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University of Wisconsin-Madison, Department of Nutritional Sciences, Madison, WI 53706
2To whom correspondence should be addressed. E-mail: ney{at}nutrisci.wisc.edu.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • total parenteral nutrition • jejunal mucosa and muscularis • IGF-I
Renewal of the epithelial cells lining the digestive tract is regulated by enteral or luminal nutrients as well as systemic or parenteral nutrients. Total parenteral nutrition (TPN)3 is a useful tool with which to study intestinal adaptation because TPN eliminates stimulation of the gastrointestinal tract by exogenous luminal nutrients without the complications induced by malnutrition or fasting. TPN induces mucosal hypoplasia consisting primarily of a decrease in villus height in rats (1,2), rabbits (3), dogs (4), piglets (5), and normal humans (6). The degree of mucosal hypoplasia induced by TPN differs somewhat between species in association with different rates of epithelial cell turnover. For example, rats show dramatic TPN-induced hypoplasia that is specific to the small bowel mucosa, rather than the muscularis layer, and is associated with reductions in enterocyte proliferation and increased apoptosis throughout the crypt and bottom half of the villus (2). The limited studies in humans suggest that the mucosal hypoplasia induced by TPN is less severe than that observed in rats, 20 vs. 50% reduction in villus height (2,6,7), although evidence of increased intestinal permeability and remodeling of the epithelium and lamina propria structure is present (6,8). The metabolic characteristics of TPN-induced mucosal hypoplasia include decreased intestinal blood flow, decreased gut hormones, and increased protein catabolism (5).
Sepsis is a major complication of TPN in humans. The mouse TPN model has provided helpful insights regarding the effect of exogenous luminal nutrients on intestinal mucosal immunity (9–13). However, the extent of intestinal atrophy induced by TPN in mice is unclear, as reflected in conflicting reports using the same species of mice (11,12,14). It is important to clarify the degree and location of intestinal atrophy induced by TPN in mice so that we can understand how to apply this model to study the complications of TPN in humans.
Administration of systemic growth factors is under investigation to reduce the infectious, metabolic, and intestinal complications associated with TPN. Bombesin (9) and keratinocyte growth factor (11) were shown to have positive effects on intestinal immune function in TPN mice. Glucagon-like peptide-2 stimulates intestinal blood flow in association with increased protein synthesis and intestinal proliferation in TPN piglets (5) and reduces mucosal hypoplasia in TPN rats (15). Moreover, we showed that administration of insulin-like growth factor-I (IGF-I) attenuates TPN-induced mucosal hypoplasia in rats by increasing enterocyte proliferation and reducing apoptosis (2,7). Consistent with a genetic mouse model of IGF-I overexpression (16), increased expression of insulin-like growth factor-I binding protein (IGFBP)-5 is the strongest correlate of mucosal growth in TPN rats treated with IGF-I (17,18). The effect of IGF-I infusion on intestinal structure in TPN mice has not been reported and this information is needed to use genetic mouse models effectively to further our understanding of the role of the IGF-I system in intestinal growth and repair. Thus, our objective was to assess the extent of intestinal atrophy in mice maintained with TPN and the ability of systemic infusion of IGF-I to attenuate the response.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Experimental design. One day before surgery, the mice were randomly assigned to 1 of 3 groups: an oral reference group (Oral) 2 parenterally fed groups comprising a TPN group (TPN) and a TPN+IGF-I group (TPN+IGF-I). Mean initial body weight (BW) did not differ among the 3 groups (20.6 ± 0.3 g). The Oral group was not restrained and had free access to the rodent diet throughout the experiment. Mice from the 2 parenterally fed groups were anesthetized by i.p. injection of a mixture of ketamine (100 mg/kg BW) and xylazine (10 mg/kg BW). A silicone rubber catheter (0.30 mm i.d.; 0.64 mm o.d.) was inserted into the vena cava through the right jugular vein. The proximal end of the catheter was tunneled s.c. to the back of the mouse, exiting the tail at its midpoint (9). To protect the catheter during infusion, the mice were partially immobilized by tail restraint (Fig. 1). Mice tolerate this partial restraint without evidence of physical stress (19) or stimulation of corticosteroids and catecholamines (20).
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Tissue collection and analysis. The entire small intestine from pylorus to ileocecal valve and the colon were rapidly removed and flushed with ice-cold saline. The weight and length of the small bowel and colon were recorded. Different segments of small bowel were collected as follows: duodenum (from pylorus, proximal 4-cm piece of small bowel), jejunum (after 4 cm, up to 10 cm proximal to ileocecal valve) and ileum (distal 10 cm of the small bowel up to ileocecal valve). The length of the jejunum was measured and each segment was weighed individually after being cut into sections for various analyses. The first 2 cm of jejunum were used for intact wet/dry weight measurements. The next 4 cm of jejunum were cut open and the mucosa was scraped from the muscularis to measure mucosal and muscularis wet/dry weights. The next 0.5 cm of jejunum was fixed in a 10% buffered formalin solution (Fisher Scientific) for morphometric analysis. The following 4 cm of jejunum were scraped and both the mucosa and muscularis were used for the measurement of protein (bicinchoninic acid protein assay, Pierce Chemical), DNA contents, and sucrase activity (24). The remainder of the jejunum (5–7 cm) was snap-frozen in liquid nitrogen for RNA extraction. Duodenum, ileum, and colon were snap-frozen for protein and DNA content and/or RNA extraction. Liver, kidney, and spleen were removed, weighed, and snap-frozen.
The fixed tissue from the proximal jejunum was embedded in paraffin and 5-µm sections were stained with hematoxylin and eosin. Villus height, crypt depth, and muscularis thickness, including inner circular and outer longitudinal muscle layers, were measured using a light microscope and SigmaScan software (21). For each mouse, 20–30 measurements from 4 different tissue sections were obtained and used to calculate a mean morphometric value; these individual values were then used to calculate the group treatment means and variances for statistical comparison. All measurements were performed by one investigator who was unaware of the treatments.
Western ligand blot. Western ligand blotting was done using 2 µL of serum as previously described (24). Bands were detected and quantified in the 2 molecular weight ranges: a lighter band in the range of 38–43 kDa and a darker band in 30–34-kDa range. The band intensities were quantified by OptiQuant and expressed as mean density light units.
IGFBP-5 and IGF-I mRNA protection assay.
A ribonuclease protection assay (RPA) was used to measure IGFBP-5 and IGF-I mRNA in intact sections of jejunum and ileum. Probes were derived from cDNAs subcloned into pGEM4z. The vectors were kindly provided by Dr. M. L. Adamo (University of Texas Health Science Center, San Antonio, TX). Both plasmids were linearized with EcoR1, and RNA Polymerase T7 was used to generate radiolabeled antisense RNA probes (MaxiScript, Ambion). The 361-bp IGFBP-5 antisense probe protected a band at 286 bp. The 386-bp IGF-I probe protected 2 bands: exon 2 at 
300 bp and exon 1, a little over 200 bp. 18S ribosomal RNA was measured along with mRNA as an internal as well as experimental control. An antisense pTRI RNA 18S control template (Ambion) was used to generate a labeled RNA probe, which protects an 80-bp fragment of 18S ribosomal RNA. After extraction using TRIzol reagent (GIBCO-BRL), RNA integrity was confirmed by ethidium bromide staining of 28S and 18S ribosomal RNAs on an agarose formaldehyde gel. Total RNA (50 µg, jejunum or 30 µg, ileum) was hybridized with radiolabeled antisense mRNA (IGFBP-5 or IGF-I) and 18S probes, and protected bands quantified as previously described (24). Relative band intensities were calculated by dividing the mRNA band intensity by the 18S band intensity in each sample and then expressing the result as a fold difference relative to Oral control.
Statistics.
Groups were compared using one-way ANOVA and the protected least significant difference technique to determine individual group differences (SAS Institute). Differences of P 
0.05 were considered significant. Statistics were performed on log-transformed data for IGFBP-5 mRNA because residual plots of this data set indicated there was unequal variance among groups. Values in the text are means ± SEM, n = 14 (Oral), 10 (TPN), and 15 (TPN+IGF-I).
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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0.05; Fig. 2). Urine collected from d 3 to 5 showed positive nitrogen balance for both the TPN (29 ± 1 mg/d) and TPN+IGF-I groups (28 ± 6 mg/d), confirming that the level of parenteral nutrition was adequate.
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Length, weight and cellularity of intact intestine. IGF-I treatment prevented the significant 25% reduction in total weight of the small intestine induced by TPN compared with oral feeding (Table 2). There was no change in the total length of small intestine among the groups and no overall effect of either TPN or IGF-I treatment on the colon.
TPN induced significant intestinal atrophy causing reduction in wet weight as well as protein and DNA content all along the small bowel (Fig. 3). The duodenum and jejunum had greater TPN-induced atrophy than the ileum. The protein:DNA ratio decreased significantly in duodenum and jejunum in the TPN alone group compared with the Oral group, suggesting a decrease in cell size as well as cell number. Mice administered TPN+IGF-I had significant attenuation of TPN-induced atrophy throughout the small intestine. In jejunum, IGF-I treatment reversed the TPN-induced atrophy such that mass and protein and DNA concentrations in these mice did not differ from the Oral group.
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Sucrase specific activity [µmol/(min · mg protein)] in jejunal mucosa was significantly reduced in the group administered TPN+IGF-I compared with the TPN group, but did not differ from the Oral group (Fig. 5). Sucrase segmental activity [µmol/(min · cm jejunum)] in jejunal mucosa did not differ among the treatment groups.
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Serum IGFBPs. TPN alone induced significantly lower levels of total serum IGFBPs as well as the IGFBPs at 30–34 kDa (IGFBP-1, 2, and 5) (25). IGF-I treatment reversed this decrease in the 30–34-kDa IGFBPs such that levels did not differ from those of the Oral group (Fig. 7). Levels of IGFBP-3 (38–43 kDa) did not differ among the groups.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Inbred mice maintained exclusively with TPN for 5 d showed significant atrophy of the proximal small intestine that was characterized by a loss of 25% of the total mass of the intact small intestine. This atrophy reflects significant decreases in mass, cell size and cell number in the muscularis, but not the mucosal layers of proximal jejunum. Atrophy of the jejunal muscularis layer was further correlated with a significant decrease in muscularis thickness compared with oral feeding. Consistent with the lack of significant changes in jejunal mucosal mass, protein and DNA concentrations, and sucrase activity, jejunal villus height and crypt depth did not differ in the TPN group compared with the Oral group. These observations contrast with the rat TPN model in which 5–7 d of TPN induced jejunal mucosal hypoplasia, characterized by a 40–60% decrease in mucosal mass, protein and DNA, and significant decreases in villus height and crypt depth (2,7). Thus, compared with the rat TPN model, mice maintained with TPN showed a reduction in the extent (25 vs. 40–60%) and location (muscularis vs. mucosal layers) of the jejunal atrophy induced by TPN. The extent of TPN-induced atrophy in mice is more similar to that of humans [20% atrophy (6)] than to TPN-induced atrophy in rats.
Previous studies characterizing the extent of TPN-induced atrophy in mice showed either no effect on mucosal histology (14) as we noted or a significant 15–31% decline in villus height in association with decreased enterocyte proliferation and increased apoptosis (11,12). These disparate findings likely can be explained by the adequacy of the parenteral energy provided to the mice. We provided 8 mL/d of TPN solution or 52 kJ/d to 20-g mice [988 kJ/(kg BW0.75 · d)] and noted little change in BW with positive nitrogen balance. This is a level of energy similar to that reported by Sitren et al. (14,19) not to have altered mucosal architecture and maintained BW and promoted nitrogen balance in C57BL/6 mice weighing 20–25 g, and similar to that reported by Wu et al. (10) using ICR mice. In contrast, studies in which mucosal atrophy was observed in TPN mice infused 5–7 mL/d of TPN solution with an energy density of 5.4 kJ/mL or 27–38 kJ/d for 25-g mice (11–13). This level of energy provides 429–604 kJ/(kg BW0.75 · d) or 50% of the estimated requirement for maintenance and growth of orally fed mice, 674-1100 kJ/(kg BW0.75 · d) (23). The energy requirements of parenterally fed mice are unknown. However, energy expenditure determined by indirect calorimetry in parenterally fed rats is 20–40% greater compared with oral feeding in association with greater motor activity (26). Thus, one might expect the parenteral energy needs of mice to exceed those noted with oral feeding. Given that 24-h food deprivation in mice induces a 30–50% atrophy of the small intestine that is corrected by refeeding (27), it is likely that the reported intestinal villus atrophy reflects a response to both semistarvation (50% energy needs) as well as the absence of luminal nutrients due to TPN. Moreover, in 25-g mice compared with orally fed controls, provision of 5 mL TPN solution/d was associated with a 31% decline in villus height (12), whereas provision of 7 mL TPN solution/d was associated with a 15% decline in villus height (11).
This study provides the first evidence that IGF-I induces intestinal growth in mice maintained with TPN. The data extend previous studies of the intestinotrophic effects of IGF-I administration in TPN rats (2,7,17), orally fed mice (28), and genetic models of IGF-I overexpression (16,29). Our data on sucrase activity showed the same response as noted in TPN rats treated with IGF-I (7). Briefly, the reduction in sucrase specific activity with TPN+IGF-I compared with TPN suggests greater numbers of immature enterocytes that do not yet express sucrase activity, an effect that is compensated for by greater total cellularity when sucrase activity is expressed per unit length of jejunal mucosa (7).
The absence of an increase in villus height with IGF-I treatment during TPN may reflect the lower increase in serum IGF-I levels in this study compared with our rat studies, 78 vs. 100–160% increase in serum IGF-I (2,7). Differences in the location of histology within the jejunum may also explain the lack of an increase in villus height because Drucker et al. (28) noted increased villus height with IGF-I treatment in mice in the distal but not proximal jejunum, and we sampled only in the proximal jejunum.
Local expression of IGFBP-5 is known to potentiate the endocrine and paracrine effects of IGF-I in the intestine (29). This effect appears to reflect the tight adherence of IGFBP-5 to the fibroblast extracellular matrix and access to the IGF-I receptor (30). The most interesting observation of this paper is the direct association of jejunal muscularis atrophy and growth with the expression of IGFBP-5 that occurs with no change in jejunal IGF-I mRNA in TPN mice. In intestine, IGFBP-5 is expressed primarily in the muscularis layer as noted in rats (17), mice (16), and human small intestine (31); however, during IGF-I infusion or stressed states, IGFBP-5 has also been localized to mucosa (17,32). Thus, the 60% reduction in jejunal IGFBP-5 expression in TPN mice with atrophy of the jejunal muscularis layer and the 200% increase in IGFBP-5 expression induced by IGF-I infusion, in association with growth of jejunal mucosa and muscularis, support data that increased IGFBP-5 expression positively modulates the intestinotrophic actions of IGF-I (17). Our finding is consistent with the following studies, which demonstrate that IGFBP-5 potentiates the growth-promoting effects of IGF-I in different model systems: cultured smooth muscle cells derived from the intestine (33); transgenic mice that overexpress IGF-I in mesenchyme (16); TPN rats treated with IGF-I (17); rats with resection-induced intestinal growth (18); and a rat model of inflammatory bowel disease (34).
The serum profile of IGFBPs noted in mice was both similar and dissimilar to the rat profile (22). The primary IGFBP found in rat serum is IGF binding protein-3 (38–43 kDa) (25), whereas we noted that the lower-molecular-weight IGFBPs, (30–34 kDa, consistent with IGFBP-1, 2, and 5) were the primary IGFBPs in mouse serum, and also the primary IGFBPs to increase with IGF-I infusion. Thus, IGF-I infusion increases serum levels of IGFBPs in both rats and mice; however, the profile of IGFBPs in mice includes a predominance of smaller-molecular-weight IGFBPs compared with rats (30–34 vs. 38–43 kDa).
In summary, we demonstrated that mice maintained with TPN showed significant (25%) atrophy of the jejunum that was less severe than that observed in the rat TPN model and is specific to the muscularis layer rather than the mucosal layer of the proximal jejunum as noted in rats (2). Co-infusion of IGF-I with TPN solution attenuated TPN-induced atrophy in mice in association with increased expression of IGFBP-5 in jejunum as noted in rats (17). We conclude that the mouse TPN model is suitable in the utilization of genetically altered mice to study the role of the IGF-I system in intestinal growth and to extend understanding of the complications associated with TPN in humans.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: BW, body weight; IGF-I, insulin-like growth factor-I; IGFBP, insulin-like growth factor-I binding protein; RPA, RNase protection assay; TPN, total parenteral nutrition.
Manuscript received 21 June 2005. Initial review completed 24 July 2005. Revision accepted 5 August 2005.
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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