Oral ornithine a-ketoglutarate accelerates healing of the small intestine and reduces bacterial translocation after abdominal radiation

The effect of dietary ornithine a-ketoglutarate (OKG) on intestinal mucosal integrity and bacterial translocation was studied in rats following administration of a single dose of abdominal radiation (1100 cGy). Following the radiation injury the rats were randomized to receive a nutritionally incomplete diet which contained only water and OKG or a control diet with water and the non-essential amino-acid glycine. Four days after radiation, rats were anaesthetized and a laparotomy was performed. Cultures from mesenteric lymph nodes were taken and two tissue samples from the terminal ileum were also taken for light microscopy, protein and DNA determination. We examined the following parameters: number of villi per cm (V/cm), villus height (Vh), number of mitoses per crypt (M/c) and we measured the mucosal protein and DNA content. Nine of 16 rats who received the OKG-free diet had positive cultures but only 3 of 18 rats who received the OKG-enriched diet (P= 0.002). The group on the OKG-enriched diet had a better intestinal mucosal architecture than the group on the OKG-free diet and the studied parameters of the gut mucosa were significantly better: (V/cm: 130 +/- 8.1 vs 99 +/- 7.9, P = 0.001. Vh(mm): 0.40 +/- 0.03 vs 0.24 +/- 0.05, P= 0.002. M/c: 1.71 +/- 0.03 vs 0.34 +/- 0.2, P= 0.001, Protein (mg/cm): 2.300 +/- 0.033 vs 1.207 +/- 0.014, P = 0.002. DNA (microg/cm): 203 +/- 6.41 vs 130 +/- 4.94, P = 0.001. We conclude that OKG-enriched diet prevents the deleterious effects of radiation on intestinal mucosal morphology and integrity, abolishing thus, the increased bacterial translocation observed after abdominal radiation.     

Synergistic effect of supplemental enteral nutrients and exogenous glucagon-like peptide 2 on intestinal adaptation in a rat model of short bowel syndrome

BACKGROUND: Short bowel syndrome (SBS) can lead to intestinal failure and require total or supplemental parenteral nutrition (TPN or PN, respectively). Glucagon-like peptide 2 (GLP-2) is a nutrient-dependent, proglucagon-derived gut hormone that stimulates intestinal adaptation. OBJECTIVE: Our objective was to determine whether supplemental enteral nutrients (SEN) modulate the intestinotrophic response to a low dose of GLP-2 coinfused with PN in a rat model of SBS (60% jejunoileal resection plus cecectomy). DESIGN: Rats were randomly assigned to 8 treatments by using a 2 x 2 x 2 factorial design and maintained with either TPN or PN for 7 d. The 3 main treatment effects were the following: transection or resection (TPN alone), +/- SEN (days 4-6), and +/- GLP-2 (100 mug . kg body wt(-1) . d(-1)). RESULTS: The treatments induced differential growth of duodenal and jejunal mucosa. Significant differences in villus height, crypt depth, dry mass, and concentrations of protein and DNA were observed between the treatments and TPN alone (SEN: 15-59% increase; GLP-2: 14-84% increase; and SEN + GLP-2: 63-160% increase). Plasma concentrations of bioactive GLP-2 were significantly greater with GLP-2 infusion (TPN alone: 25 +/- 9 pmol/L; SEN: 29 +/- 10 pmol/L; GLP-2: 59 +/- 31 pmol/L; SEN + GLP-2: 246 +/- 40 pmol/L) and correlated with mucosal growth. Jejunal sucrase activity (in U/cm) was significantly greater with SEN than without SEN. SEN + GLP-2 induced dramatic mucosal growth and greater plasma concentration of GLP-2 (SEN x GLP-2 interaction, P < 0.0001). Resection significantly increased expression of proglucagon mRNA in colon. CONCLUSIONS: Combination treatment with SEN and GLP-2 induced a synergistic response resulting in greater mucosal cellularity and digestive capacity in parenterally fed rats with SBS. This shows that SEN improve the intestinotrophic response to exogenous GLP-2, possibly by stimulating enterocyte proliferation and differentiation.     

Fatty acid composition of adipocyte membrane phospholipids and stored triglycerides in infants receiving total parenteral nutrition

Fatty acid (FA) composition of membrane phospholipids (PL) and stored triglycerides (TG) from adipose tissue was studied in eight infants aged 1 to 4 months receiving total parenteral nutrition (TPN) since birth. During this period, essential fatty acid (EFA) intake consisted exclusively of soybean oil emulsion administered by intravenous route (Intralipid 20%) representing 301 +/- 88 mg/kg/24 hr of linoleic acid and 58 +/- 18 mg/kg/24 hr of alpha-linolenic acid, or 2.3 +/- 0.6% and 0.4 +/- 0.1%, respectively, of total energy intake. The results were compared with those of eight control infants of the same age receiving orally a normal milk diet with an intake of 660 +/- 260 mg/kg/24 hr of linoleic acid and 101 +/- 35 mg/kg/24 hr of alpha-linolenic acid, or 4.5 +/- 0.7% and 0.7 +/- 0.3%, respectively, of total energy intake. Although their EFA intake was significantly lower (p less than 0.01) and administered only parenterally, after 1 to 4 months the infants receiving TPN still had a membrane phospholipid FA pattern of adipose tissue which was not significantly different from that of normal children of the same age. In stored adipocyte TG, the percentage of linoleic acid was significantly lower (p less than 0.01) in infants receiving TPN. This is probably of nutritional importance as at this stage of life the child builds up its stores of EFA. The proportion of the other fatty acids in adipocyte TG was not significantly modified.     

Amino acid intake and urinary zinc excretion in newborn infants receiving total parenteral nutrition

Zinc deficiency is well described in infants on total parenteral nutrition (TPN). Urinary Zn excretion is the major source of Zn loss in the parenterally fed infant; factors causing increased zincuria will predispose the infant to Zn deficiency and affect the recommended Zn intake dosage. Histidine, threonine, and lysine have been shown to bind Zn increasing its renal ultrafilterability. The effect of the infusion of high and low lysine (206 +/- 34 vs 158 +/- 38 mg.kg-1.d-1; means +/- SD), threonine (147 +/- 24 vs 113 +/- 27), and histidine (124 +/- 34 vs 85 +/- 15) on urinary Zn excretion were determined in 23 newborns on TPN who received similar Zn intakes (6.8 +/- 1.4 mumol.kg-1.d-1). After a 72-h adaptation period each infant had urine collected for two 24-h periods. Despite the significant difference in amino acid intakes, mean urinary Zn excretion was identical (1.58 +/- 0.73 vs 1.56 +/- 0.63 mumol.kg-1.d-1). Hyperzincuria, therefore, does not occur when amino acids are infused at rates appropriate for the safety and nutritional maintenance of neonates.     

Malnutrition impairs postresection intestinal adaptation

BACKGROUND: Postresection intestinal adaptation is influenced by several factors, including luminal nutrients. Adaptation is impaired in the absence of luminal nutrients, even if the nutrition is maintained via total parenteral nutrition (TPN). Reduced enteral intake also inhibits adaptation if malnutrition is present, but the mechanism has not been completely defined. Our aim was to study the effect of reduced enteral nutrition on adaptation and enterocyte production and death after 50% proximal resection in rats. METHODS: Eighteen Lewis rats underwent either transection (n =6) or 50% proximal resection (n =12). The resected animals either ate ad libitum (n = 6) or were offered 75% of ad libitum intake (n =6). Nutritional status and intestinal adaptation were determined 14 days after surgery. RESULTS: Resected animals receiving 75% normal intake had decreased body weight (89% +/- 4% vs 112% +/- 2% and 112% +/- 1%, p < .05) and serum albumin (2.7 +/- 0.1 vs 3.2 +/- 0.0 g/dL and 3.0 +/- 0.1 g/dL, p < .05) compared with resection with normal intake and transection, respectively. Intestinal weight (0.32 +/- 03 vs 0.22 +/- 0.02 g/cm and 0.19 +/- 0.03 g/cm, p < .05) and diameter (10.5 +/- 0.5 vs 8.5 +/- 1.0 mm and 7.8 +/- 0.8 mm, p < .05) increased after resection alone compared with transection and malnourished resection groups. Gut weight and diameter and villus height were lower in malnourished resected animals than with transection. Crypt cell production rate was significantly lower in the reduced intake animals. Apoptosis was increased in both crypt and villus enterocytes in normally nourished but not malnourished resected animals. Villus apoptosis correlated with villus height. CONCLUSIONS: Intestinal adaptation is impaired by a 25% reduction in enteral nutrients, confirming that both the route and quantity of nutrient intake are important in this process. Both enterocyte production and loss via apoptosis are decreased by reduced enteral intake and malnutrition after resection. The correlation between villus height and apoptosis suggests that the reduced apoptosis reflects the smaller enterocyte number in malnourished animals rather than an adaptive response to maintain intestinal structure.     

Total parenteral nutrition energy composition affects small intestinal disaccharidase activity in the newborn miniature pig

Total parenteral nutrition (TPN) decreases disaccharidase activity in the small intestine of humans and miniature piglets. The possibility, however, that specific components of TPN (eg, the energy mix) will increase disaccharidase activity has largely been unexplored. The identification of such components would be particularly useful in the treatment of premature infants with immature gastrointestinal tracts and patients with small intestinal mucosal disease associated with decreased disaccharidase activity. To determine whether the TPN energy composition affects small intestinal disaccharidase activity, 7-day-old miniature piglet littermates were randomized to receive TPN containing either glucose (group G) or glucose and fat (group G/F) as the nonnitrogen energy source(s). The TPN regimens were isonitrogenous and isoenergetic. The piglets were not allowed oral intake during the 7 days they were maintained on TPN. At 14 days of age the piglets were killed and the small intestines analyzed for weight, protein, DNA, and disaccharidase activity. Body weight was similar between groups at both the beginning and end of the study. The TPN regimen did not affect small intestinal weight of protein and DNA content. However, jejunal and ileal sucrase and ileal maltase activities (mumol/min.kg body wt +/- SD) were greater in group G than those in group G/F (28 +/- 9 vs 19 +/- 11, p = 0.04; 13 +/- 7 vs 7 +/- 4, p = 0.037; and 31 +/- 8 vs 19 +/- 10, p = 0.0088, respectively). No differences in lactase activity were noted between groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Critically-ill patients receiving total parenteral nutrition show altered amikacin pharmacokinetics

The purpose of this clinical study was to characterise the kinetic behavior of amikacin in the parenterally-fed critically-ill adult patient. 22 critically-ill adult patients treated with amikacin (15.5 +/- 7.9 mg/kg/day) for severe gram-negative infections were enrolled into a non-randomised control trial. Malnourished patients were administered total parenteral nutrition (TPN, n = 11), while well-nourished patients received fluid therapy (FT, n = 11). Amikacin pharmacokinetic parameters were estimated by non-linear regression analysis, assuming a one-compartment model and central first-order elimination. Patients receiving TPN showed an expanded amikacin distribution volume (0.403 +/- 0.0961/kg vs. FT 0.298 +/- 0.083 l/kg, p < 0.05), and a tendency towards increased total body clearance (0.089 +/- 0.029 l/kg/h vs. FT 0.069 +/- 0.0201/kg/h, p = 0.09). TPN produced lower peak concentrations (19.3 +/- 3.1 mcg/ml vs. 23.1 +/- 3.5 mcg/ml, p < 0.05), but had no significant influence on trough concentrations (p = 0.56). Patients on TPN also showed increased body temperature (p < 0.05) and fluid intake (p < 0.05), and decreased hematocrit (p < 0.05). Stress, malnutrition, parenteral nutrition itself, fluid and osmotic overload, and fever often occur concurrently in parenterally-fed patients and appear to produce lower amikacin serum levels. Consequently, critically-ill patients receiving TPN need higher amikacin doses and individualised treatment by monitoring serum concentrations, to ensure optimal therapeutic response.     

Successful pregnancy outcome using total parenteral nutrition from the first trimester of pregnancy

A 27-yr-old gravida 3, para 2 was supported from the 8th week of pregnancy by intermittent daily total parenteral nutrition (TPN) following the loss of her small bowel. Nutrient intake was adjusted by monitoring nitrogen balance and the rate of increase in fetal cranial enlargement. Maternal calcium balance proved difficult to maintain, since massive urinary Ca+2 losses occurred during infusion of nutrients (576 +/- 2 mg/12 hr on TPN compared to 47 +/- 12 mg/12 hr off). This increase in urine Ca+2 was due to depressed Ca+2 reabsorption by the kidney (87.1 +/- .7 vs 98.1 +/- .3%) and increased filtered load (4623 +/- 241 mg/12 hr vs 2591 +/- 329). Initially calcium balance was -180 mg/day. Nitrogen balance assessed by total stool and urine nitrogen was 1.1 g/24 hr, which was judged to be suboptimal. Deficits were corrected by increasing nitrogen intake, lengthening the duration of infusion and the oral administration of elemental calcium during periods off infusion. A normal fetus was delivered vaginally without complications at 351/2 weeks. This patient demonstrates that normal fetal growth and development as well as appropriate maternal weight gain and nitrogen balance can be maintained throughout pregnancy, including the first trimester, by intermittent daily TPN.     

Effects of glutamine-enriched parenteral nutrition on the exocrine pancreas

Total parenteral nutrition (TPN) is associated with intestinal and pancreatic atrophy and pancreatic exocrine insufficiency. Recent investigations have demonstrated that the addition of glutamine to intravenous feedings attenuates TPN-associated intestinal atrophy. However, the effect of glutamine-supplemented intravenous feedings on the pancreas of intact animals is unknown. This study compared the effects of an intravenous infusion of a 2% glutamine-enriched diet (GLN) with an isonitrogenous, isocaloric diet without glutamine (CONT) on the composition and structure of the exocrine pancreas in laboratory rats with and without a 60% small bowel resection. In nonresected, TPN-fed animals, pancreatic weight was significantly increased in the GLN group when compared to CONT (645 +/- 33 g vs 554 +/- 20 g, p less than 0.05). Nonresected GLN animals also had increased pancreatic DNA (3.82 +/- 0.19 mg vs 2.91 +/- 0.49 mg, p less than 0.005) and protein contents (93.0 +/- 5.9 mg vs 76.6 +/- 7.0 mg, p = 0.08) compared to control. Similar significant increases in pancreatic weight, DNA, and protein were observed in intestinally resected animals fed the glutamine diet. When data from CONT and GLN animals were pooled and analyzed together, glutamine significantly increased total pancreatic trypsinogen and lipase contents (p less than 0.05). The increase in trypsinogen in resected GLN animals was significantly greater than in CONT animals (283 +/- 22 vs 139 +/- 23, p less than 0.005). Biochemical and morphometric observations demonstrated that the trophic effects of glutamine on the exocrine pancreas were manifest by acinar hyperplasia and not hypertrophy. Glutamine appears to be an important nutrient for pancreatic exocrine tissue during TPN.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of starvation on sucrase regulation by dietary sucrose in the rat

We have studied the action of sucrose on jejunal sucrase activity. Rats (175 g) were first starved or fed a digestible carbohydrate-free diet for 60 h and then fed a high sucrose diet for varying times up to 84 h. 1) Rats starved for 60 h showed mucosal atrophy with a decrease in protein content/10 cm (18.00 +/- 1.4 versus 40.1 +/- 3 mg (controls p less than 0.001) and in villus height (357 +/- 18 versus 526 +/- 5 microns, p less than 0.001) which was fully repaired only after 60 h on the sucrose diet (528 +/- 11 microns). Rats on digestible carbohydrate-free diet showed no mucosal atrophy. 2) Starved rats had a delayed (60 h) sucrase activity response to sucrose (53 +/- 7 versus 122 +/- 4 microns/mg protein, p less than 0.001). Maximum activity was obtained after 12 h on sucrose diet in rats maintained on the carbohydrate-free diet: 38 +/- 1 versus 108 +/- 2.3 microns/mg protein, p less than 0.001. 3) Villus and crypt cell analysis after starvation and 12 h on a high sucrose diet localized the increase in sucrase activity to the villus-crypt junction. No change occurred in the upper villus. The increase was complete all along the villus by 36 h. In contrast, after the carbohydrate-free diet, sucrase activity increased maximally at all levels of the villus by 12 h on the high sucrose diet.(ABSTRACT TRUNCATED AT 250 WORDS)     

The intestinal trophic response to enteral food is reduced in parenterally fed preterm pigs and is associated with more nitrergic neurons

In term neonates, total parenteral nutrition (TPN) induces mucosal atrophy, whereas the first intake of milk is followed by intestinal growth. This may be explained in part by an NO-mediated increased blood flow. We hypothesized that the immature gut has an altered response to TPN and enteral nutrition. In Expt. 1, preterm caesarean-delivered pigs were administered elemental nutrients for 3 d, infused parenterally (TPN, n = 7) or enterally (TENT, n = 7). In Expt. 2, preterm pigs were fed sow's colostrum, cow's colostrum, or infant formula for 2 d after a 3-d TPN period (TPN-SOW, TPN-COW, TPN-FORM, n = 8-11). Intestinal morphology and the number of enteric neurons containing nitric oxide synthase-1 (NOS-1) were quantified. Both the TPN and TENT groups had increases in intestinal mass, circumference, and mucosal mass, volume, and surface density, relative to values at birth (+30-50%, P < 0.05). In Expt. 2, the magnitudes of the intestinal trophic responses to feeding were similar to those in Expt. 1, but were also associated with an increased number of nitrergic myenteric neurons and some mucosal damage, most frequently observed for the formula group. We conclude that 1) a short period of TPN does not induce mucosal atrophy in preterm pigs, whereas elemental nutrients infused luminally do not mimic the trophic response seen with milk diets, 2) enteral feeding of preterm pigs after a short period of TPN is associated with a modest, diet-dependent trophic response that may be related in part to the actions of an increased population of enteric NOS-1 neurons.     

Intralipid-based short-term total parenteral nutrition does not impair small intestinal mucosa-related cellular immune reactivity in the healthy rat

BACKGROUND: The lipid component of total parenteral nutrition (TPN) has reportedly been associated with trophic effects on the intestinal mucosa and suppressive effects on the immune system. METHODS: We have challenged these hypotheses using a 7-day TPN rodent model comparing the effects of isocaloric, isonitrogenous lipid-based (TPN-lipid, 50% of calories as long-chain triacylglycerol) and carbohydrate-based TPN (TPN-CH, 100% of calories as carbohydrates) on mucosal morphology and immune function. Enterally fed animals were included to establish a baseline for immunologic read-outs. The study was performed in healthy, metabolically stable animals to avoid interference by septic or trauma-related stress factors. RESULTS: Both TPN regimens resulted in a significantly smaller weight gain (TPN-lipid, 29.8 +/- 4.0 g; TPN-CH, 30.3 +/- 4.4 g) compared with enterally fed reference animals (49.2 +/- 3.2 g; p = .007), with no difference in nitrogen balance between the TPN groups. Mucosal sucrase activity was significantly lower in both TPN groups (TPN-lipid, 8.8 +/- 1.0 x 10(-7) katal per gram (kat/g) of protein; CH: 11.9 +/- 1.6 x 10(-7) kat/g of protein) compared with enteral feeding (17.4 +/- 0.9 x 10(-7) kat/g of protein; ANOVA: p = .0007). Morphometric analysis of the small intestine revealed no differences between the two TPN groups although a significantly depressed villus height in the TPN-lipid group could be observed in comparison to enterally fed reference rats (TPN-lipid, 0.47 +/- 0.02; TPN-CH, 0.50 +/- 0.01; enteral, 0.56 +/- 0.02 mm; ANOVA: p = .0298). Light and electron microscopy revealed a normal surface architecture in all three groups of rats. Cellular immune reactivity was evaluated using a novel specific immunization protocol: animals were immunized against OVA 4 weeks before TPN. OVA-induced lymphoproliferative responses and phenotypic data from draining popliteal and mesenteric lymph nodes were evaluated after the different regimens. Results did not differ among the three groups. CONCLUSIONS: In healthy rodents, short-term lipid-based and carbohydrate-based TPN regimens lead to limited mucosal atrophy with preserved surface architecture compared with enteral feeding. However, peripheral and mesenteric cellular immune responsiveness after both TPN regimens remained comparable to enterally fed reference animals. Therefore, mesenteric and systemic cellular immune reactivity does not appear to be impaired by lipid-based or carbohydrate-based TPN.     

Biochemical and morphological changes in the digestive tract of rats after prenatal and postnatal malnutrition

Six-week-old rats subjected to prenatal and postnatal dietary restriction (maternal and weanling intake = 50% that of controls) were studied. Compared with controls, malnourished rats not only had reduced body (78 +/- 12 vs 187 +/- 21 g) and organ weights (small intestine: 4.51 +/- 0.46 vs 9.89 +/- 0.61 g; colon: 0.75 +/- 0.08 vs 1.77 +/- 0.18 g; liver: 2.75 +/- 0.34 vs 9.13 +/- 1.33 g; pancreas: 0.78 +/- 0.14 vs 1.67 +/- 0.49 g) but also decreased body weight-length ratios (6.5 +/- 0.3 vs 10.8 +/- 1.4 g/cm) and serum albumin levels. The small intestinal mucosa was hypotrophic (protein-DNA ratio: 5.02 +/- 1.43 vs 8.82 +/- 0.68, malnourished vs controls, respectively) with reduced mucosal thickness, villus height, and crypt depth. Specific activities of lactase, maltase, and sucrase were diminished (53%, 66%, 54% of control values, respectively). Colonic mucosa was hypoplastic with decreased mucosal thickness and crypt depth. Liver and pancreas were both hypotrophic and hypoplastic. The findings suggest that, in contrast to colonic mucosa, pancreas, and liver, the small intestinal mucosa maintained cell number during prolonged prenatal and postnatal malnutrition.     

Vitamin E status of patients receiving long-term parenteral nutrition: is vitamin E supplementation adequate?

Vitamin E status of eight patients receiving total parenteral nutrition (TPN), including 10 IU of all-racemic alpha-tocopheryl acetate daily and Intralipid 20% (500 mL; 12 mg of RRR-alpha- and 92 mg of RRR-gamma-tocopherols) two to three times per week for 69 +/- 45 (mean +/- SD) months was assessed by measuring plasma and adipose tissue tocopherol concentrations. Plasma alpha-tocopherols of TPN patients were similar to controls (17.5 +/- 6.6 mumol/L vs 22.4 +/- 5.1), whereas gamma-tocopherols were significantly reduced (6.0 +/- 3.1 vs 11.2 +/- 3.6, p less than 0.03). The adipose tissue alpha- and gamma-tocopherol/triglycerides (TG) were similar (369 +/- 215 nmol/mmol vs 452 +/- 228, and 125 +/- 102 vs 140 +/- 130, respectively), but cholesterol/TG were increased in the TPN patients (7.8 +/- 2.5 mumol/mmol vs 5.1 +/- 3.5, p less than 0.05), suggesting that adipose tissue was relatively TG-depleted and tocopherol/cholesterol measurements better reflect vitamin E status. The mean alpha-tocopherol/cholesterol ratios were significantly lower in the TPN patients than the controls (55 +/- 36 vs 106 +/- 63, p less than 0.04). Thus, current vitamin E supplementation of TPN patients seems insufficient for maintenance of adequate tissue stores.     

Essential fatty acid deficiency in patients receiving simultaneous parenteral and oral nutrition

Essential fatty acid deficiency is a common finding in patients nourished parenterally with hypertonic glucose and amino acids. In this study, we measured the linoleate concentration in the livers of 3 groups of patients. All the patients had operable upper gastrointestinal tract malignancies. Group I ate the hospital's regular diet ad libitum. Group II were given total parenteral nutrition (TPN), Group III received both enteral and parenteral nutrition and obtained about 35% of their caloric intake from food. The percentage of total liver fatty acids as linoleate were group I, 15.2 +/- 1.2%, group II, 3.7 +/- 1.4%, and group III, 2.8 +/- 1.6%. Data are expressed as the mean +/- 1 SEM. The patients who received 35% of their calories by mouth as food and the patients on TPN were found to be equally depleted in linoleate.     

Glutamine-enriched total parenteral nutrition maintains intestinal interleukin-4 and mucosal immunoglobulin A levels

BACKGROUND: Total parenteral nutrition (TPN) prevents progressive malnutrition but fails to maintain intestinal gut-associated lymphoid tissue (GALT) or established respiratory antiviral or antibacterial mucosal immunity. Our previous work demonstrated that decreases in intestinal immunoglobulin A (IgA) were associated with decreases in Th2-type IgA-stimulating cytokines, interleukin (IL)-4 and IL-10. Because glutamine supplementation of TPN partially preserves respiratory defenses and normalizes GALT, we investigated the ability of parenteral glutamine to normalize respiratory and intestinal IgA levels and measured Th2 cytokines in intestinal homogenates. METHODS: Animals were cannulated and randomly assigned to receive chow (n = 17), TPN (n = 18), or an isonitrogenous, isocaloric TPN solution formulated by removing the appropriate amount of amino acids and replacing them with 2% glutamine (n = 18) for 5 days. Respiratory tract and intestinal washings were obtained for IgA and the intestine homogenized and analyzed for IL-4 and IL-10. RESULTS: TPN decreased intestinal and respiratory IgA in association with decreases in intestinal IL-4 and IL-10 compared with chow-fed animals. Glutamine significantly improved respiratory and intestinal IgA levels, significantly improved IL-4 compared with TPN animals, and maintained IL-10 levels midway between chow-fed and TPN animals. CONCLUSIONS: Glutamine-enriched TPN preserved both extraintestinal and intestinal IgA levels and had a normalizing effect on Th2-type IgA-stimulating cytokines.     

Effect of recombinant human growth hormone on the intestinal structure of rats receiving bowel resection and parenteral nutrition

Recombinant human growth hormone (rHGH) can improve nitrogen balance and promotecell proliferation. Little is known about the relationship between rHGH and gastrointestinal mucosal structure and function after bowel resection and parenteral nutrition (PN). The aim of this study was to determine the effect of rHGH on bowel mucosal structure and barrier function in rats receiving 50% small intestinal resection and PN. Thirty Wistar rats with central vein catheterization plus 50% small bowel resection were divided into three groups: chow (chow), standard (STD) and rHGH (rHGH). The chow group received chow food; the STD group was given standard PN; the rHGH group received standard PN plus rHGH (4.8 mg/kg/day, subcutaneously). The groups were maintained on their respective diets for 8 days and then killed. Body weight, small intestinal mucosal thickness, villus height and Goblet cells in the villus were measured. Body weight loss in the STD group was significantly greater than that in the chow and rHGH groups (P< 0.01). The mucosal thickness and villus height of rHGH group were significantly greater than the STD and chow groups (mucosal thickness: 806 +/- 5.5 vs. 533 +/- 6.0 and 593 +/- 6.0 microm; Villus height: 506 +/- 6.0 vs. 295 +/- 5.5 gm and 400 +/- 6.7 lam, respectively) (P< 0.05). The number of Goblet cells in the STD group was significantly greater than the rHGH and chow groups (9.06 +/- 1.07 vs. 5.35 +/- 1.48 and 6.10 +/- 1.51/per villus) (P < 0.01). rHGH can maintain body weight and promote bowel mucosal cell growth and might improve the barrier function of the bowel in rats after 50% small intestinal resection and PN.     

The effect of the route of nutrient delivery on gut structure and diamine oxidase levels

Diamine oxidase (DAO) is an intestinal mucosal enzyme which serves as a marker of cellular maturity and integrity in ontogeny and after mucosal injury in the gastrointestinal tract. Since total parenteral nutrition is known to result in intestinal hypoplasia, this study was done to determine the effect of enteral and parenteral delivery of nutrients on gut structure and DAO levels. Central venous catheters were placed in 27 Sprague-Dawley rats (180-260 g), which received nutrients for 12 days via parenteral nutrition (GpI n = 10), oral intake of the parenteral solution (GpII n = 8), or standard rat chow (GpIII n = 9). Gross and microscopic measurements were made at sacrifice. Mucosal DAO levels were determined by metabolism of [3H] putrescine. Group III animals had a greater caloric intake than groups I and II, and were the only group with a significant increase in body weight. Gut weight, mucosal weight, and villous height were significantly less in group I vs groups II and III; group II values were less than group III (p less than 0.05). Both DAO specific activity and total gut DAO were significantly less in group I and group II. Mucosal DAO content correlated with total gut and mucosal weight. DAO mucosal levels decrease with parenteral nutrition, reflecting the intestinal hypoplasia that occurs. Mucosal DAO content may be dependent on both caloric intake and diet composition. Since serum DAO levels are known to correlate with mucosal DAO content, DAO activity may prove useful as a circulating marker of the effect of nutritional therapy on the intestinal mucosa.     

Short-chain fatty acids and total parenteral nutrition affect intestinal gene expression

BACKGROUND: The supplementation of total parenteral nutrition (TPN) formulas with short-chain fatty acids (SCFAs) increases glucose uptake and the expression of glucose transporters in parenterally fed animals. Several signals may be involved in intestinal adaptation; however, increased messenger RNA (mRNA) levels for proglucagon and several early-response genes, including c-myc and c-fos, are seen in animals receiving SCFA-supplemented TPN. Although the effects of a mixture of SCFAs are well documented, the relative contribution of individual SCFAs is unknown. Butyrate is a preferred fuel of colonocytes, with documented effects on cellular proliferation and gene expression. Accordingly, this study was undertaken to determine the relative role of butyrate in initiating an adaptive response in nonresected rats receiving TPN. METHODS: Animals received standard TPN for 66 hours, followed by 6 hours of either standard TPN, TPN supplemented with a mixture of SCFAs (acetate, propionate, and butyrate, 60 mmol/L total), or TPN supplemented with butyrate alone (9 mmol/L). An oral control group was fed an elemental diet, similar in macronutrient content to the TPN, so that all animals received the same amount of energy daily. RESULTS: SCFAs increased ileal glucose transporter 2 (GLUT2) mRNA expression compared with the orally fed group. SCFAs also increased proglucagon mRNA expression compared with the TPN group. No changes in Na+K(+)-adenosine triphosphatase or early-response gene expression were found in this study. CONCLUSIONS: In a rat model of TPN, the use of 9 mmol/L butyrate did not have the same effect on GLUT2 and proglucagon expression as a 60-mmol/L mixture of SCFAs. This suggests that the effect of a mixture of SCFAs on intestinal gene expression is not butyrate specific.     

Effect of glutamine supplementation on protein metabolism and glutathione in tumor-bearing rats

The effect of glutamine (GLN)-supplemented total parenteral nutrition (TPN) on tumor growth and protein metabolism was investigated in tumor-bearing rats. Six days after implantation of AH109A hepatoma, rats received isonitrogenous TPN without or with alanyl-glutamine (25% of total N) for a period of 6 days. Protein turnover was assessed by continuous infusion of l4C-leucine and levels of GLN and glutathione were determined in muscle, jejunum and liver. Diet had no effect on tumor parameters: weight (mean = 4.4 g), GLN and glutathione concentrations, protein synthesis rate and bromodeoxyuridine-labeling index. Body weight loss was less pronounced in the GLN group (-5.5 +/- 1.2 vs. -9.4 +/- 1.4 g/5d). Decrease in plasma and muscle GLN concentrations (-30% and -17% vs. healthy controls, respectively) was limited in tumor-bearing rats receiving GLN-enriched TPN (-15% and +3%). GLN-supplemented TPN increased muscle and jejunum fractional synthesis rates (36% and 25% vs. standard TPN, respectively) and reduced body protein breakdown in tumor-bearing animals (303 +/- 33 vs. 421 +/- 66 mumol Leu/Kg/h). Decrease in jejunum glutathione levels was partially abolished in the GLN group: -50% vs. -64% in the standard TPN group; no effect was noticed in other tissues. The authors conclude that GLN-supplemented TPN improves protein metabolism at both the whole body and the tissue level, and prevents GLN and glutathione deficiencies associated with tumor implantation.