Enteral branched-chain amino acids increase the specific activity of jejunal glutaminase and reduce jejunal atrophy

Branched-chain amino acid (BCAA)-enriched nutrient solutions reduce gut atrophy associated with parenteral nutrition. We hypothesized that this effect was mediated by phosphate-dependent glutaminase. Thirty male Wistar rats (300–350 g) underwent a standardized surgical procedure and were then randomized into three groups to receive 6 days of ad libitum enteral nutrition. The animals were fed a solution of conventional nutrients, a solution of conventional nutrients enriched with 2.0% BCAA or a solution of conventional parenteral nutrients enriched with 2.5% glutamine. When compared with rats fed conventional nutrients, rats fed BCAA and glutamine had less jejunal atrophy (P< 0.05) and a greater specific activity of phosphate-dependent glutaminase in the jejunum (131%; P< 0.05). It is concluded that enteral BCAA reduce atrophy of the jejunum via the generation of glutamine.     

Nonspecific adaptation of jejunal amino acid uptake in the rat

Luminal nutrients are a major effector of intestinal adaptation. Amino acids are trophic to the intestine, but their role in regulating amino acid transport is not well documented. The presence of several distinct amino acid transport systems raises the question of whether adaptation is class-specific. Studies were carried out in parenterally nourished rats receiving a 7-day jejunal infusion of a 3% solution of either aminoisobutyric acid, aspartic acid, glutamine, histidine, lysine, or valine. While all amino acids were trophic to the intestine, their effects on the in vitro uptake of 0.1, 1.0 and 10.0 mM aspartic acid, lysine, and valine (representative acid, basic, and neutral amino acids) were variable and nonspecific. Compared to controls receiving either total parenteral nutrition alone or total parenteral nutrition plus luminal saline, prior lysine and aspartic acid infusion significantly increased in vitro uptake of all three amino acids tested, whereas valine had little effect on transport. No effect on transport was seen with glutamine (actively metabolized by the intestine as is aspartic acid), aminoisobutyric acid (a nonmetabolizable amino acid congener), or histidine (the most trophic amino acid). In conclusion, while individual amino acids cause an adaptation of amino acid uptake, the effects are nonspecific and independent of their metabolic or trophic potential.     

The effect of minimum luminal nutrition on bacterial translocation and atrophy of the jejunum during parenteral nutrition

In situations of catabolic stress, the gut becomes atrophic and may have diminished barrier function as evidenced by an increase in bacterial translocation. The aim of this study was to examine the effect of minimum luminal nutrition during parenteral nutrition on the extent of jejunal atrophy and rate of bacterial translocation. Central venous lines were inserted into 30 rats before they underwent randomization to receive nutritional support with: (a) conventional parenteral nutrition; (b) conventional parenteral nutrition with 3 g/day of rat food (i.e., minimum luminal nutrition); or (c) rat food ad libitum. The rats were assessed after 10 days for nutritional status, extent of jejunal atrophy, caecal flora, as well as the extent of bacterial translocation to the mesenteric lymph nodes, liver and spleen. Rats in the rat food ad libitum group lost the smallest amount of weight and had the least amount of jejunal atrophy, yet had a similar rate of bacterial translocation as the parenterally nourished groups. When compared with the conventional parenteral nutrition group, the minimum luminal nutrition group had better preservation of the weight of the small bowel and its isolated mucosa (P < 0.01), but had a similar rate of bacterial translocation. Minimum luminal nutrition reduced the extent of atrophy of the gut but did not affect the incidence of bacterial translocation. It is inferred that there is no direct relationship between the extent of mucosal atrophy and incidence of bacterial translocation.     

Bidirectional supply of glutamine maintains enterocyte ATP content in the in vitro Ussing chamber model

Glutamine is the principal energy source for enterocytes, but it is not known whether parenteral or enteral supplementation is most beneficial to gut integrity. The aim of this study was to evaluate the effects of glutamine in uni- or bidirectional supply on the viability of intestinal mucosa of starved rats during incubation in Ussing chambers. Segments of jejunum from rats starved for 48 h were randomly mounted in Ussing chambers with three nutrient solutions: Krebs buffer without glutamine; 6 mM glutamine added to the mucosal side; 6 mM glutamine added to the mucosal side and 0.6 mM glutamine to the serosal side. ATP content of the mucosa, electrophysiology, and 51Cr-ethylenediaminetetraacetate (EDTA) permeability were studied during 180 min of incubation. The addition of glutamine to both sides of the stripped mucosa improved ATP levels compared to the Krebs solution (P < 0.05), and the addition of glutamine resulted in an increase in short circuit current (P < 0.05). No significant differences were seen in 51Cr-EDTA permeability or epithelial electrical resistance. Glutamine supplementation to both the luminal and serosal side in the Ussing chamber was more effective than luminal glutamine only in maintaining ATP levels of intestinal mucosa. Bidirectional supplementation of glutamine might improve intestinal energy metabolism and viability in in vitro studies.     

Comparisons of the effects on satiety and eating behaviour of infusion of lipid into the different regions of the small intestine.

Food intake and feelings of hunger and fullness were monitored in paired studies carried out in two groups of six healthy non-obese male volunteers during infusion of isotonic solutions of either a 50% corn oil emulsion or saline into the jejunum or into the ileum. Infusion of the lipid emulsion at a rate of 1.2 ml/min (4.9 kcal/min) into either the ileum or the jejunum significantly reduced the period of eating (p less than 0.01) and the quantity of food consumed (p less than 0.01), but neither affected the rates of drinking or the amount of fluid consumed. Infusion of the lipid emulsion into the jejunum also significantly reduced the sensations of hunger before the meal (p less than 0.05), and the rate of ingestion (p less than 0.01). Ileal infusion did not influence these indices. The results suggest that jejunal and ileal infusion of lipid reduces the size of the meal that could be consumed possibly by inhibiting gastric emptying. The alleviation of hunger before ingestion and the slower rate of eating, however, suggests that jejunal lipid activates an additional mechanism that influences the appetite centre in the hypothalamus directly.     

Acute exposure of small intestine to ethanol induces mucosal leakage and prostaglandin E2 synthesis.

The small intestines of healthy volunteers were challenged with ethanol during regional perfusion of a defined jejunal segment. Infusion of 30 mL of 5000 mmol/L ethanol to the perfused jejunal segment gave a maximum ethanol concentration of 973 +/- 98 (SEM) mmol/L in the jejunum lumen. This ethanol challenge induced within 20-30 minutes a 10-fold increase in albumin (P less than 0.001) and a two-fold increase in the glycosaminoglycan hyaluronic acid (P less than 0.05) in the perfusion fluid. Later during the challenge and simultaneously with a decreased jejunal loss of albumin, the jejunal recovery of prostaglandin E2 increased fourfold (P less than 0.01). The jejunal fluid concentrations of histamine and eosinophil cationic protein remained stable during the ethanol challenge. No changes in the jejunal appearance of albumin or other measured substances were seen when the maximum jejunal fluid concentrations of ethanol were less than 400 mmol/L achieved during challenge with smaller amounts of ethanol. The increased jejunal fluid appearance of hyaluronic acid after ethanol challenge indicates increased leakage from the interstitial/lymph fluid of the gut wall due to altered mucosal permeability. The relatively larger jejunal losses of albumin suggest that ethanol induces increased microvascular permeability of the jejunum as well.     

lactulose和glutamine对梗阻性黄疸大鼠空肠黏膜的影响

目的:研究梗阻性黄疸时空肠黏膜的变化及lactulose和glutamine对梗阻性黄疸大鼠空肠黏膜的影响．方法:Wistar大鼠84只,随机分为4组．通过手术结扎切断大鼠胆总管得到梗阻性黄疸模型．对梗阻性黄疸大鼠分别经胃灌注lactulose和glutamine药物,比较给药前及给药后5,10 d各组大鼠空肠黏膜绒毛高度变化,同时与未行胆管结扎的假手术对照组进行比较．结果:无论胆总管结扎与否,给药前各组空肠黏膜的绒毛高度无明显差异．胆总管结扎后大鼠空肠黏膜高度减低(5 d:q=4．32,P<0．01;10 d:q=11．03,P<0．01);应用生理盐水组大鼠的空肠黏膜绒毛高度明显低于应用lactulose和glutamine组大鼠的空肠黏膜绒毛高度,且应用glutamine组与胆总管未结扎组相近(5 d:q= 3．62,P>0．05;10 d:q=3．83,P>0．05);而应用lactulose和glutamine的2组大鼠空肠黏膜绒毛高度无明显差异(P>0．05)．结论:结扎大鼠胆总管可导致其空肠黏膜萎缩．经胃肠道应用lactulose或glutamine对胆道梗阻所致的大鼠空肠黏膜萎缩均具有保护作用,且二者对肠黏膜的保护作用无明显差异．     

Effect of bowel rehabilitative therapy on structural adaptation of remnant small intestine: animal experiment

AIM To investigate the individual and thecombined effects of glutamine, dietary fiber,and growth hormone on the structural adaptationof the remnant small bowel.METHODS Forty-two adult male Sprague-Dawley rats underwent 85% mid-small bowelresection and received total parenteral nutrition(TPN) support during the first threepostoperational days. From the 4thpostoperational day, animals were randomlyassigned to receive 7 different treatments for 8days: TPNcon group, receiving TPN and enteral20g·L~1 glycine perfusion; TPN Gin group,receiving TPN and enteral 20 g·L~1 glutamineperfusion; ENcon group, receiving enteralnutrition (EN) fortified with 20 g·L~1 glycine; EN Gin group, enteral nutrition fortified with20g·L~1 glutamine; EN Fib group, enteralnutrition and 2 g·d~1 oral soybean fiber; EN GHgroup, enteral nutrition and subcutaneousgrowth hormone (GH) (0. 3IU) injection twicedaily; and ENint group, glutamine-enriched EN,oral soybean fiber, and subcutaneous GHinjection.RESULTS Enteral glutamine perfusion duringTPN increased the small intestinal villus height(jejunal villus height 250μm 29μm in TPNcon vs 330μm±54μm in TPN Gln, ileal villus height260μm±28μm in TPNcon vs 330μm±22μm inTPN Gln, P<0.05) and mucosa thickness(jejunal mucosa thickness 360μm ± 32μm inTPNcon vs 460μm±65μm in TPN Gln, ilealmucosa thickness 400μm ± 25μm in TPNcon vs490μm ± 11μm in TPN Gin, P<0.05) incomparison with the TPNcon group. Either fibersupplementation or GH administration improvedbody mass gain (end body weight 270 g ± 3.6 g inEN Fib, 265.7 g ± 3.3 g in EN GH, vs 257g±3.3g in ENcon, P<0.05), elevated plasmainsulin-like growth factor (IGF-I) level(880μg·L~1±52μg.L~(-1) in EN Fib, 1200μg·L(-1) 96μg·L~(-1) in EN GH, vs 620μg·L~(-1) ±43μg·L~1 in ENcon, P<0.05), and increased thevillus height (jejunum 560μm ± 44μm in EN ± Fib,530μm ± 30μm in EN±GH, vs 450μm±44μm inENcon, ileum 400μm ± 30μm in EN Fib, 380μm±49μm in EN ± GH, vs 320μm ± 16μm in ENcon,P<0.05) and the mucosa thickness (jejunum740μm ± 66μm in EN ± Fib, 705μm ± 27 μm in EN ±GH, vs 608μm ± 58μm in ENcon, ileum 570μm ±27μm in EN ± Fib, 560μm ± 56μm in EN ± GH, vs480μm ± 40μm in ENcon, P<0.05) in remnantjejunum and ileum. Glutamine-enriched ENproduced little effect in body mass, plasma IGF-I level, and remnant small bowel mucosalstructure. The ENint group had greater bodymass (280g ± 2.2 g), plasma IGF-1 level(1450μg.L~1 ± 137μg.L~1), and villus height(jejunum 620μm ± 56μm, ileum 450μm ± 31μm)and mucosal thickness (jejunum 800μm ± 52μm,ileum 633μm ± 33μm) than those in ENcon, EN Gln (jejunum villus height and mucosa thickness450μm ± 47μm and 610μm ± 63μm, ileum villusheight and mucosa thickness 330μm ± 39μm and500μm±52μm), EN GH groups (P<0.05), andthan those in EN Fib group although nostatistical significance was attained.CONCLUSION Both dietary fiber and GH whenused separately can enhance the postresectionalsmall bowel structural adaptation. Simultaneoususe of these two gut-trophic factors can producesynergistic effects on small bowel structuraladaptation. Enteral glutamine perfusion isbeneficial in preserving small bowel mucosalstructure during TPN, but has little beneficialeffect during EN.     

Colonic preservation reduces need for parenteral therapy, increases incidence of renal stones, but does not change high prevalence of gall stones in patients with a short bowel.

Forty six patients with less than 200 cm of normal jejunum and no functioning colon were compared with 38 patients with similar jejunal lengths in continuity with a functioning colon. Women predominated (67%), and the most common diagnosis in each group was Crohn's disease (33 of 46 no colon, 16 of 38 with colon). All patients without a colon and less than 85 cm of jejunum and all those with a colon and less than 45 cm jejunum needed long term parenteral nutrition. Six months after the last resection 12 of 17 patients with less than 100 cm jejunum and no colon needed intravenous supplements compared with 7 of 21 with a colon. Between 6 months and 2 years, little change occurred in the nutritional/fluid requirements in either group, though there was weight gain. Of 71 patients assessed clinically at a median of 5 years, none with more than 50 cm of jejunum and a colon needed parenteral supplements. Most (25 of 27) of those without a colon who did not need parenteral supplements required oral electrolyte replacement compared with few (4 of 27) with a colon. None of the patients without a colon developed symptomatic renal stones compared with 9 of 38 (24%) with a colon (p < 0.001). Stone analysis in three patients showed calcium oxalate. Gall stone prevalence was high but equal in the two groups--43% of those without and 44% of those with a colon.     

The effect of minimum luminal nutrition on mucosal cellularity and immunity of the gut

Many catabolic patients can only consume small volumes of enteral nutrients. The aim of this study was to evaluate markers of cellularity and immunity in the small intestine of rats randomized to receive 6 days of parenteral nutrition, 25% enteral and 75% parenteral nutrition (i.e. minimum luminal nutrition) or enteral nutrition. The same glutamine-enriched solution was used for both parenteral and enteral nutrition. Enteral nutrition was associated with the least amount of jejunal atrophy ( P < 0.01), with the results from the minimum luminal nutrition group approximating those of the parenteral nutrition group. Parenteral nutrition was associated with the greatest number of CD2+ cells ( P < 0.05) and the lowest CD4/CD8 cell ratio ( P < 0.01) in the jejunal mucosa. In essence, we failed to demonstrate that there are any appreciable benefits associated with the enteral consumption of 25% of a nutrient load.     

Effects of short-chain fatty acid-supplemented total parenteral nutrition on intestinal pro-inflammatory cytokine abundance

We examined the effect of short-chain fatty acid-supplemented total parenteral nutrition on proinflammatory cytokine levels in piglets. Piglets (N = 22) received either standard total parenteral nutrition or total parenteral nutrition supplemented with short-chain fatty acids. After seven days of continuous nutrient infusion, proinflammatory cytokine (TNF-, IL-1, IL-6) abundance in plasma, jejunal, and ileal samples and small intestinal myeloperoxidase was determined using western blotting. No differences were seen in TNF- small intestinal abundance. IL-1 was higher in the small intestine of the short-chain fatty acid group (P < 0.05). IL-6 was higher in intestinal samples of the short-chain fatty acid group (P = 0.05), with the ileum having a greater abundance of IL-6 than the jejunum (P < 0.005). No differences in proinflammatory cytokine abundance in the plasma or tissue myeloperoxidase were seen. These results indicate short-chain fatty acids beneficially increase small intestinal abundance of IL-1 and IL-6 during total parenteral nutrition administration, while not affection systemic production of these cytokines or intestinal inflammation.     

Origin of gas retention and symptoms in patients with bloating

BACKGROUND & AIMS: Patients reporting abdominal bloating exhibit impaired tolerance to intestinal gas loads. The aim of this study was to identify the gut compartment responsible for gas retention. METHODS: In 30 patients predominantly reporting abdominal bloating (24 with irritable bowel syndrome and 6 with functional bloating) and 22 healthy subjects, gas (nitrogen, carbon dioxide, and oxygen) was infused into the intestine for 2 hours while measuring rectal gas outflow. First, in 12 patients and 10 healthy subjects, gas transit (24 mL/min jejunal infusion labeled with 74 MBq bolus of 133 Xe) was measured by scintigraphy. Second, in groups of patients and healthy subjects, the effects of gas infusion (12 mL/min) in the jejunum versus ileum, jejunum versus cecum, and jejunum versus sham infusion (n=6 each) were compared by paired tests. RESULTS: In patients, total gut transit of gas was delayed (50% clearance time, 33 +/- 4 min vs 23 +/- 4 min in healthy subjects; P <.05) owing to impaired small bowel transit (50% clearance time, 20 +/- 2 min vs 12 +/- 3 min in healthy subjects; P <.05), whereas colonic transit was normal (50% clearance time, 13 +/- 2 min vs 11 +/- 2 min in healthy subjects; not significant). Furthermore, jejunal gas infusion in patients was associated with gas retention (329 +/- 81 mL vs 88 +/- 79 mL in healthy subjects; P <.05), whereas direct ileal or colonic infusion was not (61 +/- 103 mL and -143 +/- 87 mL retention, respectively). CONCLUSIONS: In patients reporting bloating, the small bowel is the gut region responsible for ineffective gas propulsion.     

Effect of parenteral nutrition supplemented with short-chain fatty acids on adaptation to massive small bowel resection

After massive small bowel resection, total parenteral nutrition (TPN) is prescribed to maintain nutritional status. However, TPN reduces the mass of the remaining intestinal mucosa, whereas adaptation to small bowel resection is associated with increased mucosal mass. Short-chain fatty acids (SCFAs) have been shown to stimulate mucosal cell mitotic activity. This study determined whether the addition of SCFAs to TPN following small bowel resection would prevent intestinal mucosal atrophy produced by TPN. Adult rats underwent an 80% small bowel resection and then received either standard TPN or TPN supplemented with SCFAs (sodium acetate, propionate, and butyrate). After 1 wk, jejunal and ileal mucosal weights, deoxyribonucleic acid, ribonucleic acid, and protein contents were measured and compared with the parameters obtained at the time of resection. Animals receiving TPN showed significant loss of jejunal mucosal weight, deoxyribonucleic acid, ribonucleic acid, and protein and ileal mucosal weight and deoxyribonucleic acid after small bowel resection, whereas animals receiving SCFA-supplemented TPN showed no significant change in the jejunal mucosal parameters and a significant increase in ileal mucosal protein. These data demonstrate that SCFA-supplemented TPN reduces the mucosal atrophy associated with TPN after massive bowel resection and thys may facilitate adaptation to small bowel resection.     

Effects of bombesin,calcitonin, and enkephalin on canine jejunal water and electrolyte transport

The aim of this investigation was to study the effects of the peptides bombesin, calcitonin, and enkephalin on net jejunal water and electrolyte fluxes using the triple-lumen gut perfusion technique in conscious dogs. Intestinal transport was measured during intravenous infusions of bombesin (1 microgram/kg/hr, 8 studies), or calcitonin (3 micrograms/kg/hr, 5 studies), or methionine enkephalin (20 micrograms/kg/hr, 6 studies); each dog was used as its own control with infusion of 150 mmol/liter NaCl preceding and succeeding each peptide infusion. Net water absorption was reduced from a control value of 17 +/- 4.18 to 7 +/- 1.79 microliter/cm/min by bombesin (P less than 0.05) and increased from a control value of 15 +/- 3.95 to 29 +/- 5.58 microliters/cm/min by enkephalin (P less than 0.05). Bombesin reduced net sodium and chloride absorption, while enkephalin increased net absorption of sodium and bicarbonate. Calcitonin did not have any detectable effect in the dose used in this study in dogs. We conclude that bombesin and enkephalin can effect the transport of water and electrolytes in the canine jejunum.     

持续早期肠内营养联合肠黏膜保护对重症急性胰腺炎肠屏障功能影响的多中心随机对照临床试验

目的 观察持续早期肠内营养(EEN)联合肠黏膜保护对重症急性胰腺炎(SAP)患者肠屏障功能的影响.方法 选取2004年5月至2006年6月四个中心SAP患者79例,分为EEN联合肠黏膜保护组(联合组,39例)和完全肠外营养(TPN)组(40例).在发病后72 h内分别给予等氮源、等热量EEN和TPN.联合组给予肠内营养多聚合剂、精氨酸、谷氨酰胺和肠黏膜保护药物;TPN组采用中心静脉或外周静脉输注.入选后第1、7、14、21天行急性生理学及慢性健康状况(APACHE-Ⅱ)评分并检测血淀粉酶、二胺氧化酶(DAO)、内毒素、尿液肠脂肪酸结合蛋白浓度(IFABP-c)、肠脂肪酸结合蛋白含量(IFABP-t)、乳果糖与甘露醇(L/M)比值和肠道菌群变化,并观察并发症和住院时间、费用.结果 两组患者均无死亡.两组APACHE-Ⅱ评分随住院天数增加均呈递减趋势,联合组第7天APACHE-Ⅱ评分为6.00±1.60,低于TPN组(7.08±2.34,P＜0.05).第7,14,21天联合组血内毒素分别为(39.30±15.82)、(22.64±14.31)、(14.81±10.93)Eu/L,L/M比值分别为0.28±0.25、0.21±0.18和0.08±0.04,IFABP-c分别为(15.62±5.26)、(5.46±1.18)和(3.26±0.94)pg/ml,均明显低于TPN组(P值均＜0.05).联合组肠道菌群结构无明显变化,而TPN组出现肠道菌群结构变化.TPN组感染率(包括胰腺感染、腹腔感染和泌尿道、呼吸道感染)高于联合组(26.47%比3.44%,P＜0.01).联合组住院费用为(25 900±14 200)元,平均住院天数为(20.0±5.7)d,均低于TPN组[(46 800±4030)元和(34.5±19.9)d,P值均＜0.05)].结论 EEN联合肠黏膜保护可降低SAP患者肠道通透性,改善肠道灌注,保持肠道菌群,减少内毒素易位,对肠屏障功能有保护作用,且缩短病程、节约住院费用.     

Evidence of a vicious cycle in glutamine synthesis and breakdown in pathogenesis of hepatic encephalopathy–therapeutic perspectives

There is substantial clinical and experimental evidence that ammonia is a major factor in the pathogenesis of hepatic encephalopathy. In the article is demonstrated that in hepatocellular dysfunction, ammonia detoxification to glutamine (GLN) in skeletal muscle, brain, and likely the lungs, is activated. In addition to ammonia detoxification, enhanced GLN production may exert beneficial effects on the immune system and gut barrier function. However, enhanced GLN synthesis may exert adverse effects in the brain (swelling of astrocytes or altered neurotransmission) and stimulate catabolism of branched-chain amino acids (BCAA; valine, leucine, and isoleucine) in skeletal muscle. Furthermore, the majority of GLN produced is released to the blood and catabolized in enterocytes and the kidneys to ammonia, which due to liver injury escapes detoxification to urea and appears in peripheral blood. As only one molecule of ammonia is detoxified in GLN synthesis whereas two molecules may appear in GLN breakdown, these events can be seen as a vicious cycle in which enhanced ammonia concentration activates synthesis of GLN leading to its subsequent catabolism and increase in ammonia levels in the blood. These alterations may explain why therapies targeted to intestinal bacteria have only a limited effect on ammonia levels in patients with liver failure and indicate the needs of new therapeutic strategies focused on GLN metabolism. It is demonstrated that each of the various treatment options targeting only one the of the ammonia-lowering mechanisms that affect GLN metabolism, such as enhancing GLN synthesis (BCAA), suppressing ammonia production from GLN breakdown (glutaminase inhibitors and alpha-ketoglutarate), and promoting GLN elimination (phenylbutyrate) exerts substantial adverse effects that can be avoided if their combination is tailored to the specific needs of each patient.     

Effects of octapeptide-cholecystokinin,secretin, and glucagon on intestinal mucosal growth in parenterally nourished rats

Nutrients in the lumen of the small intestine may cause the release of enteric hormones which directly or indirectly stimulate intestinal mucosal growth. Male Sprague-Dawley rats with either an intact small bowel or following jejunal resection were maintained on total parenteral nutrition (TPN). C-terminal octapeptide-cholecystokinin alone or combined with secretin, or glucagon alone were added to the intravenous nutrient solution and continuously infused. Control rats received only TPN or gastric infusion of isocaloric amounts of TPN solution. After 7 days, intestinal hypoplasia was noted in rats with an intact bowel maintained on TPN alone compared with the gastrically infused group. TPN did not maintain the proximal-distal gradient of mucosal mass. Continuous intravenous infusion of octapeptide-cholecystokinin alone and together with secretin in rats maintained on TPN significantly stimulated small bowel mucosal growth, partially restoring the proximal-distal gradient. Glucagon infusion did not stimulate mucosal growth. Rats with a jejunal resection and maintained on TPN for 7 or 14 days failed to develop mucosal hyperplasia of the ileum in contrast to rats given the TPN solution intragastrically. Continuous intravenous infusion of octapeptide-cholecystokinin in rats maintained on TPN after jejunal resection caused significant mucosal growth in the ileum compared with the rats maintained on TPN alone, but not to the extent seen in gastrically fed animals. Intravenous infusion of octapeptide-cholecystokinin stimulates small-bowel mucosal growth. Secretin appears to have an additional effect when given together with octapeptide-CCK. Although a direct trophic action by these hormones on the intestinal mucosa is possible, this effect is more likely mediated via stimulation of pancreaticobiliary secretions.This work was supported by the Morrison Trust of San Antonio. SQ 19,844 was generously provided by Dr. Miguel Ondetti of the Squibb Institute for Medical Research.     

Effects of glutamine and recombinant human growth hormone on protein metabolism in prepubertal children with cystic fibrosis

To determine whether recombinant human GH (rhGH) and glutamine (GLN), alone or in combination, have a protein anabolic effect and whether rhGH alters GLN kinetics in cystic fibrosis (CF), nine 9.6 +/- 0.5-yr-old children with CF who were either undernourished (weight/height, <50th percentile) or short (height, <5th percentile) received 2-h infusions of [(13)C]bicarbonate (to assess CO(2) production), followed by 4-h infusions of [(13)C]leucine and [(15)N]GLN, on 4 separate days in the postabsorptive state: 1) at baseline, and after a 4-wk treatment with 2) oral GLN (0.7 g/kg.d), 3) rhGH (0.3 mg/kg.wk), and 4) GLN and rhGH combined (GLN and rhGH regimens were in randomized order). No significant effect of GLN on leucine kinetics was detectable. In contrast, rhGH induced a 32% reduction in leucine oxidation and a 13% stimulation of nonoxidative leucine disposal, an index of protein synthesis (P < 0.05), with no change in proteolysis or GLN kinetics. The combined GLN plus rhGH regimen had similar effects as rhGH alone. We conclude that in children with CF, 1) oral GLN may not promote protein gain in the fasting state; and 2) a short course of rhGH has a potent anabolic effect that is mediated by stimulation of protein synthesis and does not affect GLN kinetics.     

Effect of cholera toxin on ileal water and solute transport after resection of the proximal small intestine in the rat.

Intestinal adaptation after extensive small bowel resection results in mucosal hypertrophy and an increased capacity of the remaining small intestine to absorb solutes and water. We tested the ability of the adapted rat ileum to respond to a secretory stimulus, cholera toxin. Six weeks after 50% jejunal resection (short gut) or sham operation water and solute transport were measured in a 16 cm segment of ileum before and after exposure to cholera toxin in a single pass in vivo perfusion system. During the control periods absorption of glucose, acetate and water per unit length of intestine was significantly greater in short gut animals (P less than 0.05 to 0.001). After exposure to cholera toxin absorption of glucose and acetate was significantly reduced in both groups (P less than 0.05 to 0.01). Sodium and chloride secretion and net change in water movement in response to cholera toxin were significantly greater (P less than 0.05 to 0.01) in short gut animals. Generally the differences between short gut and sham operation animals disappeared when the data were normalised for mucosal weight. Chloride secretion per gram mucosa was less in short gut animals (P less than 0.001). The data indicate that the adapted small bowel is not only capable of enhanced absorption but also of enhanced net secretion in response to cholera toxin. The changes reflect the increased number of enterocytes per unit length of intestine after intestinal adaptation.     

Cholecystokinin and secretin prevent the intestinal mucosal hypoplasia of total parenteral nutrition in the dog.

Because the pancreas undergoes involutional changes during total parenteral nutrition (TPN) and because pancreatico-biliary secretions are trophic to the intestine, we studied jejunal and ileal structure and function and exocrine pancreatic function before and after 6 weeks of TPN in two groups of beagle dogs, one of which had TPN alone, the other having TPN plus daily stimulation of pancreatico-biliary secretions with intravenous infusions of cholecystokinin (CCK) and secretin. The injections of 1 U each per kg of body weight per day of CCK and secretin completely prevented the proximal and distal small bowel mucosal hypoplasia which developed in the TPN alone group. They also resulted in significant increases in in vivo galactose absorption (64 mM) per unit length of jejunum and ileum. However, there was no significant change in mucosal alpha-glucosidase and catalase activity or in in vitro mucosal uptake of 1 mM [14C]leucine when expressed per unit weight of intestinal mucosa. The capacity of the pancreas to respond to CCK and secretin was unaffected by excluding food from the intestine with 6 weeks of TPN in terms of pH, volume, and peak secretion rates of bicarbonate and protein, but maximum amylase output (units per 15 min per kg of body weight) fell significantly (P less than 0.05) from a mean of 1022 +/- 155 to 874 +/- 426 in TPN alone group and to 472 +/- 79 in the TPN dogs given CCK and secretin. These results show that daily CCK and secretin is trophic to the intestine of dogs nourished by TPN but do not indicate whether this trophic effect is attributable to CCK alone, secretin alone, the combination of the two hormones, or to the resultant stimulation of pancreatico-biliary secretions.