Journal of Parenteral and Enteral Nutrition

The primary factors in feeding premature infants are dependent on the development and maturation of digestion and absorption. The maturation of digestive and absorptive functions of carbohydrates, proteins, fats, minerals, and vitamins in the young premature infant were determined in relation to availability of hydrolytic enzymes, such as lipases, proteases, amylases, glucosidases, and lactase. The feeding is dependent on the ability of the premature infant to secrete salivary enzymes, gastric acid, pepsin, pancreatic exocrine enzymes, the presence of enterohepatic circulation, and the hydrolytic and absorptive capacity of the entercocyte. To evaluate the complexity of the gut maturation process, we proposed a unified concept where the ontogeny of the gastrointestinal system is the result of the following four major determinants: genetic endowment, intrinsic developmental and biological clock, endogenous regulatory mechanisms, and environmental influences. The developmental clock represents a predetermined temporal sequence of happenings in ontogeny that is inherently controlled. By 20 weeks of gestation, the anatomic differentiation of the fetal gut has progressed to the extent that it resembles that of a newborn. Secretory and absorptive functions, however, develop at different rates; the intestinal absorptive process is only partially available before 26 weeks of gestation, whereas gastric and pancreatic secretion is only basal and can be stimulated only partially even in the full-term newborn period. Regulatory mechanisms control the expression of the genetic endowment at various stages in gastrointestinal development. Neural-hormonal factors play major roles in the ontogeny of the gut. Adrenalectomy, hypophysectomy, and thyroidectomy delay the development of the gut. Administration of glucocorticoids or thyroxine at the critical stage in maturation causes early appearance of enzymes within the intestine. Other hormones that are potentially important in regulating gastrointestinal development include cholecystokinin, gastrin, secretin, which have trophic effects on the gastrointestinal tract, and insulin, insulin-like growth factors, and epidermial growth factor.

The development of gastrointestinal secretory function, particularly in response to hormonal stimulation, has received considerable attention. The degree of response of the target cell is determined not only by the amount of effective hormone reaching it but also by the number and affinity of receptors on its surface. Human newborns have high levels of gastrin in their sera, yet have low acid output. Exogenous gastrin is an ineffective stimulant despite the presence of seemingly "anatomically developed" parietal cells. It seems that neither endogenous nor exogenous gastrin has an effect on the target cell. If one accepts the role of circulating gastrin levels in the regulation of its own receptor, one can hypothesize the absence of a regulatory effect of gastrin in the newborn period. It was shown that hormonal regulation of migrating activity by motilin is also absent in the preterm and term infant. Plasma levels of motilin in neonates are comparable to those found in adults, but migrating motor complexes occur in the absence of cycling of plasma concentrations. Interestingly, however, the motilin receptor appears to be present.

In conclusion, the feeding mode content, concentration, and volume of the very young premature infant can be assessed by the development of digestive and absorptive capacity and gut motility. The concomitant changes in gut hormones and regulatory peptides during ontogeny and feeding will add a new dimension in the understanding of when, what, and how to feed the very young premature infant. (Journal of Parenteral and Enteral Nutrition23:S3-S6, 1999)

The host is continuously exposed to the environment via the mucosal surface. To this end, a large number of infectious agents, allergens and foreign proteins enter the inside of our bodies via the oral region, nasal and upper respiratory tracts, intestine and reproductive tract. The total area of these mucosal surfaces, which cover these tube-like tissues are at least two hundred times larger than those of skin. To provide an optimal first line of defense for these large surface areas, the mucosal immune system including secretory immunoglobulin A (S-IgA), mucosal αβ and γδ T-cells and epithelium play an essential role. The goal of our research is aimed at understanding the molecular and cellular aspects of the mucosal immune system and their defense against infectious diseases, inflammation and immunological disorders. Further, it is important to quickly apply our fundamental findings of the mucosal immune system to the development of mucosal vaccines. (Journal of Parenteral and Enteral Nutrition23:S7-S12, 1999)

Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency in the neonatal intensive care unit. It is a disease of medical progress in that more very low-birth-weight neonates are surviving than ever before and are thus susceptible to this potentially devastating disease. NEC received very little attention in the literature before the 1970s but now is well known to all neonatologists and pediatric surgeons. The 1500 to 2000 infants that die every year from this disease in the United States and the large number of infants who develop short gut syndrome from this disease only represent the tip of the iceberg of the problems NEC causes. The widespread fear of NEC among neonatologists and pediatric surgeons has contributed in large part to the use of the IV route rather than the gastrointestinal tract for nourishing these infants for relatively long periods. The consequences of this include a high incidence of sepsis, high hospital costs, and potential long-term neurodevelopmental disability because of poor nutrition during a very vulnerable period of growth and development. The purpose of this review is to provide a brief overview of the clinical presentation and current treatment for NEC, then provide a discussion of the pathophysiology on which strategies for prevention can be formulated. (Journal of Parenteral and Enteral Nutrition23:S13-S17, 1999)

In 1999, children seen in the emergency room of a developed country for watery diarrhea and dehydration will most likely receive an intravenous infusion of fluid, followed by instructions to give oral rehydration solution (ORS) and clear liquids for a day, followed by half-strength lactose-free formula. In fact, the majority of these children could best be managed with supervised ORS followed by early (within 4-6 h) refeeding of their normal diet, based on large numbers of clinical trials and a meta-analysis. In the next decade, effective therapy in addition to glucose-containing oral rehydration solutions should be available which should reduce diarrheal volume and duration of purging. These include amino acid-supplemented "Super ORSs," ORS with soluble fibers, liquid zinc, and probiotic milks containing bacteria which boost the immune response and reduce stool number. In addition, children wealthy enough to be able to afford the new tetravalent vaccine will be largely protected from dehydrating rotavirus diarrhea, the most common cause of dehydration in infants. (Journal of Parenteral and Enteral Nutrition23:S18-S19, 1999)

The etiology and pathogenesis of inflammatory bowel disease (IBD) remains an area under intense investigation. Cytokine secretion, which is important in the regulation of normal gastrointestinal immune responses, appears to be dysregulated in IBD. In Crohn's disease, there appears to be an excessive TH1 T-cell response to an antigenic stimulus, leading to increased levels of proinflammatory cytokines, such as interferon-γ (IFN-γ), interleukin (IL)-12, IL-1, IL-6, and tumor necrosis factor-α (TNFa). In ulcerative colitis, a TH2 T-cell response appears to be the pathological process responsible for the inflammatory disease. New and innovative therapeutic strategies targeting cytokines, such as TNF-α, are producing some promising results in animal and human studies. As more is learned about the complex cytokine interactions in IBD, more effective treatments will undoubtedly ensue. (Journal of Parenteral and Enteral Nutrition23:S20-S24, 1999)

Background: The main feature of ulcerative colitis (UC) is numerous infiltration of not only lymphocytes and plasma cells but also neutrophils and macrophages, indicating acute on chronic inflammation. Recent studies show that apoptosis may play an important role in the regulation of gut-associated lymphoid tissues (GALT). Therefore, this study was performed to clarify apoptosis of lymphocytes in the peripheral blood and colonic mucosa of UC. Methods: Three-color flow cytometry was used to clarify apoptosis of lymphocytes in the peripheral blood and colonic mucosa of patients with active and inactive UC compared with controls using fluorescence-labeled monoclonal and polyclonal antibodies such as Fas (CD95), Fas ligand, CD4, CD8, CD45RO, etc. Results: The ratio of Fas and CD45RO double-positive cells in the peripheral blood of UC patients was significantly increased in CD8 but not CD4 T cells when compared with controls. The ratio of Fas-positive and CD45RO-negative cells was significantly increased in CD4 and CD8 T cells of UC when compared with controls. There was unbalanced immunoregulation between CD4 and CD8 T cells in the colonic mucosa of UC probably due to apoptosis through Fas-Fas ligand system. Conclusions: Abnormal GALT system was found in UC probably due to dysregulation of T cells through Fas-Fas ligand system. (Journal of Parenteral and Enteral Nutrition23:S25-S28, 1999)

Among other functions, the liver serves to regulate both glucose and nitrogen economy in the body, and in humans, the amino acid glutamine is a major gluconeogenic substrate and the primary extrahepatic ammonia shuttle. Accordingly, the liver acinus possesses a unique heterogeneous metabolic architecture suited to carry out these functions with glutamine-consuming urea cycle and gluconeogenic enzymes in the periportal hepatocytes and a high capacity for glutamine synthesis in the perivenous hepatocytes, resulting in net glutamine balance across the hepatic bed under most conditions. Cytoplasmic levels of glutamine are significantly governed by the activity of the System N transporter in the plasma membrane of parenchymal cells; in this capacity, this glutamine carrier has been shown to represent a rate-limiting step in metabolism via glutaminase. The unique properties of System N allow it to rapidly adapt in support of the dynamic demands of whole body ammonia and glucose homeostasis. In contrast to System N in normal hepatocytes, human hepatoma cells take up glutamine at rates several-fold faster through a broad-specificity higher affinity transporter with characteristics of System ASC or B0. It is currently hypothesized that the expression of this high activity carrier by hepatoma cells combined with accelerated metabolism and tumor-induced derangements in hepatocellular architecture result in net glutamine consumption, and may underlie the diminished plasma glutamine levels observed in patients with hepatocellular carcinoma (HCC). The transport of glutamine through System ASC has been shown to regulate growth in some human hepatoma cells, which suggests this transporter may warrant consideration as a therapeutic target for HCC. (Journal of Parenteral and Enteral Nutrition23:S33-S37, 1999)

Glutamine (Gln) is a "competence factor" necessary for intestinal cell proliferation, intestinal fluid/ electrolyte absorption, and mitogenic response to growth factors. Gln deprivation produces apoptosis. Gln stimulation of quiescent cells produces immediate-early gene expression and MAP kinase activation. However, EGF signals more powerfully through MAPKs than Gln. Interestingly, EGF-stimulated mitogenesis is ineffective in the absence of Gln. In the intact intestinal epithelia in vivo, Gln has powerful effects on absorption of sodium and chloride. Gln-stimulated absorption is greater than and additive to glucose-stimulated absorption in cryptosporidial enteritis. In the piglet ileum, Gln metabolism stimulates apical amiloride-inhibitable Na+/H+ exchange. Although one might predict powerful effects of oral Gln on absorption in babies with diarrhea, 3 clinical trials to date (one published) have not shown an advantage of GIn-supplemented oral rehydration solutions (ORS) compared to standard glucose ORS. Severely dehydrated subjects have not been studied. More important effects of Gln treatment may be seen with (1) co-administration with a growth factor and (2) in patients with severe intestinal damage, such as protracted diarrhea of infancy or AIDS enteropathy. (Journal of Parenteral and Enteral Nutrition 23:S38-S40, 1999)

Bacterial translocation (BT) is a well-known insult during total parenteral nutrition (TPN) and a high incidence of morbidity has been reported in septic patients receiving TPN. Inflammatory cytokines were shown to play an important role in the pathogenesis of critical complications following sepsis. Previous studies have indicated that supplementation of TPN with glutamine is effective in preventing BT in animals, but its effectiveness in humans is unclear. The aim of this study was to determine the effectiveness of oral glutamine supplementation to patients receiving TPN in suppressing cytokine production of mesenteric blood mononuclear cells (M-MNC). Fifteen colorectal cancer patients were divided into 3 groups according to preoperative nutrition management. (1) TPN group: TPN with conventional glutamine-free amino acid solution. (2) Gln group: TPN with oral glutamine supplementation of 30 g/d. (3) Control group: oral intake of normal food. M-MNC were obtained immediately after laparotomy and tumor necrosis factor-alpha (TNF-α) and interleukin-10 (IL-10) production of M-MNC was evaluated with or without lipopolysaccharide (LPS) stimulation. TNF-α and IL-10 production by LPS-stimulated M-MNC was increased in the TPN group and suppressed in the Gln group. In conclusion, oral glutamine supplementation to patients with TPN was shown to be effective for the prevention of M-MNC activation to avoid excessive production of cytokines. (Journal of Parenteral and Enteral Nutrition23:S41-S44, 1999)

Glutamine serves as a shuttle of useful nontoxic nitrogen, supplying nitrogen from glutamine-producing (eg, muscle) to glutamine-consuming tissues. True production rates of glutamine are difficult to measure, but probably are less than 60 to 100 g/d for a 70-kg man. During catabolic stress increased amounts of glutamine are released from muscle, consisting of protein derived glutamine, newly synthesized glutamine, and glutamine losses from the intramuscular free pool. The large and rapid losses of free muscle glutamine are difficult to restore, presumably as a result of disturbances in the Na+ electrochemical gradient across the cell membrane. Whereas increased amounts of glutamine are released from muscle, glutamine consumption by the immune system (liver, spleen) also is enhanced. Thus, during catabolic stress changes occur in the flow of glutamine between organs. These changes are not necessarily reflected by alterations in the whole-body appearance rate of glutamine. In contrast with the gut, where glutamine is taken up in a concentration dependent manner, the immune system actively takes up glutamine despite decreased plasma concentrations. Supplementation with glutamine influences uptake by both the gut and the immune system, as evidenced by increased mucosal glutamine concentrations and gut glutathione production. There is evidence suggesting that this improves gut barrier function. Although the benefit of glutamine supplementation is most evident from experimental studies, clinical studies on the effect of glutamine do exist and suggest that glutamine supplementation has beneficial effects with regard to patient outcome. (Journal of Parenteral and Enteral Nutrition23:S45-S48, 1999)

Very low-birth-weight infants have minimal endogenous nutritional reserves and are at high risk for stresses that induce further breakdown of these diminished reserves. They frequently receive very little glutamine because enteral feedings are often delayed and glutamine is not included in parenteral nutrition. Here we describe studies of glutamine supplementation in very low-birth-weight infants and discuss potential mechanisms for the beneficial effects. (Journal of Parenteral and Enteral Nutrition23:S49-S51, 1999)

Background : Recently we have shown that glutamine-enriched enteral nutrition in trauma patients reduced the occurrence of pneumonia, bacteremia, and sepsis. In that study, no clear explanation for these results was found except for lower tumor necrosis factor (TNF)-soluble receptors, suggesting immunomodulation. Here we present data on the course of endocrine and metabolic plasma mediators that were analyzed to provide more insight into the working mechanism of glutamine. Methods: Endocrine and metabolic mediators were measured in plasma samples taken on admission (day 0) and on days 1, 2, 3, 7, and 10. Glucose, prealbumin, albumin, alanine, C-reactive protein, α1-antitrypsin, complement factors, cortisol, glucagon, insulin, and growth hormone were assessed by standard techniques. Results: The rate of feeding, demography, and injury severity did not differ between the glutamine and control group. There was a sustained hyperglycemic response in both groups. Insulin levels rose in the second phase of the period of observation. A moderate cortisol and glucagon response was seen in both groups. There was no alteration in growth hormone levels in either group. C-reactive protein, α1-antitrypsin, and complement factors showed similar increases in both groups but levels remained in the normal range. The course of alanine, albumin, and prealbumin also showed no difference between the groups. Conclusions: Glutamine-enriched enteral nutrition had no influence on the endocrine and metabolic response in trauma patients. Therefore, the reduction in infectious morbidity seen in glutamine-supplemented trauma patients is most likely not explained by a modulation of the humoral stress response and its metabolic consequences. (Journal of Parenteral and Enteral Nutrition23:S52-S58, 1999)

New strategies for immunonutritional support include administration of special nutrients such as glutamine. Glutamine is important in several key metabolic processes of immune cells and enterocytes. Exogenous glutamine augments the functions of lymphocytes and macrophages. Neutrophils also reportedly utilize glutamine at a significant rate. Our recent studies demonstrated that glutamine enhances neutrophil function. This article focuses on the effects of glutamine on neutrophil function in surgical stress. Enteral glutamine administration enhanced peritoneal and hepatic bacterial clearance in our rat peritonitis model. Furthermore, IV glutamine supplementation improved the outcome of animals with severe surgical stress. Our in vitro study revealed that supplemental glutamine augmented the bacterial killing function of neutrophils from postoperative patients. Glutamine increased phagocytosis of the neutrophils. In addition, glutamine dose-dependently increased production of reactive oxygen intermediates (ROI) by neutrophils. Thus, our studies suggest that glutamine supplementation may improve bactericidal function of neutrophils by increasing both phagocytosis and ROI production. In conclusion, glutamine plays an important role in neutrophil function. Glutamine may be useful for the prevention, and treatment, of severe infection in critical illness and trauma. (Journal of Parenteral and Enteral Nutrition23:S59-S61, 1999)

Purpose: To evaluate the impact of alanyl-glutamine (Ala-Gln)-supplemented parenteral nutrition (PN) on clinical safety, nitrogen balance, intestinal permeability, and clinical outcome in postoperative patients. Methods: One hundred twenty patients undergoing major abdominal surgery were enrolled. Protocol was approved and informed consent obtained. A double-blind protocol was designed as used in Europe. The clinical safety and outcome were observed for 60 patients in 2 centers (30 each). Sixty patients from 2 additional centers (30 each) were observed for clinical safety, nitrogen balance, intestinal permeability, and clinical outcome. All patients received isonitrogenous (0.20 g/kg body wt per day) and isocaloric (30 kcal/kg body wt per day) parenteral nutrition. The study group received Ala-Gln (Dipeptiven, Fresenius Kabi, Bad Homberg, Germany) 0.50 g/kg per day. Clinical chemistry variables, plasma amino acids profile, nitrogen balance, intestinal permeability (lactulose/mannitol ratio [L/M ratio]) were measured; hospital stay and infection rate were monitored. Statview was used for analysis of variance (ANOVA) or χ 2 tests. Data were expressed as means ± SD, and the significance level was p < .05. Results: The patients in both groups were comparable prior to the operation. Vital signs and clinical chemical parameters were similar between groups. L/M ratio was 0.047 ± 0.029 in control and 0.058 ± 0.049 in study group before the operation (AOD-3). The L/M ratio was 0.132 ± 0.081 in the control group, and 0.097 ± 0.063 in study group on the seventh postoperative day. The difference of L/M ratio between groups was significant (p = .02). The cumulative nitrogen balance values were -5 ± 162 mg/kg for 6 days in control and 144 ± 145 mg/kg for 6 days in study group (p = .0004). All the patients recovered without incision infection. However, there were 3 cases that had infection-related complications in the control group; the difference was not significant between groups. The hospital stay in the study group was 12.5 days, which was 4 days less than that of the control group (p = .02). Conclusions: Ala-Gln-supplemented PN was clinically safe, had better nitrogen balance, and maintained intestinal permeability in postoperative patients. The clinical outcome of the patients in study group was better; it was significantly different from the control group. (Journal of Parenteral and Enteral Nutrition 23:S62-S66, 1999)

IL-11 is a multifunctional cytokine that has pleiotropic effects on a variety of tissue including the bone marrow and intestinal mucosa. IL-11 is useful in elevating the platelet count in cancer patients with chemotherapy-induced thrombocytopenia and has a cytoprotective effect on the bowel mucosa in a variety of causes of gut damage and a trophic effect on the villi after massive bowel resection. (Journal of Parenteral and Enteral Nutrition 23:S67-S69, 1999)

Background: We investigated the effects of pectin, a soluble dietary fiber, on the morphological parameters of the small intestine. In addition, we tested the effects of butyrate enemas on dextran sulfate sodium (DSS)-induced experimental colitis. Methods: Male Wistar rats were fed an elemental diet containing 2.5% pectin for 14 days, and several parameters were then determined. DSS-induced colitis was evoked by the oral administration of water containing 3% DSS for 10 days. The butyrate enema (3 mL of 100 mmol/L butyrate per day) was begun 7 days before the DSS treatment. Interleukin (IL)-8 secretion in the human intestinal epithelial cell line HT-29 was determined by enzyme-linked immunosorbent assay (ELISA). Results: Pectin feeding induced a significant increase in the villus height and crypt depth in the small intestine. These effects correlated with a significant increase in plasma enteroglucagon levels. Pretreatment with a butyrate enema significantly blocked the development of DSS-induced experimental colitis. In the in vitro experiment, sodium butyrate dose-dependently inhibited tumor necrosis factor (TNF)-α-induced IL-8 secretion in HT-29 cells. Conclusions: A trophic effect due to dietary fiber was directly observed. The generation of short-chain fatty acids and the induction of enteroglucagon release might play an important role in this process. Butyrate, one of the major metabolites of dietary fiber, exerted a potent anti-inflammatory effect both in vivo and in vitro. Dietary fiber may therefore play important roles in the regulation of normal and pathological conditions in the intestine. (Journal of Parenteral and Enteral Nutrition23:S70-S73, 1999)

Background: Dietary nucleotides play an important role in the growth and development of the intestine. Parenteral supplementation of nucleic acids may be necessary to maintain the mucosal proliferation and barrier functions during parenteral nutrition (PN). Methods: Male Wistar rats were divided into 3 groups: FED (food ad libitum with saline infusion); PN (a standard PN solution); and OG (OG-6, a mixture of nucleotide and nucleosides, in addition to the PN solution). The mucosal wet weight, protein, and DNA contents, villous height and crypt depth, electronmicroscopic examination of the intercellular junctions, proliferating activity of the mucosal cells, mucosal permeability, bacterial translocation, and mucosal cathepsin activities were examined. Results: The wet weight, protein, and DNA contents of the jejunal mucosa were significantly increased in the OG group, compared with those in the PN group. The morphometric examination revealed a significant increase in the villous height but not in the crypt depth in the OG group. The widths of both the tight and intermediate junctions were narrower in the OG group than those in the PN group. The activity of diamine oxidase was increased in the OG group, compared with that in the PN group. The ratio of proliferating cell nuclear antigen positive cells and the index of bromodeoxy uridine labeling index in the OG group were as high as in the FED group, and significantly higher than those in the PN group. The portal concentration of fluorescein isothiocyanate-dextran 70,000 after intragastric loading was significantly higher in the PN group than that in OG group. Likewise, the rate of urinary lactulose excretion after intragastric loading was higher in the PN group. The positive rate of bacteria cultured in mesenteric lymph nodes was higher in the PN group than in the OG group although the difference was not significant. The activities of mucosal cathepsins (B, H, and L), markers for phagocytic degradation of extrinsic substances and organisms, were higher in the PN group than those in the OG and FED groups. Conclusions: Parenteral supplementation of nucleic acids supports the mucosal cell proliferation and functions. (Journal of Parenteral and Enteral Nutrition23:S74-S77, 1999)

Background: Glutamine (GLN) plays many important roles for the enterocytes in health and disease, but no liquid enteral products contain GLN because of its instability. We hypothesized that glutamate (GLU) may replace GLN in supplementation to an enteral diet, and compared the metabolic effect of GLU and GLN on the gut to each other. Methods: Rats suffering from a 30% burn received an enteral diet containing 30% GLU (m/w to total amino acids; GLU group), 30% GLN (GLN group), or a standard amino acid formula (CTR group). After a 64-hour feeding period, the small intestine and the portal and arterial blood were harvested to observe portal and arterial amino acid levels, and glutaminase activity and glutathione in the jejunal mucosa. In another study, 3H uptake into the mucosal protein was examined after a massive dose injection of 3H-phenylalanine. Results: Alanine, a product of GLN or GLU catabolism, significantly increased in the portal blood of the GLU group compared with the GLN group. In the gut mucosa of the GLU group, 3H uptake into protein and total glutathione were higher than those of other two groups. GLN did not elevate the glutaminase activity. Arterial GLU levels increased in the GLU group, however remained within safety limits. Conclusions: Enterally delivered GLU may be a preferable fuel for the enterocytes and enhance the mucosal protein synthesis. GLU probably can substitute for GLN in supplementation to an enteral diet regarding many roles GLN plays in the intestinal mucosa under stress situations. (Journal of Parenteral and Enteral Nutrition23:S78-S82, 1999)

Epidermal growth factor (EGF) is an important constituent of several gastrointestinal secretions. Many studies in both animals and humans have shown EGF to have multiple effects upon gut epithelial cells. These include cytoprotection, stimulatory effects on cell proliferation and migration, induction of gene expression such as mucosal enzymes and trefoil proteins, and inhibitory effects on gastric acid secretion. The main conundrum associated with EGF action is the disparity between experimental studies on its luminal and systemic actions. Opinion is sharply divided as to whether or not EGF has any action when given luminally and on the site of the EGF receptors on gut epithelial cells. Most studies agree that the EGF receptors are located on the basolateral surface, in which case EGF should only be active if surface ulceration has occurred—unless there is translocation across the epithelium. There are several clinical situations in which EGF might be useful in cytoprotection and in stimulating repair and regeneration in the gut. These include necrotizing enterocolitis and mucositis, and it is to be hoped that the solid basis of experimental studies on EGF might stimulate work on this topic. (Journal of Parenteral and Enteral Nutrition23:S83-S88, 1999)

After superficial intestinal injury, the mucosal integrity is reestablished by rapid migration of epithelial cells from the adjacent area in a process called restitution. Our previous study suggested that growth hormone improves intestinal healing in an experimental small bowel ulceration, mediated by insulin-like growth factor-1 (IGF-1). The aim of the present study was to assess the role of IGF-1 in mucosal epithelial restitution using an in vitro epithelial wound model. Wounds were established in confluent monolayers of the intestinal cell line, IEC-6. Migration was quantitated in the presence or absence of IGF-1 as the number of cells migrating across the wound edge. Proliferation was assessed by thymidine incorporation. IGF-1-enhanced epithelial cell migration by 2- to 2.5-fold after 12- and 24-hour treatment, respectively, the first step involved in gastrointestinal wound healing. Cell proliferation was significantly stimulated by IGF-1 as well. In addition, expression of transforming growth factor-β (TGF-β) mRNA was significantly enhanced in the wounded monolayers treated with IGF-1. IGF-1 receptor mRNA was found to be detectable throughtout the gastrointestinal mucosa and in the intestinal epithelial cells. In conclusion, these findings suggest that IGF-1 plays an important role in reconstitution of intestinal epithelial integrity after mucosal injury. (Journal of Parenteral and Enteral Nutrition23: S89-S92, 1999)

The effects of insulin-like growth factor-1 (IGF-1) on the catabolic and immune response induced by thermal injury were studied in burned rats fed by TPN. An increase of synthesis greater than the increase of breakdown resulted in improved nitrogen retention in the IGF-1 group. There was no effect on the mRNA in the structural proteins of the skeletal muscle and liver. However, the gene expression of albumin and the structural proteins of the diaphragm increased significantly in the rats receiving IGF-1. The proliferation of the gut mucosa and the fractional protein synthesis rate of the small intestine increased, and the endotoxin content of the liver and spleen were smaller in the burned rats that received IGF-1. Delayed type hypersensitivity increased significantly (p < .01) in the IGF-1 group. In conclusion, IGF-1 improved the whole-body protein metabolism, and albumin and respiratory muscle protein synthesis in the burned rats. It significantly promoted the proliferation of the intestinal mucosa, and reduced the intestinal translocation of endotoxin. Cellular immunity was also enhanced. (Journal of Parenteral and Enteral Nutrition23:S93-S97, 1999)

Background: Glucagon-like peptide-2 (GLP-2), a 33 amino acid, proglucagon-derived peptide with intestinotrophic activity, is secreted from enteroendocrine cells in the small and large intestine. Methods: This review describes recent advances in our understanding of GLP-2 physiology from rodent experiments in vivo. Results: GLP-2 administration induces mucosal epithelial proliferation in small and large bowel and stomach. GLP-2 is rapidly degraded by the enzyme dipeptidyl peptidase IV (DPP-IV) to produce the biologically inactive form GLP-2(3-33), however, GLP-2 analogs that confer resistance to DPP-IV exhibit enhanced biologic activity in vivo. GLP-2-treated bowel retains normal to enhanced functional absorptive capacity. Furthermore, GLP-2 infusion prevents total parenteral nutrition (TPN)-associated intestinal hypoplasia, and enhances bowel adaptation and nutrient absorption in rats following small bowel resection. GLP-2 also reverses weight loss and improves histologic and biochemical parameters of disease activity in mice with experimental colitis. Conclusions: GLP-2 is an intestine-derived peptide with intestinotrophic properties that may be therapeutically useful in diseases characterized by intestinal damage or insufficiency. (Journal of Parenteral and Enteral Nutrition 23:S98-S100, 1999)

Gut function and the degree of intestinal insufficiency or failure in short bowel patients can be quantified with respect to wet weight and energy absorption by the use of balance studies. This enables the physician to distinguish patients with extreme intestinal failure inconsistent with the restoration of intestinal autonomy by dietary manipulation from short bowel patients with borderline gut failure in whom dietary manipulations may result in the weaning from parenteral support. A high-carbohydrate, low long-chain fat diet and a diet where long-chain fat has been replaced by medium-chain triglycerides increase absorption of energy in patients with small bowel failure, provided that they have a preserved colon in continuity. This is due to the ability of the colonic flora to ferment carbohydrates malabsorbed in the small bowel to the short-chain fatty acids (SCFAs). These SCFAs are easily absorbed across the colonic mucosa resulting in a salvage of carbohydrate energy that otherwise would have been lost in feces. In contrast, long-chain fatty acids are not absorbed by the colon, and long-chain fat malabsorbed in the small bowel of short bowel patients are not retained in the large bowel. Recent work has indicated that the water soluble medium-chain fatty acids are effectively absorbed in the large bowel similar to the SCFAs. This may explain an almost complete absorption of medium-chain triglycerides in short bowel patients, even in patients with virtually no absorption of long-chain fat, and why this only occurs in patients with a colon in continuity. Manipulation of the dietary fat:carbohydrate ratio is much less efficacious in short bowel patients with no colonic function, and the use of medium-chain triglycerides has no proven effect on overall energy absorption from short bowel patients without a large bowel in continuity. Hence, the colon has increasingly important digestive functions as small bowel failure proceeds, not only when it comes to absorption of water and sodium, but also of energy from carbohydrates and medium-chain fat. (Journal of Parenteral and Enteral Nutrition23:S101-S105, 1999)

Background: Because of advances in parenteral nutrition (PN), the prognosis for patients with short bowel syndrome (SBS) has recently shown great improvement. Even infants with a small bowel measuring only 20 cm either with or without an ileocoecal valve can now survive. However, because of the increased periods of PN, severe complications associated with PN have been observed. Patients and Methods: We analyzed 17 patients with SBS treated by long-term PN to investigate the complications of PN, particularly hepatic dysfunction, micronutrient deficiency, and intoxication. Results: Eleven of 17 patients (64.7%) had hepatic dysfunction, mostly cholestasis. The main causes of hepatic dysfunction were loss of enteral feeding and infections. Regarding the complications of the micronutrients, zinc and copper deficiencies have been observed less often because of trace element supplements. However, manganese deposition, especially in the basal ganglia, was recognized in one patient. Conclusions: We therefore need to pay more attention to these problems when treating this disease in order to improve the overall prognosis significantly. (Journal of Parenteral and Enteral Nutrition 23:S106-S109, 1999)

We reviewed 12 pediatric and 18 adult patients with short bowel syndrome (SBS) from Osaka University Hospital and compared clinical characteristics between them. The length of the residual small intestine ranged from 0 to 75 cm (mean 47 cm) in pediatric patients and from 0 to 150 cm (mean 47 cm) in adult patients. In all cases, total parenteral nutrition (TPN) was started immediately after surgery and was gradually replaced by enteral nutrition. Eight pediatric patients (67%) and 4 adult patients (22%) were weaned from TPN. Residual intestinal length in these patients ranged from 27 to 75 cm (mean 57 cm) in pediatric patients and 57 to 150 cm (mean 96 cm) in adult patients. Pediatric patients with residual small intestinal lengths of 0, 16, 25, and 45 cm were not weaned from TPN. None of the adult patients with residual small intestinal length less than 40 cm could achieve complete intestinal adaptation. Five adult patients died due to liver failure (2 cases), heart failure (2 cases), or pneumonia (1 case), whereas all pediatric patients survived. The average life span of indwelling central venous catheters was 511 days and 780 days, and the rate of catheter-related sepsis per 1000 catheter days was 0.73 and 0.48 in pediatric and adult patients, respectively. Plasma levels of arginine and citrulline in patients receiving TPN were significantly decreased compared with those in patients receiving TPN without SBS both in pediatric and adult patients (p < .01). These results indicate that pediatric and adult patients with SBS can survive with TPN and enteral nutrition. The minimum remaining intestinal length necessary for complete bowel adaptation is shorter for pediatric patients than adults, suggesting better bowel adaptation in pediatric patients. (Journal of Parenteral and Enteral Nutrition 23:S110-S112, 1999)

Because epidermal growth factor (EGF) has multiple effects on the intestinal epithelium and endogenous EGF plays an important role in maintaining normal intestinal structure and the response to injury, EGF should be important in the intestinal adaptive response to resection. The accumulated data in the literature support a role for endogenous EGF in the intestinal adaptive response. Endogenous EGF is increased in saliva and diminished in urine after intestinal resection. This suggests increased tissue utilization of endogenous EGF during adaptation. Intestinal EGF receptor activity is increased after resection. Intestinal adaptation is impaired in animals with defective EGF receptors. Thus EGF receptor activity also is important during adaptation. The results of experimental studies suggest that EGF administered at the time of resection enhances the intestinal adaptive response. Both structural and functional adaptation are augmented. The route, dose, and timing of EGF administration are important factors. EGF has additive effects with glutamine and growth hormone on adaptation. Several observations from these reports have relevance to the potential clinical application of EGF therapy: (1) EGF should be given soon after resection; (2) early transient administration may lead to a substantial effect on adaptation; (3) both systemic and enteral therapy may be effective; (4) luminal nutrients are important but not essential in mediating EGF-stimulated adaptation; and (5) combined therapy with other nutrients and growth factors may have merit. In conclusion, endogenous EGF plays an important role in intestinal adaptation. Furthermore, experimental results suggest the potential clinical usefulness of EGF to stimulate intestinal adaptation after massive intestinal resection. There is currently no evidence to support the use of EGF in patients with well-adapted short bowel syndrome. (Journal of Parenteral and Enteral Nutrition23:S113-S116,1999)

ABSTR.ACT. Massive intestinal resection often results in long-term dependence on parenteral nutrition (TPN). In an effort to enhance bowel rehabilitation, the amino acid glutamine, growth hormone and a diet optimized to enhance absorption have been administered to >300 patients with the short bowel syndrome. Initially about 60% of the patients were weaned from TPN and an additional 30% had reduced TPN requirements. At long-term follow up (2 years) 40% of the group remained off TPN, 40% had reduced TPN requirements, and 20% had the same requirements. This report addresses issues such as the optimization of diet and provides a care map which should enhance the rehabilitation of patients with the short bowel syndrome. (Journal of Parenteral and Enteral Nutrition23:S117-S120, 1999)

From November 1994 to November 1998, 20 children (2.5 to 14 years) received a jejunoileal graft alone (SBTx; n = 10) or in combination with the liver (SBLTx; n = 10 and/or the right colon (5 SBTx). Indications were intractable diarrhea of infancy (n = 8), short bowel syndrome (n = 6), extensive Hirschsprung disease (n = 4), and chronic intestinal pseudoobstruction (n = 2). Immunosuppression included tacrolimus, methylprednisolone, and azathioprine. Current follow-up ranges from 6 to 54 months. Five patients died (3 SBTx) within the first 2 months. Acute liver rejection occurred in 5 patients during the first 2 months. Sixteen episodes of intestinal rejection during the first 3 months in 11 patients (8 in 4 SBTx) were successfully treated in all but 3 by increasing tacrolimus dose and/or a 3-day methyprednisolone bolus or required antilymphoglobulins in 3 cases. Surgical complications occurred 8 times after SBLTx and 3 after SBTx. Infectious complications were more frequent in SBLTx recipients. Reversible Epstein-Barr virus-related posttransplant lymphoproliferative disease occurred in 3 recipients. Five presented cytomegalovirus infection. The SB graft was removed in 5 recipients (3 chronic rejection). All patients were started with oral and/or enteral feeding from the 7th postoperative day by using either normal food or protein hydrolysate diet. Currently, 10 of 11 children (8 SBLTx) achieved digestive autonomy after 5 to 30 weeks. All recipients gained weight; however, growth velocity remained reduced during the first 6 months because of the steroid therapy. Overall graft and patient survival is higher after SBLTx. Intestinal transplantation is indicated for patients with permanent intestinal failure. However, because parenteral nutrition is generally well tolerated, even for long periods, each indication for transplantation must be weighed carefully in terms of risk and quality of life. (Journal of Parenteral and Enteral Nutrition23:S121-S125, 1999)