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* Division of Nutritional Sciences, Department of Animal Sciences, ** Department of Food Science and Human Nutrition, and Department of Veterinary Pathobiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801 and Mead Johnson Research Center, Evansville, IN 47721
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
ACKNOWLEDGMENTS
FOOTNOTES
LITERATURE CITED
ABSTRACT 
Infectious diarrheal diseases and protein-energy malnutrition (PEM) are major causes of child morbidity and mortality worldwide. In the present study, PEM was superimposed on rotavirus infection in neonatal pigs to simulate chronic small intestinal stress in malnourished infants with viral gastroenteritis. Two-day-old cesarean-derived pigs (n = 39) were allotted to three treatment groups: 1) noninfected, full-fed; 2) infected, full-fed; and 3) infected, malnourished. Two days postinfection, severe diarrhea and weight loss (11%) were accompanied by reductions in villus height (60%) and lactase activity (78%) and increased crypt depth (32%) in infected full-fed compared with noninfected pigs (P < 0.05). Malnutrition blunted (P < 0.05) increases in crypt depth elicited by rotavirus. By 9 d postinfection, body weight was 59% less, villus height and lactase activity remained lower (50%), and crypt depth remained greater (62%) in infected full-fed compared with noninfected pigs (P < 0.05). However, diarrhea began to clear in infected full-fed, but not in infected malnourished pigs. Plasma insulin-like growth factor-I (IGF-I) was reduced 68% and crypt depth was reduced 19% in infected-malnourished compared with infected full-fed pigs (P < 0.05). Sixteen days postinfection, full-fed pigs had recovered from rotaviral infection; however, in infected-malnourished pigs, diarrhea and growth stasis persisted, and plasma IGF-I, villus height and alkaline phosphatase activity remained reduced compared with infected full-fed pigs (P < 0.05). Overall, PEM prolonged diarrhea and delayed small-intestinal recovery, indicating that nutritional status during diarrhea is essential for recovery from rotaviral enteritis.
KEY WORDS: rotavirus · malnutrition · pigs · neonate · small intestineINTRODUCTION
Diarrheal diseases and protein-energy malnutrition (PEM)6 are primary causes of child morbidity and mortality worldwide. The World Health Organization estimates that one billion diarrheal episodes occur in infants annually, resulting in 3.3 million deaths (Bern et al. 1992
). Of the episodes, 20-35 million occur in the U.S., resulting in more than 200,000 hospitalizations and 300-400 deaths (Centers for Disease Control and Prevention 1992). Rotaviruses are the major cause of infectious diarrhea (Bartlett et al. 1987), accounting for 20% of diarrhea-associated deaths in developing countries and for one third of the hospitalizations for diarrheal illnesses in the U.S. (Lieberman 1994). Rotavirus infections are characterized by viral replication in small intestinal enterocytes (Estes 1990), with subsequent cell lysis and attendant villus blunting (Theil et al. 1978), depressed levels of mucosal disaccharidases (Bishop et al. 1973), watery diarrhea (Theil et al. 1978) and dehydration. Reduced enzymatic and absorptive capacity in the small intestine is thought to result in a malabsorptive-type diarrhea (Argenzio et al. 1990).
Nutritional status can influence diarrhea through at least two mechanisms. First, PEM can reduce the integrity of the intestinal epithelium, facilitating bacterial translocation (Cunningham-Rundles 1994) with subsequent enteritis and diarrhea. Second, epidemiologic evidence in human infants suggests that duration of diarrhea may be prolonged by PEM (Chandra 1983). Chronic PEM impairs epithelial proliferation in crypts in the small intestine, resulting in delayed cellular migration along the crypt-villus axis (Guiraldes and Hamilton 1981). Therefore, structural epithelial repair and restoration of enzymatic and absorptive capacity may be delayed in undernourished infants with enteritis (Butzner et al. 1985).
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Table 2. Insulin-like growth factor binding proteins (IGFBP) in plasma and small intestine tissue at 2, 9 and 16 d postinfection for noninfected, infected full-fed and infected-malnourished pigs1 |
We postulate that PEM will delay recovery from rotavirus infection and have compared metabolic and intestinal consequences of rotaviral infection in full-fed and malnourished neonatal piglets in the present study. Small intestinal morphology and digestive enzyme activities were measured to monitor intestinal structure and function. Plasma insulin, glucagon, insulin-like growth factors (IGF )-I and -II, and IGF-binding proteins (IGFBP) were measured as indices of nutritional status (Thissen et al. 1994). Together, the present results improve our understanding of how PEM affects metabolic and cellular mechanisms underlying intestinal recovery from rotavirus. This information should aid in the design of nutritional strategies for the management of infectious diarrhea in malnourished and well-nourished children.
MATERIALS AND METHODS
). Cubicles were disinfected prior to use with consecutive washes of bleach, a virucide/bactericide solution (Nolvasan, Fort Dodge Laboratories, Fort Dodge, IA) and a bactericide solution (Ster-Bac Blu, Ecolab, St. Paul, MN). Metabolic cages and materials used for feeding were sterilized by autoclaving at 120°C for 20 min prior to use.
. A simulated sow milk diet was prepared by the Mead Johnson Nutritional Group (Evansville, IN) as a nonsterile dry powder. The diet composition (g/kg diet) was as follows: protein, 300; fat, 360; carbohydrate, 251; water, 40; vitamin and mineral premix,7 49. The diet contained 22.8 MJ metabolizable energy/kg diet (25.2 MJ gross energy/kg diet). Bovine whey protein was used as protein source, coconut oil and corn oil were used as fat sources (55:45), and lactose was used as carbohydrate source (McClead et al. 1990). The diet met nutritional requirements for growing pigs from birth through 3 wks of age (McClead et al. 1990). The dry diet was reconstituted daily by addition of deionized water (183 g/L) using a blender (Waring Products, New Hartford, CT). Fresh liquid formula was provided at 12-h intervals. The formula was not sterile, but tested negative for potential pathogens.
) was passed through 1-d-old gnotobiotic pigs to amplify the amount of virus and to retain pathogenicity. Feces from infected pigs were collected and centrifuged for 15 min (5000 × g, 4°C). Supernatants were qualitatively assayed for presence of group A specific rotavirus antigen by micro-ELISA (Gelberg et al. 1991), and rotavirus-positive supernatants were centrifuged for 15 min (9000 × g, 4°C). Resultant supernatants were extracted twice with equal volumes of trichlorotrifluoroethane in a Dounce tissue grinder (Wheaton Scientific, Millville, NJ) and centrifuged for 10 min (1750 × g). The aqueous phase of the solvent was extracted twice with equal volumes of minimal essential medium (MEM), and aqueous phases were pooled and centrifuged for 30 min (9000 × g). Virus particles were then pelleted at 20,000 × g. The pellet was homogenized in MEM and refrigerated overnight. The viral suspension was filtered consecutively through 0.45- and 0.22-mm filters for sterilization. Presence of group-A specific rotavirus antigen was confirmed by micro-ELISA, and purified virus was visualized with an electron microscope (Basgall et al. 1988).
) with modifications (Rolsma 1995) executed as follows. Monolayers of MA-104 cells in 24-well culture plates were rinsed twice with PBS. One milliliter of serum free medium was added to each well and the plates were incubated at 37°C and 5% CO2 for 3 h. Virus was treated with 10 mg/L crystallized trypsin for 30 min at 37°C. Serial dilutions of virus suspension were added in triplicate and then the plates were rotated every 15 min for 1 h at 37°C. After washing, plates were incubated with MEM at 37°C and 5% CO2 for 16-18 h. Plates were then rinsed and fixed with methanol/glacial acetic acid (9:1) for 2 min, and rehydrated subsequently for 5 min in 70% ethanol, 50% ethanol and wash buffer. Virus-containing cells were enumerated by immunocytochemistry using rabbit anti-human rotavirus antibody (Dako, Carpinteria, CA), biotinylated goat anti-rabbit IgG (Vector Laboratories, Burlingame, CA) and TrueBlue chromagen (Kirkegaard and Perry Laboratories, Gaithersburg, MD).
0.75·d1). At 1 d of age, pigs were injected subcutaneously with 1 mL of a 100 g/L iron dextran solution (Butler, Columbus, OH). At 2 d of age, pigs were randomly allotted, within litter, to three treatment groups. Group 1 included noninfected pigs given undiluted formula, n = 12; Group 2 included infected pigs given undiluted formula, n = 14; Group 3 included infected pigs given 50% diluted formula [diluted with electrolyte solution; 1.91 g KCl, 0.15 g NaCl and 1.65 g Na citrate (tri-sodium)/L of deionized water], n = 13. Following randomization, pigs in groups 2 and 3 were infected with 2 mL of porcine rotavirus inoculum (1 mL stock solution + 1 mL PBS). To prevent differences in nutrient intake between noninfected and infected pigs, formula intake (mL·kg body wt0.75·d1) for each of the three groups was restricted throughout the remainder of the study, according to the following schedule: 1 d postinfection, 300; 2 d postinfection, 240; 2-12 d postinfection, 240-480 (gradual increase); 12-16 d postinfection, 480. The feeding protocol was based upon feed intake data from rotavirus-infected pigs in previous work (Zijlstra et al. 1994). Pigs were weighed daily and formula consumption was measured twice daily for each pig. Diarrhea was scored daily based on consistency of feces (0, no diarrhea; 1, stiff flowing feces; 2, easy flowing feces; 3, severe, watery diarrhea). On d 2, 9 and 16 postinfection, four pigs per treatment were killed by electrocution followed by exsanguination. Blood was collected in heparinized tubes and the gastrointestinal tract was removed. Blood samples were placed on ice, centrifuged at 3000 × g, and plasma was frozen at 
80°C until analyzed.
Plasma analyses.
Insulin and glucagon. Concentrations of the pancreatic hormones were determined by RIA as described previously (Zijlstra et al. 1996). Intra-assay CV were 3% for insulin and 4% for glucagon.
Insulin-like growth factors.
To dissociate IGF-I and -II from their binding proteins, plasma samples were chromatographed, and IGF-I and -II were measured in separate RIA as described (Donovan et al. 1994). The following dilution factors were used: 1:10 to 1:50 for IGF-I analysis and 1:50 for IGF-II analysis. Analyses for each peptide were run within a single assay and intra-assay CV were 4% for IGF-I and 6% for IGF-II.
IGF binding proteins.
Plasma samples (3 mL) were separated on SDS-PAGE gels, and IGFBP were analyzed by radioligand blotting, autoradiography and densitometry as described (Donovan et al. 1994).
Intestinal sampling.
The small intestine was dissected free of mesenteric attachments and placed on a smooth surface in six parts of equal length. This arrangement allowed collection of tissue at seven equidistant points along the length of the small intestine from the duodenum (segment 1) and proximal jejunum (segment 2) to distal jejunum (segment 6) and distal ileum (segment 7) (Cranwell and Moughan 1989). Thus, regardless of animal size, tissues were collected from the same relative site along the small intestine. Intestinal content was removed from tissue samples with mild saline washes. Tissue samples (~ 3 cm) from each segment were weighed and either frozen in liquid nitrogen for IGFBP analysis or immersed in 10% neutral buffered formalin for histological analysis. Additional tissue samples (7-15 cm), immediately distal to each segment division, were measured for length and weighed. Mucosa was scraped from these samples with a clean microscope slide, weighed and used for subsequent determination of mucosal enzyme activities. Intestinal samples for IGFBP and enzyme analyses were stored at 70°C until assayed.
Small intestine analyses. Morphometry. Tissue samples were processed for light microscopy, and nine villi and nine crypts were measured for each intestinal segment as described previously (Zijlstra et al. 1994
). Subsequently, means for villus length and crypt depth were calculated per segment.
Mucosal enzyme activities.
Mucosal samples were processed and analyzed for disaccharidases [lactase (EC 3.2.1.23), maltase (EC 3.2.1.20), leucine aminopeptidase (EC 3.4.11.1), alkaline phosphatase (EC 3.1.3.1)], and protein as described (Zijlstra et al. 1994). Results were expressed as specific activities (units per gram or milligram protein). For disaccharidases, 1 unit was defined as the activity that liberates 1 µmol glucose per minute per gram of protein. For other brush border enzymes, 1 unit was defined as the activity that hydrolyzes 1 µmol substrate per minute per gram (leucine aminopeptidase) or milligram (alkaline phosphatase) of protein.
IGF binding proteins.
Whole-tissue samples (mucosa + underlying muscle layers) were homogenized (100 g/L) in Laemmli sample buffer (100 g/L glycerol, 20 g/L SDS, 62.5 mmol/L Tris-HCl, pH 6.8) containing 8.3 g/L Triton X-100, 0.003 mmol/L phenylmethylsulfonylfluoride, 0.041 g/L iodoacetic acid, 0.17 g/L trypsin inhibitor and 0.17 g/L EDTA. Protein content was determined in the homogenate by the method of Lowry et al. (1951) with modifications (Hartree 1972) using bovine serum albumin as a standard. Homogenate samples (250 mg protein) were separated on SDS-PAGE gels, and IGFBP were analyzed by radioligand blotting as described (Donovan et al. 1994).
Statistical analyses.
Data were analyzed according to a randomized complete-block design (blocked by litter) using the General Linear Models procedure of the SAS statistical package (SAS 1985). Infected pigs fed undiluted formula (group 2; infected full-fed: d 2, n = 5; d 9, n = 5; d 16, n = 4) were compared by one-way ANOVA with either noninfected pigs (group 1: d 2, n = 4; d 9, n = 4; d 16, n = 4) for a rotavirus infection effect or with infected-malnourished pigs (group 3: d 2, n = 4; d 9, n = 5; d 16, n = 4) for a nutrition effect within infected pigs (Steel and Torrie 1980). For analysis of body weight data, body weight at d 2 was used as a covariate. Significance of differences was calculated using the LSMEANS statement, and results are presented as least-square means ± pooled SEM. Differences were considered significant when P < 0.05. Instances in which P < 0.1 are discussed as trends.
RESULTS
0.75·d1): 300, 1 d postinfection; 240, 2 d postinfection; 240-480 (gradual increase), 2-12 d postinfection; 480, 12-16 d postinfection. Although nutrient intake was reduced for infected-malnourished pigs, daily water intake was similar to infected full-fed pigs, because formula was diluted 50% with an electrolyte solution.
Plasma insulin and glucagon radioimmunoassay. Rotavirus infection alone did not affect plasma insulin or glucagon concentrations (Table 1) or the insulin:glucagon ratio (not shown); however, malnutrition did. Plasma glucagon concentrations of infected-malnourished pigs were twofold higher at 2 d postinfection (P < 0.1) and were 45% less at 9 d postinfection than those of infected full-fed pigs (P < 0.1). At 16 d postinfection, plasma insulin concentrations of infected-malnourished pigs were 83% less than those of infected full-fed pigs and the plasma insulin:glucagon ratio (not shown) was 86% less (P < 0.05).
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Table 1. Plasma insulin, glucagon and insulin-like growth factor-II (IGF-II) concentrations at 2, 9 and 16 d postinfection for noninfected, infected full-fed and infected- malnourished pigs1,2 |
Table 3.
Mucosal lactase specific activity at 2, 9 and 16 d postinfection for noninfected, infected full-fed and infected-malnourished pigs for six of seven equally spaced segments of the small intestine1,2
Table 4.
Mucosal maltase specific activity at 2, 9 and 16 d postinfection for noninfected, infected full-fed and infected-malnourished pigs for six of seven equally spaced segments of the small intestine1,2
Table 5.
Mucosal leucine aminopeptidase specific activity at 2, 9 and 16 d postinfection for noninfected, infected full-fed and infected-malnourished pigs for six of seven equally spaced segments of the small intestine1,2
Table 6.
Mucosal alkaline phosphatase specific activity at 2, 9 and 16 d postinfection for noninfected, infected full-fed and infected-malnourished pigs for six of seven equally spaced segments of the small intestine1,2
DISCUSSION 
Fig. 4.
Plasma insulin-like growth factor-I (IGF-I) concentrations at 2, 9 and 16 d postinfection for noninfected, infected full-fed and infected-malnourished pigs. Values are least-square means, and pooled SEM per time point is symbolized as a single error bar; *, differs from infected full-fed, P < 0.05; **, differs from infected full-fed, P < 0.01.
[View Larger Version of this Image (28K GIF file)]
Fig. 5.
Radioligand blots for insulin-like growth factor binding proteins (IGFBP) in plasma (panel A) and small intestine tissue (panel B) at 9 d postinfection for noninfected, infected full-fed and infected-malnourished pigs. Results of densitometric analyses of both variables for each day postinfection are presented in Table 2. Rat plasma was used as control for the blot in panel A and pig plasma for the blot in panel B (right lanes).
[View Larger Versions of these Images (35 + 43K GIF file)]
mucosa weight) specific weight in the proximal and medial small intestine (P < 0.05; Fig. 6). At 16 d postinfection, total small intestine relative weight did not differ in noninfected and infected full-fed pigs. Total small intestine relative weight of infected-malnourished pigs was 25% less than that of infected full-fed pigs by 9 d postinfection and 38% less by 16 d postinfection (P < 0.01; Fig. 6), resulting predominantly from a 45% reduction of mucosal specific weight and a 26% reduction of muscle specific weight in the proximal small intestine (P < 0.05; Fig. 6).
Fig. 6.
Total small intestine relative weight (g/kg body weight) at 2, 9 and 16 d postinfection for noninfected, infected full-fed and infected-malnourished pigs. The dividers within graph bars indicate the fraction of total small intestine weight that is muscle (below divider) or mucosa (above divider). Data are pooled across intestinal segments. Effects of rotavirus or malnutrition on specific intestinal regions are noted in Results. Values are least-square means, and pooled SEM per time point is symbolized as a single error bar. Asterisks above graph bars indicate significant differences in total small intestinal weight between noninfected and infected, full-fed animals, or between infected, full-fed and infected, malnourished animals. Asterisks to the right or left of graph bars and above (mucosa) or below (muscle) the dividing lines indicate significant differences in either of those fractions for the same treatment comparisons; **, differs from infected full-fed, P < 0.01.
[View Larger Version of this Image (44K GIF file)]
Fig. 7.
Villus height and crypt depth at 2 d (panel A), 9 d (panel B) and 16 d (panel C) postinfection for noninfected, infected full-fed, and infected-malnourished pigs for seven equally spaced segments of the small intestine; segment 1 is proximal, segment 7 is distal. Values are least-square means, and pooled SEM per segment is symbolized as a single error bar; *, differs from infected full-fed, P < 0.05; **, differs from infected full-fed, P < 0.01; ***, differs from infected full-fed, P < 0.001.
[View Larger Versions of these Images (34 + 32 + 37K GIF file)]
), partly because of the view that malabsorption is a major mechanism underlying rotaviral diarrhea. Impaired digestion and absorption are thought to result from a reduced villus surface area composed predominantly of immature, undifferentiated cells. Reduced enzymatic activities would result in undigested material within the small intestine causing malabsorptive-type diarrhea (Perman 1985). Following the malabsorptive diarrhea paradigm, rotaviral and other diarrheal diseases are commonly treated by "bowel rest," i.e., reduction of luminal nutrients in the gastrointestinal tract during the diarrheal episode (Lieberman 1994). An opposing view is to resume normal feeding as soon as possible to avoid consequences of reduced nutrient intake (Centers for Disease Control and Prevention 1992) because nutrients are absorbed even during diarrhea (Lieberman 1994). The malabsorptive diarrhea paradigm is partially supported by present evidence that diarrhea in infected pigs at 2 d postinfection coincided with reductions of small intestine villus surface area and specific activities of mucosal enzymes. However, both metabolic and intestinal data from the present study bring into question the extent to which malabsorption contributes to rotaviral diarrhea.
, Thissen et al. 1994). Plasma IGF-I, IGFBP and insulin concentrations were similar between noninfected and infected full-fed pigs, indicating that nutritional status was not compromised in infected pigs, and therefore, that digestion and absorption may not have been impaired by rotaviral diarrhea. In infected full-fed pigs, a reduction in the severity of diarrhea (7-9 d postinfection) coincided with the resumption of weight gain, and complete clearance of diarrhea at 10 d postinfection corresponded with a rate of body weight gain similar to noninfected pigs. Thus, the present data demonstrate that providing nutrients to rotavirus-infected piglets during the diarrheal episode does improve nutritional status and contributes to more rapid recovery of weight gain.
), was also reduced at 9 d postinfection. That response may reflect a more rapid clearance of IGF-II as a result of the large reduction (86%) in its primary carrier protein (IGFBP-3; Thissen et al. 1992) in response to malnutrition. Plasma insulin concentrations indicated malnutrition at 16 d postinfection but not at 9 d postinfection. Insulin is likely to be more sensitive than IGF-I to time elapsed between last meal and blood sampling, because insulin, unlike IGF-I, is not bound to binding proteins. Thus, plasma IGF-I concentration appears to be a more useful indicator of chronic nutritional stress than plasma insulin.
). Receptors for IGF are located on both apical and basal membranes of enterocytes (Morgan et al. 1996). Therefore, both orally and systemically administered IGF could modulate structure and function of the small intestine. Recent evidence indeed indicates that circulating IGF-I can regulate protein synthesis in intestinal mucosa (Lo et al. 1996). Pigs in the present study did not receive colostrum, and exogenous IGF-I was not added to the formula. Thus, reduced plasma IGF-I in infected-malnourished pigs, compared with infected full-fed pigs, could partially explain delayed small-intestinal recovery following rotavirus infection. Experimental colitis in rats increased IGF-I binding to IGFBP in muscle underlying the intestinal epithelium, suggesting an important role for IGFBP in modulating local IGF effects during intestinal inflammation and repair (Zeeh et al. 1995). In the present study, intestinal IGFBP were increased by rotavirus infection, supporting that possibility. In addition, intestinal IGFBP-2 concentrations were higher in infected-malnourished than infected full-fed pigs, indicating that IGFBP might modulate IGF-I effects within the tissue in response to nutritional status. Additional studies are required to determine the cellular source of intestinal IGFBP. Nevertheless, the present results suggest for the first time a potentially important role for IGF-I and its binding proteins in intestinal recovery from viral insults. Evidence that intestinal IGF physiology is modulated in response to malnutrition is particularly intriguing.
). Histomorphological analysis verified disruption of the epithelium (data not shown) and villus atrophy in the present study. Immediately following rotavirus infection, stem cells in the crypts undergo hyperplasia resulting in crypt elongation. In the present study, crypt elongation in the small intestine of infected-malnourished pigs was diminished relative to infected full-fed pigs, indicating that PEM reduced stem cell division, thereby limiting the production of fully developed enterocytes. Intestinal recovery was complete by 16 d postinfection in full-fed but not in malnourished pigs, based on villus height data.
); lactase activity is expressed predominantly in the upper villus (James et al. 1987), and maltase activity is located toward the base of the villus (James et al. 1987). Lactase, leucine aminopeptidase and alkaline phosphatase specific activities, but not maltase specific activity, were reduced by rotavirus infection. These results provide additional verification that rotavirus infects enterocytes on the upper villi. In the distal small intestine, lactase and alkaline phosphatase activities remained reduced at 10 d postinfection in infected-malnourished compared with infected full-fed pigs, providing further evidence that malnutrition hampers the regeneration of intestinal villi.
ACKNOWLEDGMENTS
FOOTNOTES
Manuscript received 27 September 1996. Initial reviews completed 2 December 1996. Revision accepted 11 February 1997.
LITERATURE CITED
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