centrations closely followed abomasal pH. The data from
API and LPI sheep for abomasal pH and log10 serum gas-
trin concentrations were fitted to log-linear sigmoidal
models: for the API group r2 = 0.70, SEM at
log V50 = 0.16; for the LPI group r2 = 0.59, SEM at
log V50 = 0.21 (Fig. 3). For all data combined from the
three groups, log V50 = 3.67, r2 = 0.68 and SEM at
log V50 = 0.06, where log V50 is the midpoint between top
and bottom.

3.3. Relationship between properties of gastric contents and 4. Discussion

serum gastrin concentration
Serum gastrin concentrations were elevated above pre-
infection levels in both the API and LPI groups (Fig. 3),
in spite of abomasal contents containing inhibitory activity
in the in vitro test system. In contrast, serum gastrin con-
Abomasal fluid collected from unparasitised sheep usu-
ally weakly stimulated in vitro gastrin secretion by an ovine
antral mucosal preparation. In contrast, gastrin release was
inhibited by abomasal contents of sheep parasitised by
O. circumcincta when the pH of the fluid was elevated.

Fig. 3. Serum gastrin concentrations and log-linear plots of serum gastrin concentrations against abomasal pH in individual sheep infected with 20,000
adult (API) or 40,000 L3 (LPI) or O. circumcincta or maintained as uninfected controls (CTR). Times of infection of API and LPI sheep and drenching of
API sheep with ivermectin are indicated. The data from API and LPI sheep were fitted to log-linear sigmoidal models: for the API group r2 = 0.70, SEM at
log V50 = 0.16; for the LPI group r2 = 0.59, SEM at log V50 = 0.21, where log V50 is the midpoint between top and bottom. The horizontal and vertical
dotted lines indicate the mean for serum gastrin concentrations and abomasal pH in uninfected animals, respectively.
 D.C. Simcock et al. / Research in Veterinary Science 81 (2006) 225–230
The inhibitory activity was not due to interference in the
gastrin assay nor, in the majority of cases where tested,
was it due to gastrin breakdown. The presence of the inhib-
itor appeared to be primarily determined by abomasal pH,
however, there was no evidence that this inhibitory activity
played any role in controlling gastrin secretion in the par-
asitised animal in vivo.
The potential for gastric microbes to affect in vitro gas-
trin secretion was first identified in studies of abomasal
nematode ES products when it was suspected that bacterial
contamination was the source of potent inhibitory activity
in a small number of worm incubates (Lawton et al., 2002;
Haag et al., 2005). Subsequently, aerobic cultures in HBSS
of abomasal contents of uninfected sheep were shown var-
iably to develop an inhibitor or stimulant of gastrin secre-
tion, or occasionally the ability to reduce the assayable
concentration of known gastrin standard solutions (Sim-
cock et al., 2006), presumably because of proteolytic break-
down. In no case, was the abomasal fluid used for those
cultures initially inhibitory to gastrin secretion, nor did it
affect the assay of gastrin in solution. This contrasted with
the properties of rumen fluid samples tested in that study
which were both inhibitory and contained ‘‘proteolytic’’
activity.
In the present experiments, abomasal fluid was collected
from uninfected sheep and from animals either infected
with L3 or after transplantation of adult worms. In the first
experiment, only the net effect of the three possible effectors
was monitored, whereas in the subsequent experiment, the
proteolytic activity was also estimated for all samples and
found to be insignificant in all but two of 22 samples (see
Table 1). As there was also no interference in the gastrin
RIA by abomasal fluid, it was therefore assumed that the
in vitro effect on gastrin secretion could be attributed in vir-
tually all samples in both experiments to either a gastrin
stimulant or an inhibitor of secretion.
Abomasal contents from uninfected sheep generally
were stimulatory, whereas samples from parasitised sheep
were inhibitory (see Fig. 1), but strongly dependent on pH
being elevated (see Fig. 2). The stimulants in abomasal
contents may well be amino acids or dietary ammonia,
which increase gastrin secretion during the gastric phase
of digestion in vivo (Van Bruchem, 1977; Strunz et al.,
1978) and increase gastrin release by ovine tissue
in vitro (Lawton et al., 2002). Gastrin breakdown and
interference in the RIA do not contribute significantly
to the inhibitory activity in abomasal fluid seen at high
pH, which is likely therefore to be the microbial gastrin
inhibitor previously demonstrated in cultures of gut con-
tents. The similarity of the pH dependence over the range
3–5.5 of the gastrin inhibitory activity (see Fig. 2) and
abomasal microbial numbers (Simcock et al., 1999) sup-
port the contention that the gastrin inhibitor in parasi-
tised abomasal contents is the product of the microbial
population.
The nature of the inhibitor which was generated by
in vitro culture of abomasal fluid (Simcock et al., 2006) is
229
not known and attempts to isolate it have been unsuccess-
ful to date, as it is adhered firmly to columns and filters and
solvents able to elute it were toxic to the tissue in the
in vitro system (Simcock, 2000). As previously proposed
by Simcock et al. (2006), the mode of action may not be
through physiological inhibitory mechanisms involving
increased release of somatostatin (Holst et al., 1993; Debas
and Carvajal, 1994; Koop et al., 1997; Weigert et al., 1998),
but instead through disrupting a more fundamental cell
process such as exocytosis of vesicles containing gastrin
(Burgoyne and Morgan, 2003). If this were so, the G-cell
may not be the normal target of the bacterial product,
but this test system is detecting in vitro a chemical which
targets another cell population in vivo.
There is no clear evidence from the present experiments
that serum gastrin concentrations in parasitised sheep can
be acutely reduced by the presence of a gastrin inhibitor
in the abomasal contents of the sheep. Those particular
animals, however, did not show the marked decreases in
serum gastrin during periods of elevated abomasal pH
which are sporadically seen in parasitised sheep in similar
experiments (Lawton et al., 1996; Przemeck, 2003; Fox
et al., unpublished data). Serum gastrin concentrations
were related to abomasal pH in both groups of infected
sheep over the range about pH 3.5–5.5 (Fig. 3) but not at
normal or very high pH. This is consistent with the lack
of correlation between abomasal pH and serum gastrin in
control animals, as has also been reported from calves
(Fox et al., 1993). These experiments suggest that unex-
plained decreases in serum gastrin concentration in parasi-
tised sheep cannot be attributed to the presence of an
inhibitor in the abomasal contents, unless there is some
as yet unknown condition that facilitates this action in
some animals.
Acknowledgements
We thank Dr. J. Hansky for gastrin Ab 74 and the C.
Alma Baker Trust, E. and C. Thoms Bequest and Massey
University Research Fund for generously providing finan-
cial support for the experimental work and personal sup-
port for D.C. Simcock.
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