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The Journal of Nutrition Vol. 128 No. 12 December 1998,
pp. 2727S-2729S
Departments of Surgery-Pediatric Division, The Johns Hopkins University, School of Medicine, Baltimore, MD 21205
KEY WORDS: small intestine · atrophy · milk feedings · swine
Intestinal mass and function are maintained by stimulation from enteral nutrients, trophic hormones, adequate blood flow and neurologic input. Nutrients and ingredients exert profound trophic effects on the small intestine by several mechanisms. Ingested nutrients present mechanical and chemical stimuli to the intestine, which in turn releases endogenous and hormonal secretions. Second, the type and amount of ingested nutrients mechanically alter the mucosal cell mass by affecting the rate of stem cell division and the rate of mucosal cell renewal. Third, the gastric, duodenal and pancreaticobiliary secretions that normally accompany eating, digestion and absorption are known to promote mucosal structure and function. Small volume enteral feedings of milk have been shown to ameliorate some aspects of intestinal disuse atrophy in pigs. Enteral feedings begun immediately after enterostomies performed in dogs led to significantly increased mature collagen concentration and bowel strength at the site of the resection by d 5 (Moss et al. 1980 Materials and methods.
Five litters of Hampshire × Duroc piglets were selected on the basis of body weight (BW) (2.0-2.8 kg) at 4 d of age and used in a 4-wk TPN study followed by a 2-wk refeeding study. Three littermates were randomly assigned to one of the three following treatments: 1) 100% enterally fed sow's milk replacer (SMR); 2) total parenteral nutrition (TPN); 3) 90% of total energy as TPN plus 10% enterally as SMR (PEN). SMR-fed piglets were positive controls and represented normal intestinal development, whereas TPN-fed piglets served as negative controls. Piglets were maintained in accordance with the Johns Hopkins Medical Institutions Animal Care and Use Committee Guidelines and the Committee on Care and Use of Laboratory Animals from the Institute of Laboratory Animal Resources. Medical grade silastic catheters (1.0 mm i.d., 2.1 mm o.d., 91 cm) (Dow Corning, Midland, MI) were surgically placed in the left and right external jugular veins of all piglets. The catheter tips were inserted into the cranial vena cava; the proximal end of the catheter was subcutaneously tunneled to the dorsum, passing cranially to the shoulder and exiting 5-10 cm posterior to the ear. Catheters were used for administering parenteral nutrition and obtaining blood samples. Weekly blood samples were drawn for complete blood cell count with a differential and serum profile.6 All piglets were individually housed in stainless steel (60 × 60 × 60 cm3) cages with plastic mesh-covered screened floors and maintained in nylon open mesh vests with an attached stainless steel tether line (Spalding Medical Research Products, Birmingham, AL) and swivel infusion system.
Nutritional treatments.
All piglets suckled sow's colostrum/milk until delivered to the laboratory at 4 d of age; they also received an iron dextran (Iron Dextran Complex, TechAmerica, Elwood, KS) injection (100 mg intramuscularly) at 3 and 10 d of age. The TPN solution was formulated to have a nutrient profile similar to SMR and the recommended dietary concentrations for piglets <5 kg BW (NRC 1988) (Table 1). The TPN solution was administered as a three-in-one solution [dextrose, amino acids and lipid (Liposyn III 20%, Abbott Laboratories, Chicago, IL)]. The amino acid component of the TPN solution was made by adding 56 mg/mL of nonessential amino acids (Sigma Chemical, St. Louis, MO) to a commercially available 11.4% amino acid product. The zinc concentration of the parenteral solution was reduced from the NRC recommendation of 50 to 12 mg/kg because of high hepatic zinc concentrations (>500 mg/kg wet tissue) that approached toxic levels in earlier piglet studies (Gabrielson et al. 1996 Results.
The initial body weights of piglets were not different across assigned treatments (2.63 ± 0.4 kg). During the first 4-wk feeding trial, daily nutrient intakes of energy, protein and fat were significantly lower in the TPN and PEN groups than in the SMR treatment group because of automatic pump shut-offs and occlusions, and TPN piglets did have a significantly lower rate of weight gain than SMR and PEN piglets (Table 2). During the subsequent 2-wk milk refeeding phase, there were no nutrient intake differences among treatment groups. Final body weights (7.23 ± 1.4 kg) were not different across groups. Organ measurements per unit of body weight were compared across treatments as a more conservative method by which to test relative gastrointestinal atrophy. Intestinal weights and lengths, and pancreas weights were not significantly different across treatment groups after 2 wk of oral refeedings. Liver weights were significantly greater in the TPN-fed piglets (>6% BW) compared with SMR-fed piglets (4.0% BW). Liver weight of PEN-treated piglets (4.9%) was an intermediate value and not significantly different from the TPN or SMR group. There was no evidence of jaundice in the piglets and the livers appeared grossly normal in shape and color at necropsy. During the last week of feeding, serum bilirubin levels (total, direct and indirect), alanine aminotransferase and alkaline phosphatase were not different among treatment groups; however, aspartate aminotransferase in TPN pigs was significantly lower (30.5 U/L) than that in the SMR and PEN pigs (60.8 and 46.3 U/L, respectively). There was no histologic evidence of fat infiltration or cholestasis in any liver sections. Jejunal villous heights and crypt depths (Table 2) apparently recovered from the TPN-induced atrophy with 2 wk of milk refeeding, in that there were no differences among treatment groups. Ileal villous heights in TPN-treated piglets remained significantly less than those of SMR- and PEN-treated piglets and apparently had not completely recovered after 2 wk of refeeding. The jejunal and ileal mucosal disaccharidase activities (lactase, sucrase and maltase) were not different among treatment groups after 2 wk of milk refeeding.
Discussion.
Four weeks administration of TPN to piglets produces a small bowel (SB) disuse atrophy and is assumed to have occurred in this study (Remillard et al. 1998
INTRODUCTION
Introduction
References
). In brief, feeding enterally is the most powerful stimulus to maintaining normal morphology and function (Jackson and Grand 1991), yet clinical orders of nothing per os (NPO)5 are common practice. In hospitalized patients, a multitude of factors including loss of luminal trophic factors, altered splanchnic blood flow and nutritional deprivation lead to intestinal mucosal atrophy (Rock et al. 1990). The smallest volume, composition and feeding rate most effective in ameliorating disuse atrophy and maintaining intestinal functions are not known. Reintroduction of food enterally is known to reverse intestinal atrophy eventually; however, the time required for full intestinal recovery is also not known. Piglets, in contrast with rats, have become the preferred small intestinal research model because of the homology among the intestinal tracts of swine, humans and companion animals. The information derived from a swine research model of small intestinal atrophy is also relevant to the small bowel changes occurring in NPO dogs, cats and foals. The objective of this study was to assess the ability of the intestinal tract to recover from disuse atrophy with 2 wk of milk feedings by mouth vs. small volume milk feedings concurrently with total parenteral nutrition (TPN)-inducing atrophy.
View this table:
Table 1.
Nutrient profile of total parenteral nutrition (TPN) solution and sow's milk replacer (SMR) fed to piglets1
View this table:
Table 2.
Small bowel parameters in piglets fed by different routes and refed enterally
). The parenteral solutions were made twice weekly using a high speed compounder (Automix Plus, Clintec Nutrition, Deerfield, IL) and stored at 4'C until needed. All piglets were administered 527 kJ/(kg BW · d) of their respective nutritional treatments on the basis of daily body weights and were maintained on these diets as the sole source of nutrition for 4 wk. The sow's milk replacer (Acidified Pig Milk Replacer, Milk Specialties, Dundee, IL) (Table 1) was a whey-based commercially available product designed for young growing piglets. A 20% SMR solution was made daily and offered to the SMR piglets in amounts equal to the energy intake of TPN piglets. PEN piglets received 90% of their energy intake similarly to the TPN piglets and the remaining 10% as SMR piglets. The daily allotted volume of SMR was offered at one time to the SMR and PEN piglets using a plastic feeder attached to the cage and was consumed in a single-meal feeding pattern. After 4 wk of their respective treatments, TPN and PEN piglets were disconnected from infusion pumps. All piglets were caged individually in 10 m2 pens and were fed a 20% SMR solution once daily, which provided 544 kJ/(kg BW · d) as the sole source of nutrition for 2 wk; water was available at all times.
70'C for mucosal disaccharidase assay. Piglets were killed by exsanguination while under general anesthesia as the visceral organs were removed and weighed. The remaining intestinal tract was flushed free of digesta with tap water and measured in sections as suspended with a 15-g free-hanging weight. The total small intestinal weight and length were calculated adding back all segments removed. Jejunal and ileal villous height and crypt depth were determined by a pathologist with the use of hematoxylin and eosin-stained tissues at an average of 12 vertically oriented sites. Lactase, sucrase and maltase brush border activities were measured in jejunal and ileal mucosal samples using a Tris/glucose oxidase reagent (Dahlqvist 1984). Mucosal protein was determined using a bovine plasma 
-globulin standard (Protein Assay Kit, Bio-Rad DC Laboratories, Richmond, CA). Data were statistically analyzed using a one-factor (treatment) ANOVA; significance was established at P
0.05, and results are reported as treatment means ± 1 SD. The mean separation Scheffé F-test was used to compare TPN, PEN and SMR treatments.
). However, the results of this study indicate that most of the parameters used to assess SB atrophy were not different from controls after 2 wk of oral refeeding of milk. Small or large intestinal weights or lengths, jejunal villus:crypt ratios and SB brush border enzyme activities had returned to normal with 2 wk of refeeding. Only one point in time of refeeding was evaluated, and therefore, no statement concerning the rate or pattern of SB morphologic recovery can be made. However, liver weights in TPN piglets remained significantly greater and ileal villous heights remained less compared with SMR piglets. This undesirable relationship between long-term parenteral feeding and hepatic changes has been recognized in humans and other species; it is thought to be multifactorial but is not yet well understood (Duerksen et al. 1996, Freund 1991). Small volume enteral feedings (PEN) in conjunction with parenteral therapy did ameliorate the ileal villous atrophy and hepatomegaly associated with TPN therapy because liver weights and ileal villous heights of partially enterally fed piglets were not significantly different from those of SMR piglets. There are definitive advantages to providing small enteral feedings (10% of energy) as an adjunct to parenteral therapy whenever clinically possible. Noncolostral milk has been shown to promote normal small intestinal morphology, increase gastric and intestinal weights, induce digestive enzyme activity and promote amino acid absorption equally as well as colostrum. Milk contains nutrients and growth factors (epidermal growth factor, transforming growth factor, insulin, insulin-like growth factor and lactoferrin), promotes gastric, duodenal and pancreaticobiliary secretions, and stimulates the release of systemic growth factors and hormonal stimulation, which are known to promote, individually and in concert, intestinal structure and function (Castillo et al. 1990). This study cannot determine which aspects of milk feeding promoted the intestinal recovery noted in TPN piglets, or the preservation of intestinal morphology in the PEN piglets. In summary, most aspects of intestinal disuse atrophy produced by 4 wk of NPO treatments in piglets were reversed when oral refeeding was reinstituted for 2 wk. In conclusion, feeding small volumes (2 mL/kg, twice daily by mouth) of a milk solution ameliorates some of the negative morphologic effects of NPO or TPN therapy, and therefore, would appear to be clinically beneficial in monogastric patients.
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FOOTNOTES |
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LITERATURE CITED |
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Introduction
References
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-Galactosidase (disaccharidases) and 
-glucosidases (lactase) In: Methods of Enzymatic Analysis (Bergmeyer, H. U. & Grabi, M., eds.), 3rd ed., vol. 4, pp. 208-217 and pp. 227-230. Verlag Chemie, Weinheim, Germany.
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