Biochemical and Molecular Action of Nutrients
Research Communication
Secretion of Trophic Gut Peptides
Is Not Different in Bolus- and
Continuously Fed Piglets1,2
(Manuscript received 11 September 2000. Initial review completed
12 October 2000. Revision accepted 30 November 2000.)
Johannes B. van Goudoever,* Barbara Stoll,*
Bolette Hartmann,† Jens Juul Holst,* Peter J. Reeds* and
Douglas G. Burrin*3
*U.S. Department of Agriculture/ARS Children’s Nutrition
Research Center, Department of Pediatrics, Baylor College of
Medicine, Houston, Texas 77030 and †Department of Medical
Physiology, The Panum Institute, University of Copenhagen, DK-
2200, Copenhagen, Denmark
ABSTRACT In neonates, bolus feeding is associated with
greater rates of intestinal growth than is continuous feed-
ing. We tested whether the concentrations and secretion
rates of trophic gut peptides are higher in bolus-fed than in
continuously fed piglets. Five 21-d-old piglets were surgi-
cally implanted with gastric, arterial and portal catheters
and a portal blood flow probe. At postnatal d 30 and 31, pigs
received an equal amount of primed continuous or bolus
feeding of a cow’s milk formula in a randomized, crossover
design. During a 6-h period, portal blood flow and arterial
and portal concentrations of glucagon-like peptide-2 (GLP-
2), peptide YY (PYY) and gastric inhibitory polypeptide (GIP)
were measured. All hormone levels were significantly in-
creased within 1 h of the start of the experiment, indepen-
dent of the feeding modality. There were no differences
between bolus and continuous feeding in either the arterial
concentrations or secretion rates of GLP-2, PYY and GIP. In
both treatment groups, the increases in the plasma con-
centrations of GLP-2 and GIP after feeding were substan-
tially greater than those for PYY. We conclude that the
production or circulating concentrations of GLP-2, PYY and
GIP are not significantly different in bolus- and primed
continuously fed piglets. J. Nutr. 131: 729 –732, 2001.
KEY WORDS: ● intestinal growth ● bolus feeding
● continuous feeding ● glucagon-like peptide-2 ● peptide YY
● gastric inhibitory polypeptide
Continuous intragastric feeding is administered to infants
with impaired swallowing or gastrointestinal function. How-
ever, there is evidence that continuous feeding negatively
1
The contents of this publication do not necessarily reflect the views or
policies of the U.S. Department of Agriculture, nor does mention of trade names,
commercial products, or organizations imply endorsement by the U.S. Govern-
ment. This work was sponsored by NIH grant HD-33920 (D.G.B.) and by the U.S.
Department of Agriculture/ARS under Cooperative Agreement No. 58-6250-6001.
0022-3166/01 $3.00 © 2001 American Society for Nutritional Sciences.
729
affects whole body weight gain and feeding tolerance (Schan-
ler et al. 1999). Furthermore, continuous feeding is associated
with decreased mucosal and intestinal protein mass in com-
parison with bolus feeding (Shulman et al. 1994). However,
the impact of bolus versus continuous feeding on the physio-
logical signals that affect growth of the gut has not been
examined in detail.
Glucagon-like peptide-2 (GLP-2)4 and peptide YY (PYY)
have been implicated as humoral signals that mediate the
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intestinal trophic effects of enteral nutrition. PYY and, to a
lesser extent, GLP-2 have also been reported to suppress
gastric motility, gastric and pancreatic secretion and thus are
implicated as putative endocrine signals in the ileal brake
phenomenon (Holst 1997, Pappas et al. 1986, Wojdemann et
al. 1999). Both PYY and GLP-2 are produced locally in the
endocrine L cells distributed along the distal ileum and colon
(Adrian et al. 1985, Polak et al. 1971). Feeding is a potent
stimulus for the secretion of both GLP-2 and PYY into the
circulation (Xiao et al. 1999). We recently showed in neonatal
pigs that circulating concentrations of GLP-2 and PYY are
directly correlated with the levels of enteral nutrient intake as
well as with gut growth (Burrin et al. 2000a). Moreover, there
is evidence that GLP-2 and, to a lesser extent PYY have a
trophic effect on the gut, including in neonates (Burrin et al.
2000b, Gomez et al. 1995, Lovshin and Drucker, 2000). An-
other gut peptide secreted in response to feeding, gastric in-
hibitory polypeptide (GIP), is produced in the K cells, which
are located mainly in the duodenum (Tseng et al. 1993). GIP
not only stimulates the secretion of intestinal glucagon-like
peptides (Roberge and Brubaker 1993) but also may have an
indirect growth-promoting effect via stimulation of insulin
secretion (Fehmann et al. 1995). We hypothesized that bolus
feeding compared with continuous feeding is associated with a
higher secretion of gut peptides, especially GLP-2 and PYY.
Furthermore, we hypothesized that the pattern of secretion of
GLP-2 and PYY would parallel that of GIP.
METHODS
Animals. The protocol was approved by the Animal Care and
Use Committee of Baylor College of Medicine and was conducted in
accordance with the National Research Council’s Guide for the Care
and Use of Laboratory Animals. The study involved five 30-d-old
female crossbred piglets (Large White ⫻ Hampshire ⫻ Duroc) pur-
chased from the Texas Department of Criminal Justice, Huntsville,
TX. The pigs were received at 2 wk of age and fed a cow’s milk
replacer formula (Litterlife; Merrick, Union, WI), at a rate of 50 g 䡠
kg body⫺1 䡠 d⫺1. The composition (per kg dry matter) of Litterlife is
2
J.B. van G. was supported by the Sophia Foundation for Scientific Re-
search, the Nutricia Research Foundation and the Royal Netherlands Academy of
Science and Arts (Ter Meulen Fund).
3
To whom correspondence should be addressed at 1100 Bates Street.
E-mail: dburrin@bcm.tmc.edu
4
Abbreviations used: GIP, gastric inhibitory peptide; GLP-2, glucagon-like
peptide-2; PBF, portal blood flow, PDV, portal-drained viscera; PYY, peptide YY.
730 VAN GOUDOEVER ET AL.
500 g lactose, 100 g fat and 250 g protein. The calculated energy
density is 18 MJ gross energy/kg dry matter. The formula powder was
thoroughly mixed with water before feeding to achieve 215 g pow-
der/L.
Study design. The surgical procedures and postoperative care
have been described previously (Stoll et al. 1999). In brief, at a
postnatal age of 3 wk, piglets underwent surgery after being deprived
of food overnight. Catheters were implanted into the stomach, the
portal and jugular veins and the common carotid artery. An ultra-
sonic blood flow probe (Transonic Systems, Ithaca, NY) was placed
around the portal vein. After surgery, pigs received intravenous
nutrition for 2 d. Weight gain was restored to presurgical rates within
4 d after surgery.
At a postnatal age of 30 d, the piglets were deprived of food from
1800 to 700 h. Baseline (time ⫽ 0) arterial and portal blood samples
were taken, and the portal blood flow (PBF) was measured for 30 min.
In a randomized, crossover design, the piglets received either a bolus
feed containing one third of their daily intake (⬃80 mL/kg) in their
feeder on study day 1 or a priming feed of one twelfth (⬃20 mL/kg)
of their daily intake, directly followed by a continuous intragastric
infusion at a rate of one twenty-fourth of their daily intake per hour
(⬃10 mL/kg) on study d 2. Importantly, the total formula intake
during the 6-h period was the same (80 mL/kg) in both treatment
groups. Arterial and portal blood samples were drawn at hourly
intervals until 6 h from the start of the feeding. PBF was measured
continuously.
Sample preparation. Blood samples were drawn into EDTA (4.5
mg) tubes, mixed gently and immediately centrifuged at 2000 ⫻ g at
4°C for 10 min to obtain plasma. The chilled plasma samples were
quickly frozen in liquid nitrogen and stored at ⫺70°C until analysis.
All samples assayed for a given hormone were run in one assay.
Plasma GLP-2 concentrations were quantified using a specific N-
terminal radioimmunoassay as described previously (Hartmann et al.
2000). In short, plasma samples were extracted with 75% ethanol
(final concentration) and centrifuged at 3000 ⫻ and 4°C for 30 min.
The supernatant was decanted, lyophilized, and reconstituted to the
original plasma volume in assay buffer of 80 mmol sodium phos-
phate/L buffer, pH 7.5, containing 1 g valine-pyrrolidide/L (courtesy
of Novo Nordisk, Bagsvaerd, Denmark), 0.1% wt/vol human serum
albumin (ORHA; 20/21, Behring, Marburg, Germany), 10 mmol
EDTA/L and 0.6 mmol thimerosal/L (Sigma-Aldrich Chemical, St.
Louis, MO). For standards, we used human GLP-2, and the tracer was
bovine GLP-2 with a Thr123 Tyr12 substitution, 125I labeled ac-
cording to the chloramine-T method. Approximately 300-␮L ex-
tracted samples and human GLP-2 standards were incubated with 100
␮L rabbit GLP-2 antiserum, code no. 92160 (final dilution 1:25,000),
raised against an N-terminal fragment of human GLP-2; this anti-
serum specifically recognizes the N-terminal region of both the hu-
man and porcine GLP-2. Free and bound moieties were separated
with plasma-coated charcoal (E. Merck, Darmstadt, Germany). The
experimental detection limit of this assay is ⬍5 pmol/L, and the
intra-assay coefficient of variation is 5% at a concentration of 40
pmol/L. PYY and GIP were measured using a commercially available
radioimmunoassay kit specific for the porcine peptides (Peninsula
Laboratories, San Carlos, CA). Plasma samples (100 ␮L) and porcine
PYY standards were incubated with rabbit PYY antiserum (final
dilution, 1:10,000) raised against the full-length porcine PYY (1–36)
peptide. Porcine 125I-PYY was used as a tracer. The sensitivity of this
assay is ⬃5 pg/tube, and the intra-assay coefficient of variation was
15%. GIP was measured in plasma samples (100 ␮L) incubated with
rabbit antiserum raised against porcine GIP and compared with
porcine GIP standards. Porcine 125I-GIP was used as a tracer. The
sensitivity of the assay was 25 pg/tube, and the intra-assay coefficient
of variation was 7%.
Statistical analysis. All values are shown as the means ⫾ SE.
Differences in peptide production rates between the feeding modal-
ities were assessed by one-way ANOVA. Differences in PBF and
arterial peptide concentrations during the 6-h sampling period were
analyzed by repeated measures ANOVA. A difference of P ⬍ 0.05
was considered statistically significant.
RESULTS
PBF. There was a significant increase in PBF in response
to feeding (Fig. 1) that occurred 2 h after the start of the
feeding. However, the increase was not related to the modality
of feeding. On average, PBF was elevated to ⬃130 –150% of
baseline, reaching a maximum at 3 h in the bolus-fed group
and at 6 h in the continuously fed piglets. PBF remained above
baseline flow rates from 2 h throughout the entire study period,
with no significant differences between the two feeding mo-
dalities at any time.
GLP-2. The baseline arterial and portal concentrations of
GLP-2 were 18 ⫾ 8 pmol/L (bolus-fed pigs) and 26 ⫾ 10
pmol/L (continuously fed pigs). The largest increase in con-
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centration occurred within 1 h after the start of the feeding.
The concentration at 1 h was significantly different from the
baseline concentration in both groups (P ⬍ 0.001, Fig. 2). No
differences were found in GLP-2 concentrations between the
two feeding modalities during the 6-h experiment. Hourly
production of GLP-2 by the portal drained viscera was calcu-
lated on the basis of the difference in arterial and portal
concentration multiplied by the PBF. Almost identical pro-
duction rates for the two groups were obtained for GLP-2
measured over 6 h (Table 1).
PYY. The pattern of PYY secretion was similar to that of
GLP-2 (Fig. 2). However, the magnitude of change in arterial
concentrations after the start of feeding was much smaller.
Although GLP-2 concentrations increased fourfold to eight-
fold, PYY concentrations increased by only 50%. Again, we
found a significant increase in concentration within 1 h,
independent of feeding modality (P ⬍ 0.01). Neither arterial
nor portal concentrations were different in response to either
bolus or continuous feeding. The total PYY production rate by
the PDV was not significantly different between feeding mo-
dalities (Table 1).
GIP. Arterial GIP levels increased significantly within 1 h
of feeding and remained elevated throughout the experiment
in the continuously fed and bolus-fed piglets (P ⬍ 0.01, Fig.
2).The magnitude of response to feeding resembled the re-
sponse of GLP-2, with a fivefold to ninefold increase above
baseline concentrations. The total GIP production rate by the
PDV was not significantly different between groups (Table 1).
FIGURE 1 Portal blood flow (L 䡠 kg⫺1 䡠 h⫺1) in piglets in response
to either a continuous feeding or a bolus feeding of cow’s milk formula.
Values are means ⫾ SEM, n ⫽ 5. Hours refers to the time after the
initiation of feeding. Based on repeated measures ANOVA, portal blood
flow was significantly higher at t ⫽ 1– 6 than at baseline (t ⫽ 0) in both
groups (P ⬍ 0.01).
 TROPHIC GUT PEPTIDE SECRETION
FIGURE 2 Changes in arterial concentrations (pmol/L) of gluca-
gon-like peptide-2 (GLP-2), peptide YY (PYY) and gastric inhibitory
peptide (GIP) in piglets in response to either a continuous feeding or a
bolus feeding of cow’s milk formula. Values are means ⫾ SEM, n ⫽ 5.
Hours refers to the time after the initiation of feeding. Based on re-
peated measures ANOVA arterial concentrations of all three peptides
were significantly higher at t ⫽ 1– 6 than at baseline (t ⫽ 0) in both
groups (P ⬍ 0.01).
DISCUSSION
Feeding strategies that enhance either intestinal function
or the growth rate of preterm infants will improve their clin-
ical outcome and reduce hospitalization costs. Although the
nutritional support of preterm infants varies considerably, it
has become increasingly evident that providing enteral feed-
ings is beneficial for both gut growth and body weight gain.
However, it is less certain whether a bolus or continuous
feeding regimen provides the best feeding modality. Bolus
feeding increases both weight gain and intestinal growth com-
pared with continuous feeding (Schanler et al. 1999, Shulman
et al. 1994). Thus, given the evidence that GLP-2 and PYY
stimulate gut growth, we anticipated that the secretion of
731
these trophic peptides would be greater in bolus-fed than in
continuously fed piglets. However, we did not find any signif-
icant differences in either the arterial concentrations or the
PDV production rates of these peptide hormones, despite the
fact that circulating GLP-2 concentrations were 30 – 40%
higher in bolus- versus continuously fed pigs. In fact, the portal
production rates of both PYY and GIP tended to be higher in
continuously fed than bolus-fed pigs but were not statistically
significant because of the large variation. These results suggest
that a short-term period (i.e., 6 h) of either bolus or primed
continuous feeding does not significantly affect the secretion
rate or circulating concentration of these gut peptides. It is
possible that the small priming feeding in the continuous
group was sufficient to stimulate hormone secretion to a con-
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centration that was not different from the bolus group. This
was especially true for GIP, for which the circulating concen-
trations in both groups were increased to similar levels within
1 h of feeding. Thus, given these caveats, we speculate that if
differential secretion of these hormones does indeed mediate
the intestinal trophic effect of bolus versus continuous feeding,
then additional observations are needed to detect such differ-
ences or that more prolonged treatment periods (i.e., 5–7 d)
are necessary to produce differences in hormone concentra-
tions.
Although the K and L cells producing either GIP or GLP-2
and PYY, respectively, are found at different sites along the
gastrointestinal tract (Adrian et al. 1985, Polak et al. 1971,
Tseng et al. 1993), all peptide concentrations increased sig-
nificantly within the 1st h. That GIP concentrations would
rise within 1 h was predictable, because K cells are located in
the proximal small intestine (Knapper et al. 1995). However,
it appears unlikely that within 1 h enteral nutrients would
come in direct contact with the L cells located in the distal
bowel, which implies that other mechanisms are probably
involved in the secretion of GLP-2 and PYY. Indeed, GIP
stimulates GLP-1 secretion from the L cell, and thus probably
GLP-2 as well (Roberge and Brubaker 1993). If so, it seems
that GIP has a differential effect on L-cell hormone secretion,
because the pattern of secretion of PYY was clearly different
from that of GLP-2. Besides the endocrine system, the para-
sympathetic nerves and the adrenergic system may play a role
in the secretion of these gut peptides (Rocca and Brubaker
1999, Sheikh et al. 1989). Thus, it is evident from the present
study that direct interaction of nutrients with the L cells per se
is not required to obtain a surge in GLP-2 or PYY secretion.
Furthermore, based on the differences in the rise in arterial
concentrations of PYY and GLP-2, it is likely that PYY secre-
tion, although produced in the same cell as GLP-2, is regulated
quite differently than GLP-2 secretion.
TABLE 1
Portal production rates of GLP-2, PYY and GIP in piglets
during a 6-h period after either a bolus feed or a continuous
infusion of a cow’s milk formula1
Bolus Continuous
pmol 䡠 L⫺1 䡠 kg⫺1
GLP-22 161 ⫾ 57 168 ⫾ 33
PYY 98 ⫾ 28 122 ⫾ 55
GIP 247 ⫾ 125 313 ⫾ 89
1 Means ⫾ SE, n ⫽ 5.
2 GLP-2, glucagon-like peptide-2; PYY, peptide YY; GIP, gastric
inhibitory peptide.
732 VAN
Another striking difference between the secretion pattern
of GLP-2 and GIP with that of PYY was the magnitude of the
increase after feeding. Although maximal PYY concentrations
showed a 50% increase, GLP-2 and GIP increased fourfold to
eightfold. The magnitude of increase in GLP-2 concentrations
after a meal in our study was higher than that found in adult
humans (Hartmann et al. 2000, Orskov and Holst 1987, Xiao
et al. 1999), whose GLP-2 levels increased 1.3- to 4-fold. This
might be a consequence of the stage of development, because
circulating concentrations of PYY decrease with age (Adrian
et al. 1986). However, the increase in GLP-2 levels in bolus-
fed pigs was even greater than the difference that we found
previously between neonatal pigs fed either enterally or par-
enterally (⬃2-fold) (Burrin et al. 2000a). GIP secretion in-
creases threefold in response to feeding in ⬃8-wk-old pigs to a
maximum of 400 pmol/L, yet the relative increase in the
postfeeding plasma concentrations of our younger piglets was
much higher.
The circulating concentration of these gut peptides is de-
termined not only by the production rate but also by the
clearance rate. Recent evidence shows that the kidneys are the
major site of GLP-2 clearance (Tavares et al. 2000). That
neonates have lower renal clearance rates is well known and
might explain the higher levels we found in our neonatal
piglets compared with those of older mammals. We are not
aware of any studies that measured the production of gut
hormones by the PDV, so we cannot determine whether the
relatively high concentrations of hormones we found were due
to a lower clearance rate or a higher production rate in the
neonatal pig.
In conclusion, we did not find a significant difference in the
concentrations of GLP-2, PYY or GIP in response to a primed
continuous versus bolus feeding. Moreover, the overall pro-
duction rate of these trophic peptides by the PDV was not
significantly different. Thus, if indeed bolus feeding is more
trophic to the gut mucosa than continuous feeding, the re-
sponse does not appear to be mediated via acute differences in
GLP-2, PYY or GIP secretion.
ACKNOWLEDGMENTS
We thank X. Chang for laboratory analysis and L. Loddeke for her
expert editorial assistance.
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