epidermal-growth-factor and Short-Bowel-Syndrome

Intestinal failure is defined as the inability to maintain fluid, nutrition, energy, and micronutrient balance that leads to the inability to gain or maintain weight, resulting in malnutrition and dehydration. Causes of intestinal failure include short bowel syndrome (ie, the physical loss of intestinal surface area and severe intestinal dysmotility). For patients with intestinal failure who fail to achieve enteral autonomy through intestinal rehabilitation programs, the current treatment options are expensive and associated with severe complications. Therefore, the need persists for next-generation therapies, including cell-based therapy, to increase intestinal regeneration, and development of the tissue-engineered small intestine.

Topics: Artificial Organs; Bone Morphogenetic Proteins; Enteric Nervous System; Epidermal Growth Factor; Gastrointestinal Motility; Humans; Intestinal Mucosa; Intestine, Small; Organoids; Paneth Cells; Receptors, Notch; Regeneration; Short Bowel Syndrome; Signal Transduction; Stem Cell Transplantation; Tissue Engineering; Tissue Scaffolds; Wnt Signaling Pathway

Short bowel syndrome (SBS) occurs more commonly in human neonates than in adults. There are currently no approved therapeutic agents aimed directly at stimulating intestinal adaptation in this population.. A brief review of SBS and intestinal adaptation is first presented. We then present candidate peptide growth factors that are suggested to augment intestinal adaptation in SBS, with a particular focus on glucagon-like peptide-2, as well as insulin-like growth factor-1 and epidermal growth factor. The normal physiology of these peptides and our understanding of their roles in intestinal adaptation are discussed. We further consider the roles of these peptides in the ontogeny of the gastrointestinal tract and we present the limited preclinical data on the effects of administering these peptides in neonatal SBS.. The clinical translation of trophic peptide therapies in neonatal SBS will require several challenges to be overcome. The optimal dose, timing and route of administration for the likely peptide, or combination of peptides, to be administered will be paramount. Despite their cost to patient care, trophic peptides have shown promise in preclinical models of neonatal SBS and may be especially beneficial for neonates that lack remnant ileum and suffer from irreversible intestinal failure.

Topics: Adaptation, Physiological; Adult; Animals; Drug Design; Epidermal Growth Factor; Glucagon-Like Peptide 2; Humans; Infant, Newborn; Insulin-Like Growth Factor I; Intercellular Signaling Peptides and Proteins; Peptides; Short Bowel Syndrome

The structural and functional changes during intestinal adaptation are necessary to compensate for the sudden loss of digestive and absorptive capacity after massive intestinal resection. When the adaptive response is inadequate, short bowel syndrome (SBS) ensues and patients are left with the requirement for parenteral nutrition and its associated morbidities. Several hormones have been studied as potential enhancers of the adaptation process. The effects of growth hormone, insulin-like growth factor-1, epidermal growth factor, and glucagon-like peptide 2 on adaptation have been studied extensively in animal models. In addition, growth hormone and glucagon-like peptide 2 have shown promise for the treatment of SBS in clinical trials in human beings. Several lesser studied hormones, including leptin, corticosteroids, thyroxine, testosterone, and estradiol, are also discussed.

Topics: Adaptation, Physiological; Animals; Cell Proliferation; Enterocytes; Epidermal Growth Factor; Glucagon-Like Peptide 2; Growth Hormone; Humans; Intercellular Signaling Peptides and Proteins; Intestine, Small; Peptide Hormones; Rats; Short Bowel Syndrome; Somatomedins

Topics: Adaptation, Physiological; Epidermal Growth Factor; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Human Growth Hormone; Humans; Short Bowel Syndrome

Short bowel syndrome (SBS) is used to describe a condition of malabsorption and malnutrition resulting from the loss of absorptive area following massive small bowel resection. The key to improved clinical outcome after massive small bowel resection is the ability of the residual bowel to adapt. Although still in experimental stages, a major goal in the management of SBS may be the augmented use of growth factors to promote increased adaptation. A number of growth factors have been implicated in promoting the adaptation process. The best-described growth factors are reviewed: glucagon-like peptide-2 (GLP-2), epidermal growth factor (EGF), and growth hormone (GH). This article reviews the ability of recombinant GLP-2, EGF and GH to modulate structural and functional aspects of intestinal adaptation following small bowel resection. Although these growth factors have shown promise, small sample size, inconsistent measurement parameters and uncontrolled study designs have hampered the acquisition of strong data advocating the use of growth factor treatment for SBS. Multicenter trials using well-defined outcome measures to assess clinical efficacy are needed to direct the clinical indications, timing and duration of therapy and assess potential risks associated with growth factor therapies.

Topics: Adaptation, Physiological; Animals; Epidermal Growth Factor; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Growth Hormone; Growth Substances; Humans; Intestines; Rats; Recombinant Proteins; Short Bowel Syndrome

The intestine has an inherent ability to adapt morphologically and functionally in response to internal and external environmental changes. The functional adaptations encompass modifications of the brush border membrane fluidity and permeability, as well as up- or down-regulation of carrier-mediated transport. Intestinal adaptation improves the nutritional status following the loss of a major portion of the small intestine, following chronic ingestion of ethanol, following sublethal doses of abdominal irradiation, in diabetes, in pregnancy and lactation, with ageing, and with fasting and malnutrition. Following intestinal resection, morphological and functional changes occur depending upon the extent of the intestine removed, the site studied, and the lipid content of the diet. Therefore, intestinal adaptation has important implications in the survival potential and welfare of the host. An understanding of the mechanisms of, and signals for, intestinal adaptation in the experimental setting forms the basis for the use of management strategies in humans with the short-bowel syndrome.

Topics: Animals; Biomarkers; Disease Models, Animal; Epidermal Growth Factor; Glucagon-Like Peptides; Glucocorticoids; Glutamine; Growth Hormone; Humans; Insulin-Like Growth Factor I; Intestinal Absorption; Intestinal Mucosa; Intestines; Peptides; Short Bowel Syndrome

Recently, glucagon-like peptide 2 has emerged as a potent stimulator of epithelial growth, joining insulin-like growth factor I, hepatocyte growth factor and keratinocyte growth factor as potential treatment modalities for intestinal disorders associated with loss of mucosal mass, such as short bowel syndrome. Investigations into other members of the expanded epidermal growth factor peptide family, the development of more potent peptide analogues, and advances in the development of enterally administered bioactive growth factor formulations further expands the repertoire of epithelial growth factors applicable to conditions associated with epithelial insufficiency.

Topics: Adaptation, Physiological; Epidermal Growth Factor; Fibroblast Growth Factor 7; Fibroblast Growth Factors; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Growth Substances; Hepatocyte Growth Factor; Humans; Intestinal Diseases; Intestinal Mucosa; Mucins; Muscle Proteins; Neuropeptides; Peptides; Regeneration; Short Bowel Syndrome; Somatomedins; Transforming Growth Factor alpha; Trefoil Factor-2; Trefoil Factor-3

The loss of small intestinal mucosal surface area is a relatively common clinical situation seen in both the pediatric and adult population. The most frequent causes include mesenteric ischemia, trauma, inflammatory bowel disease, necrotizing enterocolitis, and volvulus. Following surgical resection, the remnant intestine compensates or adapts to the loss of native bowel by increasing its absorptive surface area and functional capacity. Unfortunately, many patients fail to adapt adequately, and are relegated to lifelong intravenous nutrition. Research into intestinal adaptation following small bowel resection (SBR) has evolved only recently from the gross and microscopic level to the biochemical and genetic level. As understanding of this process has increased, numerous therapeutic strategies to augment adaptation have been proposed. Epidermal growth factor (EGF) is an endogenous peptide that is secreted into the gastrointestinal tract and able to influence gut ontogeny, as well as mucosal healing. Early studies have demonstrated its ability to augment the adaptive process. Focusing on a murine model of massive intestinal loss, the morphological, structural, biochemical, and genetic changes that occur during the intestinal adaptive process will be reviewed. The role of EGF and its receptor as critical mediators of the adaptive process will be discussed. Additionally, the ability of EGF to augment intestinal proliferation and diminish programmed cell death (apoptosis) following SBR will be examined. Enhancing adaptation in a controlled manner may allow patients to transition off parenteral nutrition to enteral feeding and, thereby, normalize their lifestyle.

Topics: Adaptation, Physiological; Animals; Apoptosis; Disease Models, Animal; Epidermal Growth Factor; ErbB Receptors; Humans; Intestines; Mice; Mice, Transgenic; Postoperative Period; Short Bowel Syndrome

Morphological and physiological adaptation in residual small intestine occurs after massive enterectomy and is influenced significantly by different growth factors and hormones. The mechanism of adaptation occurs through hypertrophy and hyperplasia as well as nutrient transporter changes. These transporters are classified into different classes dependent on its biological properties. The adaptation process evolves over time and different nutrient absorption profiles occur at different postoperative stages. There is an initial decrease in amino acid transport after resection followed by a return to approximately normal levels. Glucose also follows a similar pattern of changes but returns to normal later than amino acids. The time course of these changes are different for different animals with rat adaptation being much faster than rabbit. Growth hormone (GH) induces increased amino acid transport during this adaptation period, however, appears not to affect small intestine hypertrophy or hyperplasia. The increase in transport occurs via an increase in transport numbers rather than affinity. Epidermal growth factor (EGF) also increases amino acid transport in postoperative animals. Its advantage is it is orally stable when given with a protease inhibitor. EGF also reverses the down-regulating effects of the somatostatin analogue Octreotide (SMS) post resection. EGF in combination with GH has additive effects. However, the effects of the growth factors are site specific. GH and EGF combination therapy significantly increased alanine and arginine transport in distal small bowel after 70 % enterectomy but not in the proximal small bowel. The same combination increases leucine and glutamine transport in the proximal small intestine only. Understanding the specific changes that occur with these therapies may improve quality of life for patients and also reduce that need for total parenteral nutrition.

Topics: Absorption; Adaptation, Physiological; Amino Acid Transport Systems; Amino Acids; Epidermal Growth Factor; Glucose; Humans; Intestine, Small; Short Bowel Syndrome

This study examined the effects of enterally administered epidermal growth factor (EGF) on nutrient absorption and tolerance of enteral feeds in pediatric patients with short bowel syndrome (SBS).. Patients identified with severe SBS (<25% bowel length predicted for age) were prospectively enrolled in treatment using human recombinant EGF (1-53); 100 microg/kg per day given mixed with enteral feeds and patients were treated for 6 weeks. End points followed were patient weight, tolerance of enteral feeds, nutrient absorption, and intestinal permeability as determined using carbohydrate probes and hematologic values for liver function parameters.. Five patients were treated with EGF; all showed a significant improvement in carbohydrate absorption (3-0 methylglucose): absorption 24.7% +/- 9.7% pretreatment vs 34.1% +/- 13.8% posttreatment and improved tolerance of enteral feeds (enteral energy as % of total energy, 25% +/- 28% pretreatment vs 36% +/- 24% posttreatment; mean +/- SD; P < .05 by Wilcoxon's signed rank test). Epidermal growth factor treatment was not associated with significant changes in intestinal permeability, the rate of weight gain, or liver function tests. During the treatment phase, no patients developed episodes of sepsis; however, within 2 weeks of discontinuation of EGF treatment, 3 patients developed septic episodes. No adverse effects of EGF administration were noted.. These results suggest that enteral treatment with EGF in pediatric SBS improves nutrient absorption, increases tolerance with enteral feeds, and may improve the infection rate. Further studies exploring treatment strategies including the timing and duration of EGF administration are indicated.

Topics: 3-O-Methylglucose; Child, Preschool; Dietary Carbohydrates; Enteral Nutrition; Enterocolitis, Necrotizing; Epidermal Growth Factor; Gastroschisis; Humans; Infant; Infant Food; Intestinal Absorption; Intestinal Volvulus; Lactulose; Liver Function Tests; Male; Mannitol; Pilot Projects; Postoperative Complications; Recombinant Proteins; Sepsis; Short Bowel Syndrome; Weight Gain

Glucagon-like peptide-2 (GLP-2) and epidermal growth factor (EGF) treatment enhance intestinal adaptation. To determine whether these growth factors exert synergistic effects on intestinal growth and function, GLP-2 and EGF-containing media (EGF-cm) were administered, alone and in combination, in neonatal piglet models of short bowel syndrome (SBS). Neonatal Landrace-Large White piglets were block randomized to 75% midintestinal [jejunoileal (JI) group] or distal intestinal [jejunocolic (JC) group] resection or sham control, with 7-day infusion of saline (control), intravenous human GLP-2 (11 nmol·kg

Topics: Adaptation, Physiological; Animals; Animals, Newborn; Disease Models, Animal; Drug Synergism; Epidermal Growth Factor; Glucagon-Like Peptide 2; Intestinal Mucosa; Intestines; Male; Organ Size; Short Bowel Syndrome; Swine; Treatment Outcome

Adaptation is an important compensatory response to environmental cues resulting in enhanced survival. In the gut, the abrupt loss of intestinal length is characterized by increased rates of enterocyte proliferation and apoptosis and culminates in adaptive villus and crypt growth. In the development of an academic pediatric surgical career, adaptation is also an important compensatory response to survive the ever changing research, clinical, and economic environment. The ability to adapt in both situations is critical for patients and a legacy of pediatric surgical contributions to advance our knowledge of multiple conditions and diseases.

Topics: Adaptation, Physiological; Adaptation, Psychological; Biomarkers; Biomedical Research; Enterocytes; Epidermal Growth Factor; Faculty, Medical; General Surgery; Humans; Neovascularization, Physiologic; Pediatrics; Physicians; Short Bowel Syndrome; United States

The signals that govern the upregulation of nutrient absorption (adaptation) after intestinal resection are not well understood. A Gastric Roux-en-Y bypass (GRYB) model was used to isolate the relative contributions of direct mucosal stimulation by nutrients, biliary-pancreatic secretions, and systemic enteric hormones on intestinal adaptation in short bowel syndrome.. Male rats (350-400 g; n = 8/group) underwent sham or GRYB with pair feeding and were observed for 14 days. Weight and serum hormonal levels (glucagon-like peptide-2 [GLP-2], PYY) were quantified. Adaptation was assessed by intestinal morphology and crypt cell kinetics in each intestinal limb of the bypass and the equivalent points in the sham intestine. Mucosal growth factors and expression of transporter proteins were measured in each limb of the model.. The GRYB animals lost weight compared to controls and exhibited significant adaptive changes with increased bowel width, villus height, crypt depth, and proliferation indices in the alimentary and common intestinal limbs. Although the biliary limb did not adapt at the mucosa, it did show an increased bowel width and crypt cell proliferation rate. The bypass animals had elevated levels of systemic PYY and GLP-2. At the mucosal level, insulin-like growth factor-1 (IGF-1) and basic fibroblast growth factor (bFGF) increased in all limbs of the bypass animals, whereas keratinocyte growth factor (KGF) and epidermal growth factor (EGF) had variable responses. The expression of the passive transporter of glucose, GLUT-2, expression was increased, whereas GLUT-5 was unchanged in all limbs of the bypass groups. Expression of the active mucosal transporter of glucose, SGLT-1 was decreased in the alimentary limb.. Adaptation occurred maximally in intestinal segments stimulated by nutrients. Partial adaptation in the biliary limb may reflect the effects of systemic hormones. Mucosal content of IGF-1, bFGF, and EGF appear to be stimulated by systemic hormones, potentially GLP-2, whereas KGF may be locally regulated. Further studies to examine the relationships between the factors controlling nutrient-induced adaptation are suggested. Direct contact with nutrients appears to be the most potent factor in inducing mucosal adaptation.

Topics: Adaptation, Physiological; Animals; Cell Proliferation; Epidermal Growth Factor; Fibroblast Growth Factor 2; Fibroblast Growth Factor 7; Gastric Bypass; Glucagon-Like Peptide 2; Insulin-Like Growth Factor I; Intestinal Mucosa; Intestine, Small; Male; Random Allocation; Rats; Rats, Sprague-Dawley; Short Bowel Syndrome; Sodium-Glucose Transporter 1

Epidermal growth factor receptor (EGFR) stimulation enhances intestinal adaptation after massive small bowel resection (SBR), measured by taller villi, deeper crypts, and augmented enterocyte proliferation. Min mice with constitutively active beta-catenin signaling demonstrate enhanced villus growth after SBR, suggesting a role for the Wnt pathway during adaptation. Because there is crosstalk between EGFR signaling and the Wnt pathway, we hypothesized that beta-catenin is modulated by EGFR-induced enterocyte proliferation.. Rat intestinal epithelial cells were stimulated with EGF and cytoplasmic to nuclear trafficking of beta-catenin was measured. Beta-catenin-directed transcription was also tested via transfection with a TOP/FOP luciferase reporter. Downstream transcriptional target expression was measured in murine intestine after SBR.. Epidermal growth factor-treated rat intestinal epithelial cells exhibited increased proliferation compared to serum-deficient cells in the face of no detectable accumulation of nuclear beta-catenin. The luciferase assay results showed minimal transcription activity in response to EGF. In vivo experiments revealed no significant difference in expression of beta-catenin targeted genes in crypt enterocytes after SBR.. The mechanism for EGFR-induced proliferation of enterocytes does not appear to involve a transcriptional role for beta-catenin. The effects of EGFR signaling on beta-catenin-mediated cell adhesion remain to be investigated.

Topics: Active Transport, Cell Nucleus; Adaptation, Physiological; Animals; beta Catenin; Cell Division; Cells, Cultured; Cyclin D; Cyclins; Cytoplasm; Enterocytes; Epidermal Growth Factor; ErbB Receptors; Gene Expression Profiling; Genes, myc; Genes, Reporter; Intestine, Small; Luciferases, Renilla; Male; Mice; Mice, Inbred C57BL; Oligonucleotide Array Sequence Analysis; Proto-Oncogene Proteins c-myc; Rats; Rats, Sprague-Dawley; RNA, Messenger; Short Bowel Syndrome; Signal Transduction; Transcription, Genetic; Transfection; Wnt Proteins

Interleukin 11 (IL-11) is a multifunctional cytokine derived from bone marrow, which has a trophic effect on small bowel epithelium. This study compares the effects of IL-11 with epidermal growth factor (EGF), a growth factor known to enhance small bowel adaptation.. Forty Sprague-Dawley rats (90-100 g) underwent an 85% mid-small bowel resection with primary anastomosis on day 0. Rats were divided into four treatment groups: controls (group I) received bovine serum albumin (BSA), group II received IL-11, 125 mg/kg subcutaneously (SC) twice daily, group III received EGF, 0.10 mg/g SC bid, and group IV received EGF and IL-11 in the above doses. Half of the animals (five per group) were killed on day 4 of therapy, and the rest on day 8. Animals were evaluated for weight, mucosal length, and bowel wall muscle thickness on days 4 and 8, and expression of proliferating cell nuclear antigen (PCNA) in intestinal crypt and smooth muscle cells on day 8.. Body weight was similar at day 4 and 8. Mucosal thickness in groups II (IL-11) and IV (IL-11 and EGF) was significantly increased at days 4 and 8 compared with controls (group I) and EGF (group III, P < 0.001). Muscle thickness was significantly increased in the EGF and combined group IV compared with the BSA controls and IL-11 groups (P < 0.001). Thirty-two percent of the mucosal crypt cells in group I stained positive for PCNA, whereas 51%, 53%, and 60% stained positive in groups II (IL-11), III (EGF), and IV (IL-11 and EGF), respectively. In groups I and II, 2% and 1.7% of the myocytes stained positive for PCNA, whereas 11.2% and 5.2% in group III and IV.. These data suggest that IL-11 has a trophic effect on small intestinal enterocytes, causing cell proliferation and increased mucosal thickness. EGF has a more generalized effect causing proliferation of both enterocytes and myocytes. IL-11, with or without EGF may be a useful adjunct in treatment of short bowel syndrome.

Topics: Animals; Cell Proliferation; Epidermal Growth Factor; Interleukin-11; Intestine, Small; Male; Muscle, Smooth; Proliferating Cell Nuclear Antigen; Rats; Rats, Sprague-Dawley; Short Bowel Syndrome

Intestinal adaptation is the most important event in short bowel syndrome following a massive small bowel resection. Effects of various growth factors and their synergism have been well documented in intestinal adaptation. This study aimed to compare the effect of two different trophic agents, epidermal growth factor (EGF) and bombesin (BBS), on intestinal adaptation following massive intestinal resection. Sprague-Dawley male rats were assigned to one of four groups after a 75% small bowel resection. Either EGF (90 microg/kg), BBS (10 microg/kg), EGF+BBS, or bovine serum albumin (BSA) were injected subcutaneously three times a day. The animals were killed 10 days after the operation. Weight loss and morphologic parameters such as mucosal thickness, villus height, crypt depth, villus-to-crypt ratio, and muscularis propria height were measured. In the EGF+BBS group, mucosal thickness was found to be significantly increased compared with the other study groups (p<0.05). Similarly, villus height was significantly increased only in the EGF+BBS group (p<0.05). In the BBS group, both villus height and mucosal thickness showed a slight increase, but the values were not statistically significant compared with the vehicle-treated group. There were no significant differences in any of the remaining parameters between the groups. The results of this study indicate that the gut hormones EGF and BBS act synergistically in facilitating the adaptive response of the remnant ileum to massive intestinal resection.

Topics: Adaptation, Physiological; Animals; Bombesin; Drug Synergism; Epidermal Growth Factor; Intestines; Male; Rats; Rats, Sprague-Dawley; Short Bowel Syndrome

After establishing a new method of autologic-allotopic ileum mucosa transplantation as a therapy for short-bowel syndrome, the effects of glutamine and human epithelial growth factor (human EGF) on the transplanted ileum mucosa were evaluated.. Ileum mucosa was transplanted in 28 young beagle dogs in a demucosed vascularised transverse colon segment. The ileum mucosa was kept in place with silicone stents in all animals. Eight animals of the control group were irrigated with saline solution. In the second group with 10 animals, 100 mg/kg glutamine were administered daily in the lumen. The 10 animals of the third group were treated with 25 microg/kg human EGF per day subcutaneously and irrigated with saline solution. 4 weeks later, histological specimens were harvested from the colon coat-ileum mucosa complex, the normal ileum and normal colon. Lumen diameter, percentage ileum mucosa uptake as well as mucosa and colon muscle coat thickness were evaluated.. In all groups, the diameter of the lumen was larger than 10 mm after fixation, due to the silicone stent. The group with glutamine irrigation showed the largest lumen diameter. A complete mucosa lining of the inner surface of the colon muscle coat was achieved in none of the animals. The highest percentage of ileum mucosa uptake was found in the group with glutamine irrigation. In most animals, the transplanted ileum mucosa was markedly thinner than normal ileum mucosa. Only in the group with glutamine irrigation did we find two animals with nearly normal mucosa thickness. The longitudinal muscle of the transplanted colon coat was thicker in all three groups compared to normal colon. There were no differences in thickness of the circular muscle in all animals compared to normal colon.. Silicone stents maintain a lumen after autologic-allotopic ileum mucosa transplantation. However, additional irrigation with glutamine, as well as treatment with human EGF subcutaneously could not provide a complete lining of the colon muscle coat with transplanted ileum mucosa. A modification of the operative procedure is necessary to achieve a colon muscle coat that is completely lined with ileum mucosa before the absorptive capacity of the transplanted colon coat-ileum mucosa complex can be evaluated.

Topics: Animals; Colon; Dogs; Epidermal Growth Factor; Glutamine; Humans; Ileum; Intestinal Mucosa; Short Bowel Syndrome; Sodium Chloride; Stents; Therapeutic Irrigation

This study investigates the effect of epidermal growth factor (EGF) on nutrient absorption in a rat model of short bowel syndrome (SBS).. Male juvenile rats underwent either transection (Sham) or ileocecal resection leaving a 20-cm jejunal remnant. Animals underwent follow-up for 10 days, and resected animals were treated with placebo or recombinant human EGF (1-53). Animals were pair fed; in vivo nutrient absorption, intestinal permeability, morphology, and total intestinal DNA and protein content were measured.. Resected EGF-treated animals lost significantly less weight than those in the placebo group (-4.2 +/- 3 v -13.7 +/- 6.9%), absorbed significantly more 3-0 methylglucose (76.8 +/- 6.6 v 64.9 +/- 10.1%), and had reduced permeability (lactulose/mannitol ratio, 0.35 +/- 0.19 v 0.60 +/- 0.20; P <.05 for all comparisons).. These findings show that treatment of short bowel syndrome animals with EGF reduced weight loss and improved carbohydrate absorption and intestinal permeability. These findings suggest that enteral EGF may be a useful therapy for short bowel syndrome; further studies are indicated.

Topics: Absorption; Animals; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Disease Models, Animal; Epidermal Growth Factor; Male; Nutrition Assessment; Rats; Rats, Sprague-Dawley; Short Bowel Syndrome; Treatment Outcome; Weight Gain

Massive bowel resection triggers an adaptive process in the remaining intestine in spite of which, bacterial translocation (BT) is frequent under these conditions. Several trophic factors, including growth hormone (GH), epidermal growth factor (EGF) and insuline (INS) are involved in the process of adaptation in short bowel syndrome (SBS). However, the effect of GH, EGF or INS on BT has not been investigated experimentally. The aim of the study was to test the hypothesis that GH, EGF or INS administration prevents BT in rats with SBS receiving only parenteral nutrition (PN). Thirty-seven adult Wistar rats underwent central venous cannulation and were randomly assigned to one of two groups receiving for ten days four treatment regimes: PN group (N = 10) fasting, all-in-one PN solution (300 mL/kg/24 h, 280 kcal/kg/24 h), 80% gut resection including ileo-cecal valve. GH group (N = 9) fasting, same PN regime and resection plus GH (1 mg/kg/d, s.c.). EGF group (N = 9): same PN regime and resection plus EGF (150 microgr/24 h, e.v.) INS group(N = 9): same PN regime and resection plus INS (1 U.I./100 g/24 h s.c.) At the end of the experiment the rats were exanguinated and mesenteric lymph nodes and samples of systemic and portal blood were obtained and cultured. Several samples of full-thickness jejunal wall were taken for measuring cell proliferation index (PCNA) and mucosal thickness. Jejunal mucosal thickness increased by 30%, 28% and 29% and PCNA index by 21%, 20% and 25% in GH, EGF and INS, treated rats respectively in comparison with those treated with PN alone. However, contrary to our expectations, BT expressed by positive culture of intestinal germs in systemic blood was demonstrated respectively in 44%, 40% and 28% of GH, EGF and INS animals, respectively, and in 0% of PN-only rats. Although exogenous GH, EGF or INS improves gut mucosal structure in rats with SBS treated with PN, it seems to increase rather than decrease mucosal permeability to intestinal germs in them.

Topics: Animals; Bacterial Translocation; Epidermal Growth Factor; Growth Hormone; Insulin; Rats; Rats, Wistar; Short Bowel Syndrome

Our laboratory has shown that epidermal growth factor (EGF) and hepatocyte growth factor (HGF) can improve the function of normal rat small intestine. This study was designed to evaluate the role of these growth factors on the residual small intestine following massive (80%) small bowel resection. Our data demonstrate that EGF and HGF can enhance intestinal substrate absorption and mucosal mass beyond that which occurs with intestinal adaptation. These growth factors may be beneficial in the management of children with short bowel syndrome.

Topics: Animals; Child; DNA; Epidermal Growth Factor; Hepatocyte Growth Factor; Humans; Intestinal Absorption; Intestinal Mucosa; Male; Rats; Rats, Sprague-Dawley; Short Bowel Syndrome

An adaptive process starts in the remaining intestine after massive resection, and several trophic factors including growth hormone (GH), epidermal growth factor (EGF), and insulin (INS) have been shown to have a positive effect on it. Bacterial translocation (BT) is frequent after extensive small bowel resection, but the effects of GH, EGF, or INS have not been investigated in experimental short bowel syndrome (SBS). This study tests the hypothesis that GH, EGF, or INS decrease BT in SBS in rats with parenteral nutrition (PN).. Thirty-eight adult Wistar rats underwent central venous cannulation and were assigned randomly to 1 of 4 groups receiving for 10 days 4 treatment regimes: (1) PN group (n = 10): fasting, all-in-one PN solution (300 mL/kg/24 h, 280 kcal/kg/24 h), 80% gut resection including ileo-cecal valve; (2) GH group (n = 9): fasting, same PN regime and resection, GH (1 mg/kg/d, subcutaneously); (3) EGF group (n = 9): fasting, PN, resection, EGF (150 microg/24 h intravenously); (4) INS group (n = 9): fasting, PN, resection, INS (1 UI/100 g/24 h subcutaneously). At the end of the experiment they were killed, and mesenteric lymph nodes (MLN) and peripheral and portal blood samples were recovered and cultured. Several fragments of intestine were taken to determine cell proliferation (PCNA index) and morphometric parameters (villous height, crypt depth).. GH, EGF, and INS groups showed a 28%, 29%, and 30% increase in gut mucosal thickness, and PCNA index rose 21%, 20%, and 25%, respectively in comparison with PN controls. Bacterial translocation to peripheral blood was detected in 0% of PN animals and in 44%, 40%, and 28% of GH, EGF, or INS rats, respectively (P < .05). No differences were found in BT in MLN or portal blood among groups.. Administration of GH, EGF, or INS improves gut mucosal structure in rats with SBS under PN, but, surprisingly, the incidence of BT detected in peripheral blood was increased rather than decreased in animals receiving these treatments.

Topics: Animals; Bacterial Translocation; Chi-Square Distribution; Culture Techniques; Disease Models, Animal; Epidermal Growth Factor; Gram-Negative Bacteria; Growth Hormone; Insulin; Male; Parenteral Nutrition; Random Allocation; Rats; Rats, Wistar; Reference Values; Sensitivity and Specificity; Short Bowel Syndrome; Statistics, Nonparametric

Following massive small bowel resection (SBR), the expression of bax and bcl-w is associated with increased enterocyte apoptosis. Epidermal growth factor (EGF) has been shown to enhance enterocyte proliferation and retard apoptosis in the adapting bowel. This study examined the effect of EGF on the expression of these bcl-2 family members during adaptation.. Mice (C57Bl/6; n = 38) underwent a 50% SBR or sham operation and then were randomized to receive twice-daily orogastric saline or EGF (50 microg/kg/day). After 3 days, the remnant ileum was removed, apoptotic index (No. apoptotic bodies/crypt) calculated, and expression of mRNA and protein for bax and bcl-w quantified.. EGF prevented the expected increase in the apoptotic index after SBR and altered the ratio of bax to bcl-w in favor of cell survival.. Following massive small bowel resection, EGF retards rates of enterocyte apoptosis and modifies the expression of bcl-2 family members. By decreasing bax and increasing bcl-w expression, the balance between pro- and anti-apoptotic genes is shifted in favor of cell survival. Alteration of bcl-2 family member expression may be an important mechanism by which EGF reduces the increased enterocyte apoptosis that occurs after massive small bowel resection.

Topics: Adaptation, Physiological; Animals; Apoptosis; bcl-2-Associated X Protein; Blotting, Western; Cell Survival; Enterocytes; Epidermal Growth Factor; Gene Expression; Intestine, Small; Male; Mice; Mice, Inbred C57BL; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger; Short Bowel Syndrome

Interleukin-11 (IL-11) is a multifunctional cytokine derived from bone marrow, which has a trophic effect on small bowel epithelium. This study compares the effects of IL-11 with epidermal growth factor (EGF), a growth factor known to enhance small bowel adaptation.. Forty Sprague-Dawley rats (90 to 100 g) underwent an 85% mid-small bowel resection with primary anastomosis on day 0. Rats were divided into four treatment groups: controls (group I) received bovine serum albumin (BSA), group II received IL-11, 125 microg/kg subcutaneously (SC) twice daily, group III received EGF, 0.10 microg/g SC bid, and group IV received EGF and IL-11 in the above doses. Half of the animals (five per group) were killed on day 4 of therapy, and the rest were killed on day 8. Animals were evaluated for weight, mucosal length, and bowel wall muscle thickness on days 4 and 8, and expression of proliferating cell nuclear antigen (PCNA) in intestinal crypt and smooth muscle cells on day 8.. There were two deaths; both were 8-day controls. Body weight was similar at day 4 and day 8. Mucosal thickness in groups II (IL-11) and group IV (IL-11 and EGF) was significantly increased at day 4 and 8 when compared with controls (group I) and EGF (group III, P < .001). Muscle thickness was significantly increased in the EGF and combined group IV compared with the BSA controls and IL-11 groups (P < .001). Thirty-two percent of the mucosal crypt cells in Group I stained positive for PCNA, whereas 51%, 53%, and 60% stained positive in groups II (IL-11), III (EGF), and IV (IL-11 and EGF), respectively. In groups I and II, 2% and 1.7% of the myocytes stained positive for PCNA, whereas 11.2% and 5.2% of the myocytes in group III and IV stained positive.. These data suggest that IL-11 has a trophic effect on small intestinal enterocytes, causing cell proliferation and increased mucosal thickness. EGF has a more generalized effect on intestine causing proliferation of both enterocytes and myocytes. IL-11, with or without EGF, may be a useful adjunct in instances of short bowel syndrome.

Topics: Adaptation, Physiological; Animals; Cattle; Cell Division; Epidermal Growth Factor; Interleukin-11; Intestinal Mucosa; Intestine, Small; Male; Rats; Rats, Sprague-Dawley; Serum Albumin, Bovine; Short Bowel Syndrome; Time Factors

Epidermal growth factor (EGF) has been reported to enhance adaptation in damaged intestines following massive intestinal resection. Studies were performed to determine whether EGF influences the recovery of intestinal function after small bowel transplantation in rats. Recipient Lewis rats underwent resection of the distal 80% of the small bowel, which was replaced with a 20-cm isograft. EGF (30 microg/kg/day) or its vehicle (control) was infused intraperitoneally for 3 days after transplantation. After 7 days, the graft was isolated for morphologic studies and was used for analysis of glucose and water absorption and the expression of sodium glucose cotransporter (SGLT1). These were used as indicators of functional adaptation. The EGF-treated group exhibited significantly increased mucosal villous height, crypt cell proliferation, glucose and water absorption, and expression of SGLT1 protein compared to the control group. No significant differences were found in body weight change or crypt depth between the two groups. These results demonstrate that EGF augments structural and functional adaptation of intestinal grafts in rats. EGF may be useful after intestinal transplantation in patients with short bowel syndrome.

Topics: Animals; Epidermal Growth Factor; Glucose; Humans; Intestinal Absorption; Intestine, Small; Membrane Glycoproteins; Monosaccharide Transport Proteins; Proliferating Cell Nuclear Antigen; Rats; Rats, Inbred Lew; Short Bowel Syndrome; Sodium; Sodium-Glucose Transporter 1; Transplantation, Isogeneic

Epidermal growth factor (EGF) and Insulin like growth factor-1 (IGF-1) increase substrate absorption beyond the normal adaptive response after massive small bowel resection in the rat. However, the mechanism for this response is unknown. This study was designed to evaluate the ultrastructural features of the rat small intestine epithelium after exposure to EGF and IGF-1 and correlate any changes with a possible hypothesis regarding the mechanism for the increased absorption.. Male Sprague-Dawley rats underwent an 80% small bowel resection and jejunostomy tube placement. Seven days later an osmotic pump placed subcutaneously and containing the test substance was connected to the jejunostomy tube. The rats were assigned to one of three groups: group 1 received normal saline (control, n = 5); group 2 received EGF at 150 microg/kg/d (n = 5); and group 3 received IGF-1 at 20 mg/kg/d (n = 5). After a 14-day infusion, a portion of mid-small bowel was resected for light and electron microscopic evaluation from each of the animals. The following features were compared between the groups: villous length, crypt length, villous-crypt ratio, villi per millimeter mucosa, goblet cell distribution, eosinophilic infiltrates, number and distribution of organelles, length of microvilli, and completeness of microvillous surface.. Ultrastructurally, the bowel epithelium was well preserved in all animals. There were no objective ultrastructural differences between the controls and growth factor-exposed animals. The mean villous-crypt ratio, mean number of villi per millimeter of mucosa (cross section), and mean microvillous height were not significantly different among the groups. However, there was a subjective increase in the number of lysosomes in the enterocytes exposed to EGF and IGF-1.. Administration of EGF and IGF-1 after massive small bowel resection does not appear to significantly alter the small intestine epithelial ultrastructure when compared with the control group. The increase in lysosomes in some of the enterocytes of the animals exposed to growth factors may be important because this finding was not seen in any of the control electron photomicrographs. Studies to evaluate enterocyte gene and protein expression are necessary to determine the mechanism of EGF and IGF-1 enhancement of substrate absorption beyond intestinal adaptation.

Topics: Animals; Disease Models, Animal; Epidermal Growth Factor; Humans; Insulin-Like Growth Factor I; Intestinal Absorption; Intestinal Mucosa; Male; Microscopy, Electron; Rats; Rats, Sprague-Dawley; Short Bowel Syndrome

Octreotide (SMS) is a somatostatin analogue utilized in patients with short bowel syndrome (SBS) to decrease output. It may inhibit small bowel adaptation by blocking the secretion of trophic hormones such as epidermal growth factor (EGF). This study delineates the effects of SMS and EGF on nutrient transport in SBS.. One week after 70% jejunoileal resection, 20 New Zealand White rabbits (2 kg) received subcutaneous infusions of saline or EGF (1.5 micrograms/kg/hr) and injections of saline or SMS s.q.b.i.d. The study groups were EGF/saline, saline/saline, saline/SMS, and EGF/SMS. After 7 days of infusion, intestinal brush border membrane vesicles were prepared and nutrient transport measured.. SMS reduced active nutrient transport. Kinetics confirmed this was secondary to a reduction in functional carriers in the brush border membrane, without a change in carrier affinity. The coinfusion of EGF ameliorated this effect. On an individual basis, EGF alone did not significantly increase nutrient transport, but when taken as a group, nutrients transport was upregulated 26%.. SMS is detrimental to small bowel adaptation. EGF reverses this effect and may benefit patients with SBS who require SMS to control high intestinal output.

Topics: Amino Acids; Animals; Biological Transport, Active; Down-Regulation; Epidermal Growth Factor; Gastrointestinal Agents; Glucose; Ileum; In Vitro Techniques; Intestine, Small; Jejunum; Male; Microvilli; Octreotide; Rabbits; Short Bowel Syndrome