August 31, 2008
Colostrum Supplementation Restores Insulin-Like Growth Factor-1 Levels and Alters Muscle Morphology Following Massive Small Bowel Resection
By Pereira-Fantini, Prue M Thomas, Sarah L; Taylor, Russell G; Nagy, Eva; Sourial, Magdy; Fuller, Peter J; Bines, Julie E
Background: Colostrum protein concentrate (CPC) contains a high level of insulin-like growth factor-1 (IGF-1). IGF-1 and IGF binding protein (IGFBPs) may play an important role during the postresection adaptation response. As smooth muscle is an important site for IGF- 1 action in the intestine, this study aims to (1) investigate the effect of CPC supplementation on circulating levels and tissue expression of IGF-1, IGF-1 receptor, and IGFBPs following massive small bowel resection (MSBR), and (2) characterize the effect of CPC on the muscular adaptation response following MSBR. Methods: Four- week-old piglets underwent either a 75% MSBR or sham operation. Piglets received either a polymeric infant formula (PIF) diet or PIF supplemented with CPC for 8 weeks. Serum was analyzed by enzyme- linked immunosorbent assay, and ileal tissue assessed by molecular and histological analysis. Results: There was no difference in IGF- 1 or IGFBPs mRNA among groups. CPC treatment resulted in significant increases in circulating levels of IGF-1 and IGFBPs and a concurrent increase in muscle width and the number of muscle cells, but did not alter muscle cell size. Conclusions: Strategies aimed at increasing muscular adaptation may decrease Gl transit and allow greater mucosal contact time for absorption. We have shown that CPC supplementation following resection results in increased levels of circulating IGF-1, IGFBP-2, and IGFBP-3 and muscular hypertrophy. Our results suggest that IGF-1 and its mediators may play a role in the muscular adaptation response and warrant further exploration as a treatment option for short bowel syndrome. (JPEN J Parenter Enteral Nutr. 2008;32:266-275) Keywords: resection; short bowel syndrome; intestinal adaptation
Intestinal adaptation after small bowel resection is believed to be influenced by several factors including luminal nutrition,11,12 pancreaticobiliary secretions,13 hormones, and peptide growth factors.14,15 We have previously shown that supplementation of an infant formula diet with bovine colostrum protein concentrate (CPC) results in enhanced mucosal adaptation and normal weight gain.16 Colostrum is the first milk produced by a mammal during the postpartum period and contains a higher content of immunoglobulins, vitamins, minerals, cytokines, and growth factors, including insulin- like growth factor-1 (IGF-1) compared with mature milk.17
Several lines of evidence suggest an important role for IGF-1 during the postresection adaptation response. IGF-1, the IGF-1 receptor (IGF-1R), and IGF binding proteins (IGFBPs) are localized to specific sites in the intestine.18,19 Elevated circulating levels of the IGFBPs and increased expression of IGF-1 and IGF-1R have been observed in the remnant small bowel after resection.20-23 In addition, exogenous administration of IGF-1 has been shown to augment several morphological and functional parameters of postresection intestinal adaptation23-26 and reverse intestinal atrophy associated with parenteral nutrition therapy.27 Increased expression of IGF-1 has also been shown to markedly accelerate the healing of colonic anastomoses.28
The effects of IGF-1 are modulated by the presence of 6 IGFBPs, and these binding proteins act by inhibiting or facilitating the interaction of IGF-1 with its receptor.29,30 IGFBPs modulate IGF-1 bioavailability by competitive binding and sequestration thereby preventing appropriate interactions with cell membrane receptors.31- 34 The action of individual IGFBPs, to inhibit or facilitate the binding of IGF-1, is both tissue and binding protein specific.29,30 IGF-1, IGFBP-4, and IGFBP-5 are expressed within rat colon, whilst IGF-1, IGFBP-3, IGFBP-4, and IGFBP-5 are expressed by smooth muscle cells cultured from the human intestine.35-39 Infusion of exogenous recombinant human IGF-1 increases the thickness of the muscularis externa in normal rats.38 Transgenic mice that overexpress IGF-1 exhibit a thickened muscularis propria.18 In vitro, IGF-1 has been shown to increase IGFBP-5 synthesis in a rat intestinal smooth muscle cell line.39 This in vivo and in vitro evidence suggests that smooth muscle may be an important site for IGF-1 actions in the intestine. Using a juvenile piglet model of SBS, the current study aims to (1) investigate the effect of CPC supplementation on circulating levels and tissue expression of IGF-1, IGF-1R, and the IGFBPs following MSBR, and (2) to characterize the effect of CPC on the muscular adaptation response following MSBR.
Materials and Methods
Animals and Experimental Design
The study protocol was approved by the Animal Ethics Committee of the Royal Children's Hospital (Parkville, Australia), and all experiments were conducted according to the National Health and Medical Research Council of Australia guidelines.40 Weaned female 3- week-old piglets (Landacre/Large White cross; Victorian Institute of Agriculture Science, Werribee, Australia) were transported to the Royal Children's Hospital animal facility and acclimatized before surgery. Piglets were housed at a temperature of 22[degrees]C with a 12-hour light-dark cycle.
The surgical procedures used in this experiment have been described previously.16,41,42 In summary, 4-week-old piglets underwent either a 75% proximal small bowel resection or sham operation. The 75% small bowel resection included the removal of the small bowel from 1 m distal to the ligament of Treitz to 2.5 m proximal to the ileocecal valve. The total bowel length at operation was an average of 12 m long between the pylorus and the ileocecal valve. During the transection procedure, the intestine was transected and re-anastomosed at a site 2.5 m proximal to the ileocecal valve.
Perioperatively, all piglets received an IV antibiotic (70 mg/kg amoxycillin; CSL, Parkville, Australia) and an intramuscular analgesic (150 mg/d flunixin meglumine; Shering Plough Inc, Baulkham Hills, Australia) from the day of operation until day 3 after the operation. Additionally, piglets were maintained on Hartmann's solution (Baxter Inc, Old Toongabie, Australia) during days 0, 1, and 2 postoperatively at 7 mL/kg/h. Water and a polymeric infant formula (PIF) diet were introduced from the third day (Karicare De- lact; Nutricia Ltd, Baulkham Hills, Australia). From the time the diet was introduced, animals also received a daily supplement of potassium, ranitidine, dibasic calcium phosphate, and iron supplements and 20% sodium chloride solution to meet the daily requirements for pigs. Colostrum-treated piglets received an additional daily supplement of 13g/kg of bovine colostrum protein concentrate (Intact(TM); Numico Research, Oakden, Australia) mixed in with their PIF feed. Treatment groups included sham-operated PIF (n = 3), resected PIF (n = 6), sham-operated PIF supplemented with CPC (PIF+CPC; n = 6), and resected PIF+CPC (n = 9).
Serum required for total protein and IGF-1 and IGFBP estimation was collected 24-48 hours before killing. At sacrifice (8 weeks after operation), ileal samples for histological and molecular studies were obtained from 10 cm below the anastomosis site in both resection and sham-operated animals. Histologic samples were placed immediately in 10% neutral buffered formalin (Australian Biostain Pty Ltd, Traralgon, Australia) before processing and subsequent paraffin embedding. Ileum samples required for molecular studies were immediately snap-frozen.
Circulating Protein Levels
The concentration of growth hormone (GH) and IGF-1 present in serum samples was measured using enzyme-linked immunosorbent assay (ELISA) kits for human GH or IGF-1 (DSL, Webster, TX), and circulating levels of IGFBP-1, IGFBP-2, and IGFBP-3 were determined using human ELISA kits (RayBiotech, Norcross, GA). All kits were used according to the manufacturers, instructions and the high level of sequence homology (>90%) between human and porcine IGF-1, GH, and the IGFBPs permitted the use of human ELISA kits in the piglet model.
Table 1. Primer Sequence for Reverse Transcription Analysis
Analysis of Messenger RNA Expression
Total RNA from ileal tissue was extracted with TRIpure reagent (Roche Diagnostics Australia, Castle Hill, Australia). Primer sequences for reverse-transcription PCR analysis were derived from published porcine complementary DNA (cDNA) sequences using the Primer 3 design program (http://frodo.wi.mit.edu; Table 1). Total RNA (2 [mu]g) was reverse transcribed into cDNA using avian myeloblastosis virus reverse transcriptase (Roche Diagnostics Australia, Castle Hill, Australia) primed with 0.2 mcg of oligo(dT). A total of 2 mcL of cDNA was amplified as follows: 10 mmol/L Tris- HCl, 50 mmol/L KCl, 2 mmol/L MgCl,, 200mcmoI/L deoxynucleoside triphosphates, 25 pmol each of forward and reverse primer, and 1.25 units Taq polymerase (Sigma-Aldrich, Castle Hill, Australia). Optimal annealing temperatures and cycle number were predetermined for each primer pair (Table 1) to ensure that amplification was in the linear range. No reverse transcriptase (RT) controls of each sample and primer pair were included to ensure that RNA sample reagents were not contaminated. A 100-bp DNA ladder was run alongside the polymerase chain reaction (PCR) samples to confirm that the amplification products were of the expected size. PCR products were visualized by agarose/ethidium bromide gel electrophoresis and quantified using the ImageJ software system (http://rsb.info.nih.gov/ij). Macroscopic and Histologic Assessment
At sacrifice, the length of gut was measured in vivo, from the pylorus to the ileocecal valve. A segment of ileum located 10 cm distal to the anastomosis site was removed and subsequently fixed in 10% neutral buffered formalin (Australian Biostain Pty Lyd, Traralgon, Australia) before processing. Paraffin sections (4 [mu]m) were stained with hematoxylin and eosin. Morphometric analysis was performed by 2 blinded observers using ImageJ software for Windows version 1.34s. At least 5 fields of view were assessed per pig. Area measurements of the circular and longitudinal muscle were manually outlined with the software drawing tool, and the program was used to generate values based on previous calibration.
Immunohistochemistry using an antibody directed toward Dysferlin (Novocastra; Mount Waverly, Australia), a protein localized to the muscle plasma membrane, was used to facilitate the quantitation of circular muscle area. After antigen retrieval (Dako AJS, Glostrup, Denmark), staining was completed using a polymer link detection kit (Novocastra) per the manufacturer instructions. After staining, cells were photographed at x40 magnification with a NikonCoolpix 4500 camera (Nikon, Japan) attached to a Leica microscope (Leica, Germany). ImageJ software for Windows version 1.34s was used to measure the cell area of a minimum of 10 cells/pig. The number of cells located in an area of 1244 mcm^sup 2^ was also recorded.
Colostrum Supplementation Increased Circulating Levels of IGF-1, IGFBP-2, and IGFBP-3 Following Resection, but Did Not Alter Circulating Growth Hormone Levels
After resection, a nonsignificant increase in circulating GH levels was observed in PIF-alone animals when compared with sham- operated controls, however, colostrum supplementation did not influence the circulating growth hormone levels of either the sham or resected, colostrumsupplemented groups (Figure 1A). There was no significant difference in circulating IGF-1 levels between PIF- alone and colostrum-supplemented sham piglets. However, after resection, PIF-alone piglets exhibited a significant decrease in circulating IGF-1 (Figure 1B; P
IGFBP-1 levels appeared to increase in both shamoperated and resected piglets following colostrum supplementation, however, this increase did not reach significance (Figure 1C).
Figure 1. Colostrum supplementation results in significantly increased levels of circulating insulin-like growth factor-1 (IGF- 1), IGF binding protein-2 (IGFBP-2), and IGFBP-3 in resected piglets. Serum was obtained from piglets fed either polymeric infant formula (PIF; white bars) or PIF supplemented with colostrum (PIF+CPC; black bars) and undergoing either a sham-operation or a 75% small bowel resection and enzyme-linked immunosorbent assay used to detect changes in (A) growth hormone (GFI), (B) IGF-1, (C) IGFBP- 1, (D) IGFBP:2, or (E) IGFBP-3. Values are mean +- SEM, **P
Circulating levels of IGFBP-2 were significantly increased in colostrum-supplemented, resected piglets when compared with both their sham-operated counterparts, and PIF-alone fed, resected piglets (Figure 1D; P
As depicted in Figure 1E, colostrum supplementation resulted in significant increases in circulating IGFBP-3 levels in both sham- operated and resected piglets, when compared with their operation counterparts that received PIF-alone (P
Colostrum Supplementation Had No Effect on Tissue Levels of IGF- 1, IGF-1R, or IGFBP mRNA in the Ileum
Semiquantitative RT-PCR was performed to examine changes in ileal expression of IGF-1, IGF-1R, IGFBP-2, IGFBP-3, and IGFBP-5 mRNA (Figure 2). Colostrum supplementation resulted in an increase in IGF- 1 and IGF-1R mRNA levels in the ileum of sham-operated piglets, but did not affect tissue levels of IGF-1/IGF-1R mRNA in resected piglets when compared with PIF alone.
Figure 2. Colostrum supplementation results in the blockage of the resection-related increase in insulin-like growth factor binding protein-3 (IGFBP-3) mRNA. Ileum tissue was obtained from piglets fed either polymeric infant formula (PIF; white bars) or PIF supplemented with colostrum (PIF+CPC; black bars) and undergoing either a sham-operation or a 75% massive small bowel resection (MSBR). mRNA levels of (A) IGF-1, (B) IGF-1 receptor (IGF-1R), (C) IGFBP-2, (D) IGFBP-3, and (E) IGFBP-5 were measured by densitometry and standardized against the housekeeping gene L32. (F) Representative electrophoresis gels. Values are mean +- SEM, *P
A significant increase in IGFBP-2 mRNA was observed in PIF-alone fed animals after resection (Figure 2C; P
Figure 3. Colostrum supplementation causes muscle hypertrophy in sham-operated and resected piglets. Ileum tissue was obtained from piglets fed either polymeric infant formula (PlF; white bars) or PIF supplemented with colostrum (P1F+CPC; black bars) and undergoing either a sham-operation or a 75% small bowel resection. Circular muscle (A) and longitudinal muscle area (B) were measured in ileum tissues, then the number of cells per area (C) and size of the circular muscle cells (D) were determined. (E) Representative photographs of circular (C) and longitudinal (L) muscle from PIF/ sham (i), PIF+CPC/sham (ii), PIF/MSBR (iii), and PIF+CPC/MSBR (iv) are shown. Values are mean +- SEM, *P
Colostrum Supplementation Results in Hyperplasia of the Circular and Longitudinal Muscle in Sham-Operated Piglets
As depicted microscopically in Figure 3E, circular muscle area was significantly increased in sham-operated, colostrum- supplemented piglets (Figure 3A, compared with PIF-alone, sham- operated piglets; P
Figure 4. Colostrum supplementation results in bowel lengthening in sham-operated piglets. The length of bowel between (A) the pylorus and anastomosis site and (B) the anastomosis site and ileocecal valve (ICV) together with (C) the total gut length was measured in piglets fed either polymeric infant formula (PIF; white bars) or PIF supplemented with colostrum (PIF+CPC; black bars) and undergoing either a sham-operation or a 75% small bowel resection. Values are mean +- SEM, *P
Colostrum Supplementation Results in Significantly Increased Bowel Length in Sham-Operated Piglets
A significant difference in gut length between the pylorus and anastomosis site was observed between PIF-alone and colostrum- supplemented sham-operated piglets (Figure 4A). There was no difference observed in resected piglets. After resection, PIF-alone fed piglets had increased gut length between the anastomosis site and the ileocecal valve (ICV, Figure 4B; P
SBS remains a major clinical problem in children and adults.43 Clinical outcome of short bowel patients is dependent on the ability of the residual intestine to adapt to the loss in bowel length. Although the majority of studies have focused on the mucosa, all layers of the bowel wall are believed to be involved in the postresection adaptive response. Changes within the muscle layer may influence clinical features of SBS such as recurrent vomiting, rapid intestinal transit, and abnormalities in intestinal motility. We have previously described significantly attenuated mucosal changes in resected piglets fed a diet supplemented with bovine colostrum protein concentrate.16 The current study explores the influence of colostrum supplementation on adaptive changes in the intestinal muscle and changes in circulating GH, and circulating and tissue levels of IGF-1, IGF-1R, and IGFBPs. Evidence obtained from rodent models suggests that members of the IGF-1 family participate in regulation of intestinal adaptation. Elevated circulating levels of the IGFBPs and IGF-1R, with unaltered levels of IGF-1 have been recorded in rat models of 60% jejunoileal and jejunocolic resection.20,21 These data are discordant with the current study in which we report a significant decrease in circulating IGF-1 levels, and no change in circulating IGFBP-1, -2, or -3 levels in a piglet model of 75% small bowel resection. There are several important differences in study design between our study and the previous rodent studies that may help explain the disparity. These differences include (1) species difference (rodent vs pig), (2) extent of intestinal resection (60% vs 75% resection), (3) time course duration (48 hours or 7 days vs 8 weeks), and (4) the age of animals used (adult rodents vs infant pigs). Early experiments by Hanson et al44 determined that the degree of intestine response to resection increases with the amount of tissue removed, and the increased amount of bowel removed in the current study may account for the more marked alteration in IGF-1 response seen. Alternatively, differences in the time course of the experiment may also have been a factor. A study by Gillingham et al20 observed increased circulating levels of IGFBP-1, -2, -3, and -5 at 7 days after resection, followed by decreased serum IGFBP-3 levels at 17 days after resection.
The current study has found that colostrum supplementation reverses the adaptation-induced decrease in circulating IGF-1 levels and increases circulating levels of IGFBP-1, IGFBP-2, and IGFBP-3 after resection. In mammals, colostrum supplementation has been associated with increased plasma IGF-1,45,46 whereas reduced colostrum feeding is associated with decreased concentrations of plasma IGF-1 and decreased IGFBP-3/IGFBP2 ratios.45 Indirect evidence has suggested that increases in plasma levels of IGF-1 and IGFBPs may be due to absorption of colostral IGF-1 and IGFBPs into systemic circulation.47 An additional influence on plasma IGF-1 and IGFBP concentrations within the supplemented and control resected groups may have been the presence of additional protein in the colostrum-supplemented group. Although the diets were isocaloric, they were not isonitrogenous due to the intrinsic protein content of colostrum. Nutrient intake has been shown to affect plasma concentrations of IGF-1 and IGFBPs19,48; however, increased protein intake is not likely to be wholly responsible for increases in plasma IGF-1 and IGFBPs after colostrum supplementation, as Wester et al49 have shown that the IGF-1 plasma concentration in neonatal piglets fed colostrum remains higher than that of control pigs, despite equivalent protein intake.
Within the GI tract, IGF-1 receptors have been localized to both the mucosal and muscle layers,50 whereas IGF-1, IGFBP-3, IGFBP-4, and IGFBP-5 are expressed by smooth muscle cells cultured from the human intestine and rat colon.51 After massive small bowel resection, we found ileal levels of IGF-1 and IGF-1R mRNA remained unchanged. This finding is consistent with results in rodent models.52 Tissue levels of IGFBP-2, IGFBP-3, and IGFBP-5 mRNA increased by approximately 30%, in conflict with rodent studies in which IGFBP-3 mRNA levels are decreased in the ileum after resection.23 Species differences between the rodent and pig models and differences in the adaptation time point studied may explain these discrepancies. Of interest, colostrum supplementation appeared to have no effect on tissue levels of IGF-1, IGF-1R, IGFBP-2, or IGFBP-5 mRNA in resected piglets, but did block the resection- induced increase in IGFBP-3 mRNA levels observed in PIF-alone animals. This concurs with studies performed in neonatal cows, in which intestinal expression of IGFBPs was shown to differ between day 1 and day 5 postpartum due to differences in the amount of colostrum present in milk.53 The current study was unable to elucidate the functional importance of the increase in IGFBP3 observed after resection, however, IGFBP-3 has been shown to negatively regulate fibroblast proliferation,54 and promote apoptosis and differentiation of intestinal epithelium,55 suggesting that IGFBP-3 may play an important role in regulation of the adaptation response.
IGF-1 has been previously shown to regulate the growth of human intestinal smooth muscle by means of stimulation of proliferation and inhibition of apoptosis.56 Infusion of exogenous recombinant human IGF-1 in vivo has been shown to increase IGF-1 levels and induce proliferation of smooth muscle cells and consequently increase the thickness of the muscularis externa in normal, transected and resected rats.23,57 In this study, we have shown that colostrum supplementation causes increased circulating IGF-1 and thickening of the longitudinal and circular muscle, however, unlike the previous rodent and canine studies,2,3,5,10 we did not observe thickening of the muscle wall in response to resection alone.
IGFBP-1, IGFBP-3, and IGFBP-5 have been reported to regulate cell growth independently of IGF-1.30,58 In the current study, colostrum supplementation blocked a resection-related increase in IGFBP-3 mRNA, but had no effect on IGF-1 tissue mRNA levels. Kuemmerle et al56 have shown that IGFBP-3 directly inhibits human intestinal smooth muscle growth, and that immunoneutralization of secreted IGFBP-3 resulted in increased proliferation in cultured human intestinal smooth muscle cells.56 Similarly, IGFBP-3 protein levels have been shown to be lowest in rapidly proliferating human intestinal muscle cells,35 and in a rodent model of MSBR, IGFBP-3 mRNA levels fall within 48 hours of resection.52 Therefore, the increase in proliferation and intestine muscle area in colostrum- supplemented piglets after resection may be due to inhibition of IGFBP-3.
GH is produced in the anterior pituitary gland, with production regulated by IGF-1 at the level of the anterior pituitary through a negative feedback mechanism.59 Of interest, in the current study, we failed to detect a change in growth hormone levels after resection, despite a significant decrease in circulating IGF-1 levels. Circulating IGF-1 is mostly derived from the liver as a result of binding between circulating GH and the GH receptor in target cells; however, IGF-1 synthesis is not only regulated by GH but also by nutrient supply and by other hormones such as leptin.60,61 Our results, in which intestinal resection has resulted in reduced levels of circulating IGF-1, independent of growth hormone, warrant further exploration of the role of nutrition status and leptin in the regulation of IGF-1 postintestinal resection.
For patients with SBS, intestinal length remains as the most predictive indicator for the need of long-term parenteral nutrition supplementation.62 We have described a significant increase in bowel length between the anastomosis site and the ileocecal valve after small bowel resection, but no change in bowel length proximal to the anastomosis. This finding is in agreement with the results of previous piglet studies.63 Colostrum supplementation failed to induce a further lengthening after resection, but did result in a significant lengthening proximal to the anastomosis site in sham- operated animals. Results suggest that increased weight gain and absorptive capacity are not directly attributable to increased bowel length.
In conclusion, SBS remains a major clinical challenge as patients suffer from malnutrition and malabsorption associated with the loss of surface area after intestinal resection. Few studies have focused on changes beyond the mucosa; however, strategies aimed at increasing adaptation within the muscular layers may decrease GI transit time and allow greater mucosal contact time for nutrient and fluid absorption. This study has described adaptive changes within the muscle following small bowel resection and shown that bovine colostrum supplementation results in increased levels of circulating IGF-1 together with muscular hypertrophy and decreased ileal levels of IGFBP-3 mRNA.
The authors thank Mike Sharpe and Nutricia for their generous donation of the polymeric infant formula Karicare De-Lact. We also acknowledge the support of Tony Scammell from Numico Research for the donation of bovine colostrum protein concentrate.
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Prue M. Pereira-Fantini, B. Sci, PhD1; Sarah L. Thomas, B. Sci1; Russell G. Taylor, FRACS2; Eva Nagy, B. Med Sci, MBBS3; Magdy Sourial, B. Vet Sci1; Peter J. Fuller, MBBS, PhD, FRACP4; and Julie E. Bines, MBBS, MD, FRACP1,3,5
Financial disclosure: none declared.
From the 1 Murdoch Childrens Research Institute, and 2 Department of Surgery, Royal Children's Hospital, Parkville; 3 Department of Paediatrics, University of Melbourne, Parkville; 4 Prince Henry's Institute, Clayton; and 5 Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital, Parkville, Australia.
Received for publication November 15, 2007; accepted for publication January 24, 2008.
Address correspondence to: Prue M. Pereira-Fantini, Intestinal Failure and Clinical Nutrition Group, Murdoch Childrens Research Institute, 8th Floor, Atlantic Philanthropy Building, Flemington Road, Parkville 3052, Victoria, Australia; e-mail: [email protected]
Copyright American Society for Parenteral and Enteral Nutrition May/ Jun 2008
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