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Phelps HM, Warner BW. Intestinal adaptation and rehabilitation. Semin Pediatr Surg 2023; 32:151314. [PMID: 37276784 DOI: 10.1016/j.sempedsurg.2023.151314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Massive intestinal resection is a regrettably necessary but life-saving intervention for progressive or fulminant necrotizing enterocolitis (NEC). However, the resultant short bowel syndrome (SBS) poses its own array of challenges and complications. Within hours of such an abrupt loss of intestinal length, the intestine begins to adapt. Our ability to understand this process of intestinal adaptation has proven critical in our ability to clinically treat the challenging problem of short bowel syndrome. This review first highlights key data relating to intestinal adaptation including structural and functional changes, biochemical regulation, and other factors affecting the magnitude of intestinal adaptation responses. We then focus on intestinal rehabilitation as it relates to strategies to enhance intestinal adaptation while meeting nutritional needs and preventing complications of parenteral nutrition.
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Affiliation(s)
- Hannah M Phelps
- Division of Pediatric Surgery, Department of Surgery, Washington University in St. Louis School of Medicine, 9901 Wohl Hospital, Campus Box 8109, St. Louis, MO 63110, USA.
| | - Brad W Warner
- Division of Pediatric Surgery, Department of Surgery, Washington University in St. Louis School of Medicine, 9901 Wohl Hospital, Campus Box 8109, St. Louis, MO 63110, USA
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Chen Y, Tsai YH, Tseng BJ, Tseng SH. Influence of Growth Hormone and Glutamine on Intestinal Stem Cells: A Narrative Review. Nutrients 2019; 11:E1941. [PMID: 31426533 PMCID: PMC6724402 DOI: 10.3390/nu11081941] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Revised: 08/14/2019] [Accepted: 08/15/2019] [Indexed: 12/21/2022] Open
Abstract
Growth hormone (GH) and glutamine (Gln) stimulate the growth of the intestinal mucosa. GH activates the proliferation of intestinal stem cells (ISCs), enhances the formation of crypt organoids, increases ISC stemness markers in the intestinal organoids, and drives the differentiation of ISCs into Paneth cells and enterocytes. Gln enhances the proliferation of ISCs and increases crypt organoid formation; however, it mainly acts on the post-proliferation activity of ISCs to maintain the stability of crypt organoids and the intestinal mucosa, as well as to stimulate the differentiation of ISCs into goblet cells and possibly Paneth cells and enteroendocrine cells. Since GH and Gln have differential effects on ISCs. Their use in combination may have synergistic effects on ISCs. In this review, we summarize the evidence of the actions of GH and/or Gln on crypt cells and ISCs in the literature. Overall, most studies demonstrated that GH and Gln in combination exerted synergistic effects to activate the proliferation of crypt cells and ISCs and enhance crypt organoid formation and mucosal growth. This treatment influenced the proliferation of ISCs to a similar degree as GH treatment alone and the differentiation of ISCs to a similar degree as Gln treatment alone.
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Affiliation(s)
- Yun Chen
- Department of Surgery, Far Eastern Memorial Hospital, Pan-Chiao, New Taipei 220, Taiwan
- Department of Chemical Engineering and Materials Science, Yuan Ze University, Chung-Li, Taoyuan 320, Taiwan
| | - Ya-Hui Tsai
- Department of Surgery, Far Eastern Memorial Hospital, Pan-Chiao, New Taipei 220, Taiwan
- Department of Chemical Engineering and Materials Science, Yuan Ze University, Chung-Li, Taoyuan 320, Taiwan
| | - Bor-Jiun Tseng
- Department of Surgery, Far Eastern Memorial Hospital, Pan-Chiao, New Taipei 220, Taiwan
| | - Sheng-Hong Tseng
- Department of Surgery, National Taiwan University Hospital, Taipei 100, Taiwan.
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Chen Y, Tseng SH, Yao CL, Li C, Tsai YH. Distinct Effects of Growth Hormone and Glutamine on Activation of Intestinal Stem Cells. JPEN J Parenter Enteral Nutr 2017; 42:642-651. [PMID: 28510488 DOI: 10.1177/0148607117709435] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Accepted: 04/19/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND For patients with short bowel syndrome under parenteral nutrition support, growth hormone (GH) and glutamine (GLN) have been found to help the growth of intestinal mucosa. In this research, we studied the effects of GH and GLN on intestinal stem cells (ISCs). METHODS The in vitro and in vivo effects of GH and/or GLN on ISCs were evaluated by observing the ability of ISCs to form organoids in a Matrigel culture system. The expression levels of stemness and differentiation markers in ISCs and organoids were assessed using quantitative real-time polymerase chain reaction, immunofluorescence assay, and immunohistochemistry staining. RESULTS In vitro administration of GH activated the stemness of ISCs, whereas GLN enhanced the expression of chromogranin A and Muc2, which are differentiation markers in enteroendocrine and goblet cells, respectively. Administration of GH or GLN in mice showed that GH, but not GLN, upregulated the proliferative activity of ISCs with increased formation of crypt organoids. In addition, GH increased the expression of Lgr5 and GLN enhanced expression of Muc2 in the crypt fractions of the intestines in mice. CONCLUSION These results suggest that GH mainly enhances proliferative activities, whereas GLN promotes the differentiation potential of ISCs.
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Affiliation(s)
- Yun Chen
- Department of Surgery, Far Eastern Memorial Hospital, Pan-Chiao, New Taipei, Taiwan.,Department of Chemical Engineering and Materials Science, Yuan Ze University, Chung-Li, Taoyuan, Taiwan
| | - Sheng-Hong Tseng
- Department of Surgery, National Taiwan University Hospital, and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chao-Ling Yao
- Department of Chemical Engineering and Materials Science, Yuan Ze University, Chung-Li, Taoyuan, Taiwan
| | - Chuan Li
- Department of Biomedical Engineering, National Yang-Ming University, Taipei, Taiwan
| | - Ya-Hui Tsai
- Department of Surgery, Far Eastern Memorial Hospital, Pan-Chiao, New Taipei, Taiwan.,Department of Chemical Engineering and Materials Science, Yuan Ze University, Chung-Li, Taoyuan, Taiwan.,Department of Materials and Textiles, Oriental Institute of Technology, Pan-Chiao, New Taipei, Taiwan
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Weiming Z, Ning L, Jieshou L. Effect of Recombinant Human Growth Hormone and Enteral Nutrition on Short Bowel Syndrome. JPEN J Parenter Enteral Nutr 2017; 28:377-81. [PMID: 15568283 DOI: 10.1177/0148607104028006377] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
BACKGROUND Studies showed that bowel rehabilitation therapy, including recombinant human growth hormone (rhGH), nutrition support, glutamine, and dietary fiber, promotes intestinal adaptation in patients with short bowel syndrome. The aim of the current study was to determine if enteral nutrition and rhGH are effective in weaning short bowel patients off total parenteral nutrition (TPN). METHODS Thirty-seven patients with short bowel syndrome received bowel rehabilitation therapy for 4 weeks. Thirty-four patients were treated within 2 years after short bowel syndrome. Treatment included nutrition support from enteral nutrition 500 to 1500 kcal/d, oral glutamine 0.6 g/kg/d, plus a high-carbohydrate and low-fat diet. Once patients were in positive nitrogen balance, rhGH 0.05 mg/kg/d was administered for 3 weeks. RESULTS All patients completed the treatment; there were no deaths caused by malnutrition. Intestinal absorptive capacity and plasma levels of proteins were significantly improved after treatment (p < .05). Of the 23 patients who have been followed for >2 years after bowel rehabilitation therapy, 21 patients (57%) weaned off parenteral nutrition, among which 18 (49%) patients lived on a high-carbohydrate and low-fat diet supplemented with enteral nutrition, and 3 patients were free of enteral nutrition and relied on high-carbohydrate and low-fat diet alone. The minimal intestinal length for these patients was 15 cm with ileocecal valve and intact colon in adults. CONCLUSIONS Providing patients with enteral nutrition, glutamine, dietary fiber, and rhGH during howel rehabilitation therapy allows weaning from TPN in a sign;ficant number of patients.
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Affiliation(s)
- Zhu Weiming
- From the Department of General Surgery, Jinling Hospital, Nanjing, Jiangsu, China.
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Warner BW. The Pathogenesis of Resection-Associated Intestinal Adaptation. Cell Mol Gastroenterol Hepatol 2016; 2:429-438. [PMID: 27722191 PMCID: PMC5042605 DOI: 10.1016/j.jcmgh.2016.05.001] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Accepted: 05/06/2016] [Indexed: 12/14/2022]
Abstract
After massive small-bowel resection, the remnant bowel compensates by a process termed adaptation. Adaptation is characterized by villus elongation and crypt deepening, which increases the capacity for absorption and digestion per unit length. The mechanisms/mediators of this important response are multiple. The purpose of this review is to highlight the major basic contributions in elucidating a more comprehensive understanding of this process.
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Affiliation(s)
- Brad W. Warner
- Correspondence Address correspondence to: Brad W. Warner, MD, Washington University School of Medicine, St. Louis Children's Hospital, One Children's Place, Suite 5s40, St. Louis, Missouri 63110. fax: (314) 454-2442.Washington University School of MedicineSt. Louis Children's HospitalOne Children's PlaceSuite 5s40St. LouisMissouri 63110
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Abstract
Intestinal adaptation is a natural compensatory process that occurs following extensive intestinal resection, whereby structural and functional changes in the intestine improve nutrient and fluid absorption in the remnant bowel. In animal studies, postresection structural adaptations include bowel lengthening and thickening and increases in villus height and crypt depth. Functional changes include increased nutrient transporter expression, accelerated crypt cell differentiation, and slowed transit time. In adult humans, data regarding adaptive changes are sparse, and the mechanisms underlying intestinal adaptation remain to be fully elucidated. Several factors influence the degree of intestinal adaptation that occurs post resection, including site and extent of resection, luminal stimulation with enteral nutrients, and intestinotrophic factors. Two intestinotrophic growth factors, the glucagon-like peptide 2 analog teduglutide and recombinant growth hormone (somatropin), are now approved for clinical use in patients with short bowel syndrome (SBS). Both agents enhance fluid absorption and decrease requirements for parenteral nutrition (PN) and/or intravenous fluid. Intestinal adaptation has been thought to be limited to the first 1-2 years following resection in humans. However, recent data suggest that a significant proportion of adult patients with SBS can achieve enteral autonomy, even after many years of PN dependence, particularly with trophic stimulation.
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Affiliation(s)
- Kelly A Tappenden
- Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, Illinois
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Chaturvedi LS, Basson MD. Glucagonlike peptide 2 analogue teduglutide: stimulation of proliferation but reduction of differentiation in human Caco-2 intestinal epithelial cells. JAMA Surg 2013; 148:1037-1042. [PMID: 24068167 PMCID: PMC4574866 DOI: 10.1001/jamasurg.2013.3731] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
IMPORTANCE Short bowel syndrome occurs when a shortened intestine cannot absorb sufficient nutrients or fluids. Teduglutide is a recombinant analogue of human glucagonlike peptide 2 that reduces dependence on parenteral nutrition in patients with short bowel syndrome by promoting enterocytic proliferation, increasing the absorptive surface area. However, enterocyte function depends not only on the number of cells that are present but also on differentiated features that facilitate nutrient absorption and digestion. OBJECTIVE To test the hypothesis that teduglutide impairs human intestinal epithelial differentiation. DESIGN AND SETTING We investigated the effects of teduglutide in the modulation of proliferation and differentiation in human Caco-2 intestinal epithelial cells at a basic science laboratory. This was an in vitro study using Caco-2 cells, a human-derived intestinal epithelial cell line commonly used to model enterocytic biology. EXPOSURE Cells were exposed to teduglutide or vehicle control. MAIN OUTCOMES AND MEASURES We analyzed the cell cycle by bromodeoxyuridine incorporation or propidium iodide staining and flow cytometry and measured cell proliferation by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. We used quantitative reverse transcription-polymerase chain reaction to assay the expression of the enterocytic differentiation markers villin, sucrase-isomaltase, glucose transporter 2 (GLUT2), and dipeptidyl peptidase 4 (DPP-4), as well as that of the putative differentiation signals schlafen 12 (SLFN12) and caudal-related homeobox intestine-specific transcription factor (Cdx2). Villin promoter activity was measured by a luciferase-based assay. RESULTS The MTS assay demonstrated that teduglutide increased cell numbers by a mean (SD) of 10% (2%) over untreated controls at a maximal 500 nM (n = 6, P < .05). Teduglutide increased bromodeoxyuridine-positive cells vs untreated controls by a mean (SD) of 19.4% (2.3%) vs 12.0% (0.8%) (n = 6, P < .05) and increased the S-phase fraction by flow cytometric analysis. Teduglutide reduced the mean (SD) expression of villin by 29% (6%), Cdx2 by 31% (10%), DPP-4 by 15% (6%), GLUT2 by 40% (11%), SLFN12 by 61% (14%), and sucrase-isomaltase by 28% (8%) (n = 6, P < .05 for all). CONCLUSIONS AND RELEVANCE Teduglutide increased Caco-2 proliferation but tended to inhibit intestinal epithelial differentiation. The effects of mitogenic stimulation with teduglutide in patients with short bowel syndrome might be greater if the more numerous teduglutide-treated cells could be stimulated toward a more fully differentiated phenotype.
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Affiliation(s)
- Lakshmi S Chaturvedi
- Department of Surgery, College of Human Medicine, Michigan State University, East Lansing2Research Service, John D. Dingell Veterans Affairs Medical Center, Detroit, Michigan3Department of Anesthesiology, Wayne State University, Detroit, Michigan
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Rowland KJ, Choi PM, Warner BW. The role of growth factors in intestinal regeneration and repair in necrotizing enterocolitis. Semin Pediatr Surg 2013; 22:101-11. [PMID: 23611614 PMCID: PMC3635039 DOI: 10.1053/j.sempedsurg.2013.01.007] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Necrotizing enterocolitis (NEC) is a devastating intestinal disease resulting in major neonatal morbidity and mortality. The pathology is poorly understood, and the means of preventing and treating NEC are limited. Several endogenous growth factors have been identified as having important roles in intestinal growth as well as aiding intestinal repair from injury or inflammation. In this review, we will discuss several growth factors as mediators of intestinal regeneration and repair as well as potential therapeutic agents for NEC.
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Affiliation(s)
| | | | - Brad W. Warner
- Correspondence: Brad W. Warner, M.D. St. Louis Children's Hospital One Children's Place; Suite 5S40 St. Louis MO 63110 (314) 454-6022 - Phone (314) 454-2442 – Fax
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Brasse-Lagnel CG, Lavoinne AM, Husson AS. Amino acid regulation of mammalian gene expression in the intestine. Biochimie 2010; 92:729-35. [PMID: 20188788 DOI: 10.1016/j.biochi.2010.02.021] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2009] [Accepted: 02/16/2010] [Indexed: 12/16/2022]
Abstract
Some amino acids exert a wide range of regulatory effects on gene expression via the activation of different signalling pathways and transcription factors, and a number of cis elements were shown to respond to changes in amino acid concentration. Particular attention has been paid to the effects of glutamine and arginine, which modulate a number of cell functions through the activation of various pathways in different tissues. In the intestine, appropriate concentrations of both arginine and/or glutamine contribute to facilitate cell proliferation, to limit the inflammatory response and apoptosis, and to modulate intermediary metabolism through specific transcription factors. Particularly, besides its role as a major fuel for enterocytes, the regulatory effects of glutamine have been extensively studied and the molecular mechanisms involved appear diversified and complex. Indeed, in addition to a major role of NF-kappaB in its anti-inflammatory action and a stimulatory role of AP-1 in its growth-promoting action and cell survival, the involvement of some other transcription factors, such as PPAR-gamma or HSF-1, was shown to maintain intestinal cell integrity. The signalling pathways leading to the activation of transcription factors imply several kinases, particularly MAP kinases in the effect of glutamine and p70 S6 kinase for those of arginine, but in most cases the precise pathways from the entrance of the aminoacid into the cell to the activation of gene transcription has remained elusive.
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Affiliation(s)
- Carole G Brasse-Lagnel
- Appareil Digestif, Environnement et Nutrition (ADEN EA 4311), IFR n degrees 23, Université de Rouen, 22 boulevard Gambetta, Rouen cedex, France
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McMellen ME, Wakeman D, Longshore SW, McDuffie LA, Warner BW. Growth factors: possible roles for clinical management of the short bowel syndrome. Semin Pediatr Surg 2010; 19:35-43. [PMID: 20123272 PMCID: PMC2891767 DOI: 10.1053/j.sempedsurg.2009.11.010] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
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.
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Affiliation(s)
- Mark E. McMellen
- Division of Pediatric Surgery, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, MO, USA
| | - Derek Wakeman
- Division of Pediatric Surgery, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, MO, USA
| | - Shannon W. Longshore
- Department of Surgery, University of California, Davis Medical Center, Sacramento, CA, USA
| | - Lucas A. McDuffie
- School of Medicine, Eastern Virginia Medical School, Norfolk, VA, USA
| | - Brad W. Warner
- Division of Pediatric Surgery, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, MO, USA,Correspondence: Brad W. Warner, MD Division of Pediatric Surgery St. Louis Children's Hospital, One Children's Place Suite 5S40, St. Louis, MO 63110 Tel.: 1 314 454 6022 Fax: 1 314 454 2442
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Brasse-Lagnel C, Lavoinne A, Husson A. Control of mammalian gene expression by amino acids, especially glutamine. FEBS J 2009; 276:1826-44. [PMID: 19250320 DOI: 10.1111/j.1742-4658.2009.06920.x] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Molecular data rapidly accumulating on the regulation of gene expression by amino acids in mammalian cells highlight the large variety of mechanisms that are involved. Transcription factors, such as the basic-leucine zipper factors, activating transcription factors and CCAAT/enhancer-binding protein, as well as specific regulatory sequences, such as amino acid response element and nutrient-sensing response element, have been shown to mediate the inhibitory effect of some amino acids. Moreover, amino acids exert a wide range of effects via the activation of different signalling pathways and various transcription factors, and a number of cis elements distinct from amino acid response element/nutrient-sensing response element sequences were shown to respond to changes in amino acid concentration. Particular attention has been paid to the effects of glutamine, the most abundant amino acid, which at appropriate concentrations enhances a great number of cell functions via the activation of various transcription factors. The glutamine-responsive genes and the transcription factors involved correspond tightly to the specific effects of the amino acid in the inflammatory response, cell proliferation, differentiation and survival, and metabolic functions. Indeed, in addition to the major role played by nuclear factor-kappaB in the anti-inflammatory action of glutamine, the stimulatory role of activating protein-1 and the inhibitory role of C/EBP homology binding protein in growth-promotion, and the role of c-myc in cell survival, many other transcription factors are also involved in the action of glutamine to regulate apoptosis and intermediary metabolism in different cell types and tissues. The signalling pathways leading to the activation of transcription factors suggest that several kinases are involved, particularly mitogen-activated protein kinases. In most cases, however, the precise pathways from the entrance of the amino acid into the cell to the activation of gene transcription remain elusive.
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Affiliation(s)
- Carole Brasse-Lagnel
- Appareil Digestif, Environnement et Nutrition, EA 4311, Université de Rouen, France
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Drozdowski LA, Clandinin MT, Thomson ABR. Morphological, kinetic, membrane biochemical and genetic aspects of intestinal enteroplasticity. World J Gastroenterol 2009; 15:774-87. [PMID: 19230039 PMCID: PMC2653378 DOI: 10.3748/wjg.15.774] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The process of intestinal adaptation (“enteroplasticity”) is complex and multifaceted. Although a number of trophic nutrients and non-nutritive factors have been identified in animal studies, successful, reproducible clinical trials in humans are awaited. Understanding mechanisms underlying this adaptive process may direct research toward strategies that maximize intestinal function and impart a true clinical benefit to patients with short bowel syndrome, or to persons in whom nutrient absorption needs to be maximized. In this review, we consider the morphological, kinetic and membrane biochemical aspects of enteroplasticity, focus on the importance of nutritional factors, provide an overview of the many hormones that may alter the adaptive process, and consider some of the possible molecular profiles. While most of the data is derived from rodent studies, wherever possible, the results of human studies of intestinal enteroplasticity are provided.
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Gu GS, Ren JA, Li N, Li JS. Effects of recombinant human growth hormone on enterocutaneous fistula patients. World J Gastroenterol 2008; 14:6858-62. [PMID: 19058314 PMCID: PMC2773883 DOI: 10.3748/wjg.14.6858] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the effects of recombinant human growth hormone (rhGH) on intestinal mucosal epithelial cell proliferation and nutritional status in patients with enterocutaneous fistula.
METHODS: Eight patients with enterocutaneous fistulas received recombinant human growth hormone (10 μg/d) for 7 d. Image analysis and immunohisto-chemical techniques were used to analyse the expression of proliferating cell nuclear antigen (PCNA) in intestinal mucosal epithelial cells in biopsy samples from the patients who had undergone an endoscopic biopsy through the fistula at day 0, 4 and 7. Body weights, nitrogen excretion, serum levels of total proteins, albumin, prealbumin, transferrin and fibronectin were measured at day 0, 4 and 7.
RESULTS: Significant improvements occurred in the expression of PCNA in the intestinal mucosal epithelial cells at day 4 and 7 compared to day 0 (24.93 ± 3.41%, 30.46 ± 5.24% vs 12.92 ± 4.20%, P < 0.01). These changes were accompanied by the significant improvement of villus height (500.54 ± 53.79 μm, 459.03 ± 88.98 μm vs 210.94 ± 49.16 μm, P < 0.01), serum levels of total proteins (70.52 ± 5.13 g/L, 74.89 ± 5.16 g/L vs 63.51 ± 2.47 g/L, P < 0.01), albumin (39.44 ± 1.18 g/L, 42.39 ± 1.68 g/L vs 35.74 ± 1.75 g/L, P < 0.01) and fibronectin (236.3 ± 16.5 mg/L, 275.8 ± 16.9 mg/L vs 172.5 ± 21.4 mg/L, P < 0.01) at day 4 and 7, and prealbumin (286.38 ± 65.61 mg/L vs 180.88 ± 48.28 mg/L, P < 0.05), transferrin (2.61 ± 0.12 g/L vs 2.41 ± 0.14 g/L, P < 0.05) at day 7. Nitrogen excretion was significantly decreased at day 7 (3.40 ± 1.65 g/d vs 7.25 ± 3.92 g/d, P < 0.05). No change was observed in the body weight.
CONCLUSION: Recombinant human growth hormone could promote intestinal mucosal epithelial cell proliferation and protein synthesis in patients with enterocutaneous fistula.
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Wang J, Li S, Wang Q, Xin B, Wang H. Trophic Effect of Bee Pollen on Small Intestine in Broiler Chickens. J Med Food 2007; 10:276-80. [PMID: 17651063 DOI: 10.1089/jmf.2006.215] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
In this study, the effects of bee pollen on the development of digestive organs were evaluated in broiler chickens. A total of 144 1-day-old AA broiler chickens were randomly and equally divided into two groups, assigned as the control group and the pollen group, respectively. The control group was fed with a basic diet, while the pollen group was fed with a basic diet supplemented with 1.5% bee pollen over a period of 6 weeks. At the end of each week, the digestive organs were obtained for comparison from 12 broilers randomly selected from each group. The results demonstrated that compared to the control group, the small intestine villi from the duodenum, jejunum, and ileum were longer and thicker in the pollen group. This difference was more significant during early development, especially through the first 2 weeks. Bee pollen increased the length of the villi by 37.1% and 29.4% in the duodenum, 28.1% and 33.7% in the jejunum, and 18.6% and 16.2% in the ileum in week 1 and 2, respectively. Furthermore, the small intestinal glands were developed at a higher density in the pollen group, and the depth of the glands was significantly increased by bee pollen in the first 2 weeks. These findings suggest that bee pollen could promote the early development of the digestive system and therefore is a potentially beneficial food supplement for certain conditions, such as short bowel syndrome.
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Affiliation(s)
- Jue Wang
- Anhui Science and Technology University, Fengyang, Anhui, People's Republic of China
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Abstract
Intestinal failure is a condition characterized by malnutrition and/or dehydration as a result of the inadequate digestion and absorption of nutrients. The most common cause of intestinal failure is short bowel syndrome, which occurs when the functional gut mass is reduced below the level necessary for adequate nutrient and water absorption. This condition may be congenital, or may be acquired as a result of a massive resection of the small bowel. Following resection, the intestine is capable of adaptation in response to enteral nutrients as well as other trophic stimuli. Identifying factors that may enhance the process of intestinal adaptation is an exciting area of research with important potential clinical applications.
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Pereira PM, Bines JE. New growth factor therapies aimed at improving intestinal adaptation in short bowel syndrome. J Gastroenterol Hepatol 2006; 21:932-40. [PMID: 16724975 DOI: 10.1111/j.1440-1746.2006.04351.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
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.
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Affiliation(s)
- Prue M Pereira
- Murdoch Children's Research Institute, Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital, Flemington Road, Parkville, Melbourne, Victoria 3052, Australia.
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Evans ME, Tian J, Gu LH, Jones DP, Ziegler TR. Dietary supplementation with orotate and uracil increases adaptive growth of jejunal mucosa after massive small bowel resection in rats. JPEN J Parenter Enteral Nutr 2006; 29:315-20; discussion 320-1. [PMID: 16107594 DOI: 10.1177/0148607105029005315] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Massive small-bowel resection (SBR) increases adaptive growth of residual intestine in animal models of short-bowel syndrome (SBS). Pyrimidine nucleotides are critical for DNA and RNA synthesis, but no previous study has evaluated whether supplementation of pyrimidines or their precursors in the diet enhances adaptive gut growth after SBR. This study determined growth responses in jejunal mucosa after 7 days of dietary supplementation with uracil, or its precursor, orotate, after massive SBR in rats. METHODS Sprague-Dawley rats ( approximately 200 g) underwent 80% jejunoileal resection (RX) or ileal transection (TX; control). Rats were pair-fed a purified (AIN-93G) powdered diet supplemented with or without 1% (wt/wt) orotate or uracil until killing at 7 days postsurgery. Defined jejunal segments were obtained for analysis of mucosal villus height (VH), crypt depth (CD), total mucosal height, bromodeoxyuridine (BrdU) incorporation, an index of cell proliferation, and full-thickness DNA and protein content as measures of intestinal adaptive growth. RESULTS Jejunal VH increased significantly with SBR, as expected, and orotate further stimulated this response. Jejunal CD and total mucosal height increased significantly with both orotate and uracil supplementation compared with resected animals receiving standard diet. Orotate administration also increased jejunal DNA content compared with the increase observed with SBR alone. Finally, orotate, but not uracil, supplementation increased BrdU incorporation compared with resected rats fed standard or uracil-supplemented diet after SBR. CONCLUSIONS Supplementation of oral diet with the pyrimidine precursor orotate and uracil stimulated adaptive jejunal growth after massive SBR in rats. Dietary orotate had more potent growth-stimulatory effects than uracil in this animal model. Dietary supplementation with orotate and uracil represents a novel nutrition approach to enhance small-bowel mucosal adaptive growth and absorptive capacity in SBS.
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Affiliation(s)
- Mary E Evans
- Department of Medicine and the Center for Clinical and Molecular Nutrition, Emory University School of Medicine, Atlanta, GA 30322, USA
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Ito K. [Example of safety measures for antineoplastic agents immediately after market launch--a case of TS-1 capsule all example use result investigation that executes safety monitoring--]. Gan To Kagaku Ryoho 2006; 33:55-67. [PMID: 16410699 DOI: 10.2217/14750708.3.1.55] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
As a measure to ensure safe use of TS-1 during the early marketing period, a drug use investigation was conducted on an all-case basis. Extra safety monitoring,rarely included in the use investigation,was also planned for patients who began therapy with this agent. Of the 4,177 subjects registered during the year beginning in March 1999, 3,882 started TS-1 therapy. Aside from 74 dropouts, 3,808 cases were evaluable for safety. The overall incidence of adverse reactions, with high frequencies of myelosuppression and gastrointestinal disorders, was 74.3%: a result similar to an incidence of 77.5% (100/129) found in the early phase II trial with gastric cancer patients. Safety monitoring made it possible to check if a given patients was eligible for proper use before treatment is begun. During TS-1 administration,collaboration was formed between physicians and medical representatives to ensure regular laboratory testing and to check the test findings. Measures were considered necessary to secure the safe use of drugs with manifest risk of serious adverse reactions, such as antineoplastic agents, during the initial period of market introduction. Our present approach proved effective as one of such measures.
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Affiliation(s)
- Kunio Ito
- Taiho Pharmaceutical Company, Tokyo, Japan
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Neves JDS, Aguilar-Nascimento JED, Gomes-da-Silva MHG, Cavalcanti RN, Bicudo AS, Nascimento M, Nochi RJ. Glutamine alone or combined with short-chain fatty acids fails to enhance gut adaptation after massive enterectomy in rats . Acta Cir Bras 2006; 21 Suppl 4:2-7. [PMID: 17293957 DOI: 10.1590/s0102-86502006001000002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
PURPOSE: To investigate the effect of oral glutamine alone or combined with short chain fatty acids (SCFA) in the intestinal adaptation of rats submitted to an massive enterectomy. METHODS: After receiving 70% small bowel resection, 30 Wistar rats were randomized to received either standard rat chow (control group, n=10) or the same diet supplemented with 3,05% of glutamine alone (glutamine group, n=10) or combined with a solution containing SCFA (glutamine+SCFA group, n=10). Animals were killed on the 14th postoperative day. Mucosal weight, crypt depth, villus height, wall width, and the mucosal content of DNA, were assessed in basal conditions (resected gut specimen) and compared to the small bowel specimen collected on the postoperative day 14, at both jejunum and ileum sites. RESULTS: All groups presented similar pattern in weight evolution. In all groups, both the morphological findings and the DNA content were significantly higher at the end of the experiment than in basal conditions, at both the jejunum and ileum. Except for the jejunum wall width that was higher in control group (808±95 µ) than in the other two groups (glutamine = 649±88 µ and glutamine+SCFA = 656±92; p<0.01), there was no difference among them in all variables at both intestinal sites after 14 days. CONCLUSION: All groups presented adaptation of the intestinal mucosa in the remnant gut. Glutamine combined or not with short chain fatty acids fails to influence the adaptive response of the small bowel.
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Jianfeng G, Weiming Z, Ning L, Fangnan L, Li T, Nan L, Jieshou L. Serum citrulline is a simple quantitative marker for small intestinal enterocytes mass and absorption function in short bowel patients. J Surg Res 2005; 127:177-82. [PMID: 15921697 DOI: 10.1016/j.jss.2005.04.004] [Citation(s) in RCA: 77] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2004] [Revised: 03/10/2005] [Accepted: 04/02/2005] [Indexed: 01/08/2023]
Abstract
BACKGROUND To investigate the clinical significance of serum citrulline in evaluating the remnant small bowel enterocytes mass and absorptive function in short bowel (SB) patients. MATERIALS AND METHODS Serum citrulline concentrations were determined using high-performance liquid chromatography (HPLC) in 22 SBS patients and 33 healthy controls. Five-hour urine D-xylose excretion and digestive protein absorption were measured using HPLC and micro-Kjeldahl method, respectively. Small bowel length and surface area were assessed on X-ray radiograph. Correlations between serum citrulline levels and small bowel length, small bowel surface, and nutritional substrate digestive absorption percentage were analyzed. For six patients receiving bowel rehabilitation therapy, serum citrulline, D-xylose excretion, and intestinal protein absorption were measured pre- and immediately postmanagement, and their correlations were analyzed. RESULTS Serum citrulline levels were significantly lower in SB patients compared with healthy controls. In SB patients, they correlated well with remnant small bowel length (r = 0.82, P < 0.001), surface area (r = 0.86, P < 0.001), 5-h urine D-xylose excretion (r = 0.56, P = 0.007), and digestive protein absorption (r = 0.48, P = 0.046). The increased percentage of serum citrulline level in six patients receiving rehabilitation therapy followed a trend of correlating with that of intestinal protein absorption (r = 0.79, P = 0.063) and urine D-xylose excretion (r = 0.81, P = 0.053). CONCLUSIONS In patients with short bowel syndrome, serum citrulline is a simple and accurate biomarker for the severity of intestinal failure and may be a candidate marker for the gut-trophic effects of bowel rehabilitation therapies.
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Affiliation(s)
- Gong Jianfeng
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, P.R. China
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Spadoni JM, Aguilar-Nascimento JED, Silva MHGGD, Spadoni-Neto B, Costa PATFBD, Aléssio DMT. Effects of the combined use of glutamine and growth hormone in the intestinal adaptation after massive resection of the small bowel in rats. Acta Cir Bras 2005; 20:382-9. [PMID: 16186963 DOI: 10.1590/s0102-86502005000500008] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
PURPOSE The aim of this study was to investigate the effects of the combined use of glutamine (GL) and growth hormone (GH) in the intestine of rats submitted to 80% small bowel resection. METHODS [24] Twenty four Wistar rats were randomized to receive either a standard rat chow--control group (CG, n = 12) or the same diet added to 4% glutamine--GL-GH group (n = 12) after 80% enterectomy. The latter group received subcutaneously 0.6 UI/day of GH. Groups of six rats in each group were killed on the 5th and 14th days. The following variables were studied: body weight, mucosal weight, histomorphometry and DNA content in the resected specimen and in the adapted intestines after necropsy. RESULTS All animals lost weight stabilizing after the 5th PO day in both groups. There was not any statistical difference in the mucosal weight associated to groups and dates. However, ileal mucosal weight decreased from basal to final results when compared to jejunal mucosa (p = 0.02). The DNA content increased from the initial to the final results (p < 0.001) in both groups, though, this increase was greater in GL-GH animals (CG = 0.53 [95% CI, 0.44-0.62] g/cm(-1) vs. GL-GH = 0.85 [95%CI, 0.76-0.94] g/cm(-1); p < 0.01), especially at the 14th day. Ileal DNA content was significantly greater than jejunal (p = 0.01). There was a significant increase in the intestinal wall width and crypt depth in the control group (p < 0.01). CONCLUSION Gut adaptation after massive resection is improved with the combined use of glutamine and GH.
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Matarese LE, Abu-Elmagd K. Somatropin for the treatment of short bowel syndrome in adults. Expert Opin Pharmacother 2005; 6:1741-50. [PMID: 16086660 DOI: 10.1517/14656566.6.10.1741] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Somatropin (rDNA origin) injection (Zorbtive) is a highly purified preparation of human growth hormone (GH) produced from a mammalian cell line by recombinant DNA technology. It is the only human GH approved for the treatment of short bowel syndrome in patients receiving specialised nutritional support. The process of intestinal adaptation begins immediately after surgery and continues for 2-3 years. During this period, the bowel begins to increase fluid and nutrient absorption. Under the influence of tropic factors, such as GH, intestinal adaptation is enhanced. Supplying a therapeutic regimen of GH, optimised diet and glutamine supplementation for 4 weeks to patients with short bowel syndrome who are dependent on parenteral nutrition, has been shown to reduce their long-term requirements for parenteral nutrition.
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Affiliation(s)
- Laura E Matarese
- University of Pittsburgh Medical Center, Thomas E. Starzl Transplantation Institute, 3459 Fifth Avenue, MUH 7 South Pittsburgh, PA 15213, USA
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Washizawa N, Gu LH, Gu L, Openo KP, Jones DP, Ziegler TR. Comparative effects of glucagon-like peptide-2 (GLP-2), growth hormone (GH), and keratinocyte growth factor (KGF) on markers of gut adaptation after massive small bowel resection in rats. JPEN J Parenter Enteral Nutr 2005; 28:399-409. [PMID: 15568286 DOI: 10.1177/0148607104028006399] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
BACKGROUND Administration of specific growth factors exert gut-trophic effects in animal models of massive small bowel resection (SBR); however, little comparative data are available. Our aim was to compare effects of a human glucagon-like peptide-2 (GLP-2) analog, recombinant growth hormone (GH) and recombinant keratinocyte growth factor (KGF) on jejunal, ileal, and colonic growth and functional indices after 80% SBR in rats. METHODS Thirty-seven male rats underwent small bowel transection (sham operation) with s.c. saline administration (control; Tx-S; n = 7) or 80% midjejuno-ileal resection (Rx) and treatment with either s.c. saline (Rx-S, n = 7), GLP-2 at 0.2 mg/kg/d (Rx-GLP-2; n = 8), GH at 3.0 mg/kg/d (Rx-GH; n = 8), or KGF at 3.0 mg/kg/d (Rx-KGF; n = 7) for 7 days. All groups were pair-fed to intake of Rx-S rats. Gut mucosal cell growth indices (wet weight, DNA and protein content, villus height, crypt depth, and total mucosal height) were measured. Expression of the cytoprotective trefoil peptide TFF3 was determined by Western blot. Gut mucosal concentrations of the tripeptide glutathione (L-glutamyl-L-cysteinyl-glycine) and glutathione disulfide (GSSG) were measured by high-performance liquid chromatography and the glutathione/GSSG ratio calculated. RESULTS SBR increased adaptive growth indices in jejunal, ileal, and colonic mucosa. GLP-2 treatment increased jejunal villus height and jejunal total mucosal height compared with effects of resection alone or resection with GH or KGF treatment. Both GH and KGF modestly increased colonic crypt depth after SBR. SBR did not affect small bowel or colonic goblet cell number or TFF3 expression; however, goblet cell number and TFF3 expression in both small bowel and colon were markedly up-regulated by KGF treatment and unaffected by GLP-2 and GH. SBR oxidized the ileal and colonic mucosal glutathione/GSSG redox pools. GLP-2 treatment after SBR increased the glutathione/GSSG ratio in jejunum, whereas KGF had an intermediate effect. In addition, GLP-2 (but not GH or KGF) prevented the SBR-induced oxidation of the glutathione/GSSG pools in both ileum and colon. CONCLUSIONS GLP-2 exerts superior trophic effects on jejunal growth and also improves mucosal glutathione redox status throughout the bowel after massive SBR in rats. Both GH and KGF increase colonic mucosal growth in this model. KGF alone potently increases gut mucosal goblet cell number and expression of the cytoprotective trefoil peptide TFF3. The differential effects of GLP-2, GH and KGF administration in this model of short bowel syndrome suggest that individual therapy with these growth factors may not be an adequate strategy to maximally improve adaptive gut mucosal growth and cytoprotection after massive small intestinal resection. Future research should address the use of these agents in combination in short bowel syndrome.
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Affiliation(s)
- Naohiro Washizawa
- Department of Surgery, Toho University School of Medicine, Tokyo, Japan
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Carneiro-Filho BA, Oriá RB, Wood Rea K, Brito GAC, Fujii J, Obrig T, Lima AAM, Guerrant RL. Alanyl-glutamine hastens morphologic recovery from 5-fluorouracil-induced mucositis in mice. Nutrition 2005; 20:934-41. [PMID: 15474885 DOI: 10.1016/j.nut.2004.06.016] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
OBJECTIVE In this study, we postulated the beneficial role of oral alanyl-glutamine, a more stable glutamine derivative to decrease 5-fluorouracil (5-FU)-induced mucositis in mice. METHODS We measured different morphologic parameters to assess structural changes over time in the small bowel, including crypt depth, villus height, villus area, mitotic and apoptotic indices at the crypt level using terminal deoxyuridine triphosphate nick end labeling, and hematoxylin-eosin staining of ileal tissue. In addition, we analyzed the effect of different alanyl-glutamine concentrations on animal weight curves after 5-FU treatment. RESULTS Neither glutamine nor alanyl- glutamine prevented the 5-FU intestinal structural damage or apoptosis in crypt enterocytes at 24 h after 5-FU challenge. However, we found that alanyl-glutamine, but not glutamine, speeds intestinal recovery when compared with 5-FU-treated controls (P < 0.05), predominantly by enhancing mitotic activity and crypt length. CONCLUSION Our findings provide important data to support clinical studies of oral alanyl-glutamine in 5-FU-induced mucositis.
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Affiliation(s)
- Benedito A Carneiro-Filho
- Department of Morphology, Institute of Biomedicine and Clinical Research Unit-University Hospital, Federal University of Ceará, Brazil
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Salamat-Miller N, Chittchang M, Mitra AK, Johnston TP. A Randomly Coiled, High-Molecular-Weight Polypeptide Exhibits Increased Paracellular Diffusion in Vitro and in Situ Relative to the Highly Ordered ?-Helix Conformer. Pharm Res 2005; 22:245-54. [PMID: 15783072 DOI: 10.1007/s11095-004-1192-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
PURPOSE The current investigation was conducted to examine the effect of secondary structure of model polypeptides on their hindered paracellular diffusion. METHODS Poly-D-glutamic acid (PDGlu) was selected as one of the model polypeptides because of its ability to form two secondary structures; a negatively charged random coil and an alpha-helix with partial negative charge at pH 7.4 and 4.7, respectively. Poly-D-lysine (PDL) was selected as a positively charged random coil conformation at pH 7.4. Transport experiments were conducted across both a Caco-2 cell monolayer and the intestinal membrane of Sprague-Dawley rats. Additionally, using NMR, an estimation for the diffusion coefficient and the equivalent hydrodynamic radius for each model polypeptide was obtained. RESULTS PDGlu in the randomly coiled conformation exhibited greater paracellular transport when compared to either the same polypeptide having an alpha-helix secondary structure or the positively charged, randomly coiled PDL. CONCLUSIONS Randomly coiled PDGlu was able to permeate through the negatively charged tight junctions of both biological membranes to a greater extent than PDGlu having an alpha-helix structure and suggests that molecular flexibility associated with the random coil conformation may play a more important role than overall charge and hydrodynamic radius on its hindered paracellular diffusion.
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Affiliation(s)
- Nazila Salamat-Miller
- Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri 64110, USA
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Ribeiro SR, Pinto PE, de Miranda AC, Bromberg SH, Lopasso FP, Irya K. Weight loss and morphometric study of intestinal mucosa in rats after massive intestinal resection: influence of a glutamine-enriched diet. ACTA ACUST UNITED AC 2005; 59:349-56. [PMID: 15654488 DOI: 10.1590/s0041-87812004000600007] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
UNLABELLED Short-bowel syndrome is responsible for significant metabolic alterations that compromise nutritional status. Glutamine is considered an essential nutrient for enterocytes, so beneficial effects from supplementation of the diet with glutamine are hypothesized. PURPOSE In this study, the effect of a diet enriched with glutamine was evaluated in rats undergoing extensive small bowel resection, with analysis of postoperative weight loss and intestinal morphometrics of villi height, crypt depth, and thickness of the duodenal and remnant jejunal mucosa. METHODS Three groups of male Wistar rats were established receiving the following diets: with glutamine, without glutamine, and the standard diet of laboratory ration. All animals underwent an extensive small bowel resection, including the ileocecal valve, leaving a remnant jejunum of only 25 cm from the pylorus that was anastomosed lateral-laterally to the ascendant colon. The animals were weighed at the beginning and end of the experiment (20th postoperative day). Then they were killed and the remnant intestine was removed. Fragments of duodenal and jejunal mucosa were collected from the remnant intestine and submitted to histopathologic exam. The morphometric study of the intestinal mucosa was accomplished using a digital system (KS 300) connected to an optic microscope. Morphometrics included villi height, crypt depth, and the total thickness of intestinal mucosa. RESULTS The weight loss comparison among the 3 groups showed no significant loss difference. The morphometric studies showed significantly taller duodenal villi in the glutamine group in comparison to the without glutamine group, but not different from the standard diet group. The measurements obtained comparing the 3 groups for villi height, crypt depth, and thickness of the remnant jejunum mucosa were greater in the glutamine-enriched diet group than for the without-glutamine diet group, though not significantly different from with standard-diet group. CONCLUSIONS In rats with experimentally produced short-bowel syndrome, glutamine-enrichment of an isonitrogenous test diet was associated with an improved adaptation response by the intestinal mucosa but not reduced weight loss. However, the adaptation response in the group receiving the glutamine-enriched diet was not improved over that for the group fed regular chow.
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Affiliation(s)
- Sidney Resende Ribeiro
- Instituto de Assistência ao Servidor Público Estadual (IAMSPE) and Clinical Investigation Laboratory, Faculty of Medicine, University of São Paulo--São Paulo/SP, Brazil
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Lardy H, Mouillé B, Thomas M, Darcy-Vrillon B, Vaugelade P, Blachier F, Bernard F, Cherbuy C, Robert V, Corriol O, Ricour C, Goulet O, Duée PH, Colomb V. Enterocyte metabolism during early adaptation after extensive intestinal resection in a rat model. Surgery 2004; 135:649-56. [PMID: 15179371 DOI: 10.1016/j.surg.2003.11.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVE A better knowledge of intestinal adaptation after resection is required to improve the nutritional support that is given to patients. The aim of this study was to understand the metabolic changes underlying early adaptation after massive intestinal resection. METHODS Rats were assigned to either 80% intestinal resection or transection. All animals received the same intragastric nutrition. On day 8, plasma glutamine turnover was measured. Substrate use was determined on isolated enterocytes that were incubated in the presence of D-[U-(14)C] glucose (2 mmol/L), L-[U-(14)C] glutamine (2 mmol/L), L-[U-(14)C] arginine (1 mmol/L), or L-[1-(14)C] ornithine (1 mmol/L). RESULTS Plasma glutamine turnover was similar in both groups. The rate of enterocyte glutamine use was significantly increased in the resection group, although the maximal glutaminase activity was unchanged. Glutathione generation was enhanced 3-fold in remnant intestine as compared with transected intestine (P <.05). L-ornithine decarboxylation was increased markedly in resected animals (P <.05), without any detectable change of maximal ornithine decarboxylase activity. CONCLUSION The early phase of intestinal adaptation after resection induces changes in enterocyte glutamine and ornithine metabolism that may be related, in part, to increased de novo polyamine synthesis. This observation suggests that a supplementation of artificial nutrition by nutrients that lead to the generation of trophic agents may be of potential interest.
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Affiliation(s)
- Hubert Lardy
- Laboratoire de Nutrition et Sécurité Alimentaire, Institut National de la Recherche Agronomique, Jouy-en-Josas, France
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Su ZD, Qin HL. Effects of growth hormone on intestinal adaptation of rat with short bowel syndrome. Shijie Huaren Xiaohua Zazhi 2004; 12:646-649. [DOI: 10.11569/wcjd.v12.i3.646] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the effects of growth hormone (GH) on the residual small intestine of rats with short bowel syndrome (SBS), including adaptive hyperplasia and absorption of glucose and amino acids.
METHODS: Forty Sprague-Dawley (SD) male rats with more than 85% small intestine resected were equally divided into five groups randomly: H-GH group (high dose at 7.5 IU/kg per day), M-GH group (moderate dose at 3.75 IU/kg per day), L-GH group (low dose at 1.88 IU/kg per day), SBS group and sham operation group. From the second to the 15th day after operation, all the GH-managed groups were treated by sc injection twice a day, while SBS group and sham group were managed with same volume normal saline for injection. All samples were gained by laparotomy under anesthesia at the 16th day after operation.
RESULTS: Weight loss of rats in H-GH group (36±4.4 g), which was the least among the four groups except sham group, was significantly less than that in SBS group (94±10.0 g) (P < 0.05). But preoperative body weight of rats in the four groups except sham group was not retrieved. Among all groups there was no significant difference in the length of jejunum and ileum, as well as no significant difference in the morphological variables of colon. Mucosal height of jejunum and ileum was greater in H-GH group and M-GH group (997±65.9 m, 752±79.3 m and 974±67.6 m, 788±75.1 m respectively) than those in SBS group (776±61.0 m, 664±64.0 m) (P < 0.05). Similarly, intestinal wall width of jejunum and ileum was also thicker in H-GH group and M-GH group (1142±65.4 m, 884±91.2 m and 1 145±78.7 m, 895±95.6 m respectively) than those in SBS group (848±194.7 m, 776±57.5 m) (P < 0.05). But mucosal height and intestinal wall width of jejunum and ileum in H-GH group were not significantly greater than those in M-GH group. Blood insulinlike growth factor 1 (IGF-1) concentration and PCNA index of liver did not differ among the five groups. No significant differences of blood glucose and amino acids concentrations were detected after nutritional administration among the five groups.
CONCLUSION: Treatment of SBS with GH only slows body weight decrease rather than promotes body weight gain by the support of enteral nutrition. GH enhances adaptive mucosal hyperplasia after massive resection of small intestine, while its enhanced effect does not parallel its dose increase. Because of GH resistance resulted from the SBS-induced malnutrition,elevation of blood IGF-1 is impaired and absorpton of glucose and amino acids is not enhanced.
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Abstract
A somatropin preparation (Zorbtive) produced by recombinant DNA technology has been evaluated in patients with short bowel syndrome. Somatropin is thought to enhance intestinal adaptation in this condition through direct or indirect effects on the intestine. In a randomised, double-blind study in patients with short bowel syndrome who were dependent on intravenous parenteral nutrition (IPN) [n = 41], recipients of subcutaneous somatropin alone or somatropin plus oral glutamine had significantly greater mean reductions from baseline in weekly total IPN volume than recipients of placebo plus glutamine. All patients received a special diet. In addition, significantly greater mean reductions from baseline in weekly total IPN calories and the mean frequency of IPN or supplemental lipid emulsion administration occurred in patients receiving somatropin alone or in combination with glutamine, compared with recipients of placebo plus glutamine. Adverse events were reported in 100% of patients with short bowel syndrome during treatment with somatropin with or without glutamine. However, a high proportion of patients also reported signs and symptoms before starting therapy or adverse events after therapy, suggesting that such patients experience numerous events attributable to their underlying condition or to complications of IPN.
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Affiliation(s)
- Gillian M Keating
- Adis International Limited, 41 Centorian Drive, PB 65901, Mairangi Bay, Auckland 1311, New Zealand.
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Thiesen A, Drozdowski L, Iordache C, Neo CC, Woudstra TD, Xenodemetropoulos T, Keelan M, Clandinin MT, Thomson ABR, Wild G. Adaptation following intestinal resection: mechanisms and signals. Best Pract Res Clin Gastroenterol 2003; 17:981-95. [PMID: 14642861 DOI: 10.1016/s1521-6918(03)00097-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
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.
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Affiliation(s)
- A Thiesen
- Nutrition and Metabolism Research Group, Division of Gastroenterology, Department of Medicine, University of Alberta, 519 Newton Research Building, 205 College Plaza, 8215-112 Street, Edmonton, Alta, Canada T6G 2C2.
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Ziegler TR, Evans ME, Fernández-Estívariz C, Jones DP. Trophic and cytoprotective nutrition for intestinal adaptation, mucosal repair, and barrier function. Annu Rev Nutr 2003; 23:229-61. [PMID: 12626687 DOI: 10.1146/annurev.nutr.23.011702.073036] [Citation(s) in RCA: 140] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Intestinal epithelial cell turnover (proliferation, migration, differentiation, and apoptosis) and gut barrier functions are dynamic processes that are markedly affected by nutritional status, the route of feeding, and the adequacy of specific nutrients in the diet. Emerging studies are defining potential therapeutic roles for specific nutrients and diet-derived compounds (including arginine, glutamate, glutamine, glutathione, glycine, vitamin A, zinc, and specific lipids) in gut mucosal turnover, repair, adaptation after massive bowel resection, and barrier function. The role and regulation of endogenous bowel flora in generating short-chain fatty acids from diet-derived fiber and other diet-derived compounds and the effects of these agents on gut function are increasingly being elucidated. Results of these investigations should define new nutritional methods for trophic and cytoprotective effects on the intestine in conditions such as inflammatory bowel disease, malnutrition, and short bowel syndrome.
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Affiliation(s)
- Thomas R Ziegler
- Department of Medicine, Center for Clinical and Molecular Nutrition, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
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Abstract
Recognition that specific nutrients can be beneficial when consumed in amounts above the accepted daily requirements has provided a major impetus for the critical examination of dietary approaches with single or multiple nutrient supplements chosen to modulate the inflammatory response, enhance immune function, or improve the blood-gut barrier. Patients suffering the effects of hypercatabolism caused by surgery, cancer, or extensive burns are prime candidates for immunonutrition, as the intervention has come to be known, as are immunosuppressed patients with the human immunodeficiency virus or other overwhelming infections. This review focuses on key nutrients used in clinical trials for which a body of information on the mode of action and metabolic pathways is available. The topics covered include the amino acids, glutamine and arginine; omega-3 fatty acids, eicosapentaenoic acid and docosahexanoic acid; vitamin A; and zinc. Lastly, we address the area of pre- and probiotics and how "friendly" microorganisms are being incorporated into therapeutic regimens aimed at sustaining health. The use of immunonutrition requires judicious consideration of the potential undesirable effects of certain additives in clinical settings where enhanced immune responsiveness can translate into tissue damage and altered mucosal defenses.
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Affiliation(s)
- Joseph Levy
- Children's Hospital of New York-Presbyterian, Columbia University, College of Physicians and Surgeons, New York, New York, USA.
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Bloomfield FH, van Zijl PL, Bauer MK, Harding JE. Effects of intrauterine growth restriction and intraamniotic insulin-like growth factor-I treatment on blood and amniotic fluid concentrations and on fetal gut uptake of amino acids in late-gestation ovine fetuses. J Pediatr Gastroenterol Nutr 2002; 35:287-97. [PMID: 12352515 DOI: 10.1097/00005176-200209000-00010] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES To investigate, in the late-gestation ovine fetus: 1) amino acid concentrations in blood and amniotic fluid, 2) the effects of intrauterine growth restriction (IUGR) induced by placental embolization on these concentrations, 3) fetal gut uptake of glutamine in healthy and IUGR fetuses, and 4) the effects of intraamniotic insulin-like growth factor-I (IGF-1) treatment on these parameters. METHODS Fetuses were randomly assigned to control (n = 9), IUGR + saline (n = 9), or IUGR + IGF-1 (n = 11) groups. IUGR was induced by uteroplacental embolization from 114 to 119 days (term = 145 days). IUGR fetuses received daily intraamniotic injections of saline or IGF-1 (20 microg/d) from 120 to 130 days. RESULTS Baseline amino acid concentration was higher in fetal blood than amniotic fluid for all essential amino acids except lysine and histidine, but was lower for serine, alanine, and methylhistidine. Embolization reduced total amino acid concentration in blood and amniotic fluid by approximately 15%. Concentrations were reduced for serine, glutamine, and methylhistidine in blood and for serine in amniotic fluid, but were increased for glycine, alanine, and asparagine in blood and for alanine in amniotic fluid. Glutamine was taken up by the fetal gut (glutamine:oxygen quotient of 0.65) and citrulline was released by the gut. IGF-1 treatment did not alter amino acid concentration in blood or amniotic fluid, but reduced gut uptake of glutamine from blood and the gut glutamine:oxygen quotient by 15%. Citrulline release was unchanged. CONCLUSIONS These data suggest that amniotic fluid amino acids are not simply filtered from fetal blood and may provide an important pool of nutrients for the fetus. They demonstrate for the first time that glutamine is taken up by the fetal gut. IGF-1 treatment may promote gut utilization of amino acids from the amniotic fluid pool.
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Affiliation(s)
- Frank H Bloomfield
- Liggins Institute, University of Auckland, PB 92019, Auckland, New Zealand
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Gu Y, Wu ZH. The anabolic effects of recombinant human growth hormone and glutamine on parenterally fed, short bowel rats. World J Gastroenterol 2002; 8:752-7. [PMID: 12174391 PMCID: PMC4656333 DOI: 10.3748/wjg.v8.i4.752] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the metabolic effects associated with administration of rhGH and/or Gln in parenterally fed, short-bowel rats.
METHODS: Forty SD rats subjected to 75% intestinal resection and maintained with parenteral nutrition were randomly divided into 4 groups as follows: -rhGH, -Gln; -rhGH, +Gln; +rhGH, -Gln; +rhGH, +Gln. Body weight and nitrogen balance were evaluated daily. After 6 d of PN, rats were killed, various organs were dissected and weighted, the carcasses were used for analysis of body composition. Serum GH and IGF-1 were determined by RIA method.
RESULTS: Weight loss in rats with rhGH (17.4 ± 12.8 g) and rhGH+Gln (23.8 ± 3.5 g) was significantly less than rats with PN alone (29.6 ± 6.9 g) and rats with Gln-supplemented PN (31.85 ± 12.8 g), P < 0.05. The accumulated NB in rats with rhGH (1252.9 ± 294.3 mg N/d) and rhGH+Gln (1261.7 ± 85.5 mg N/d) was significantly greater than those with PN alone (704.8 ± 379.0 mg N/d) and with Gln-supplemented PN (856.7 ± 284.4 mg N/d), P < 0.05. The absolute weight of gastrocnemius muscle in rats with rhGH (2683.9 ± 341.6 mg) and rhGH+Gln (2579.1 ± 359.5 mg) was greater than those with PN alone (2176.3 ± 167.1 mg) and with Gln-supplemented PN (2141.9 ± 353.6 mg). Although the absolute weight of remnant small intestine itself was not significantly different in 4 experimental groups, the weight/length of the segments was greater in rats with rhGH and/or Gln (48.7 ± 5.5, 52.7 ± 4.1 and 67.4 ± 5.3 respectively) than those with PN alone (47.8 ± 5.0), there were synergistic effects between rhGH and Gln in improvement of the weight/length of remnant small intestine, P < 0.05. Analyses of body carcass composition showed that a higher percentage of carcass weight as protein and a lower percentage of carcass weight as fat were occurred in rats with rhGH (20.8 ± 4.0, 6.0 ± 2.6) and rhGH+Gln (21.3 ± 2.4, 4.4 ± 1.5) than those with PN alone (16.4 ± 2.4, 9.2 ± 3.7) and with Gln-supplemented PN (17.8 ± 3.0, 6.3 ± 2.0), rhGH had significant effects on alteration of body composition, P < 0.05. Serum GH and IGF-1 concentration in rats with rhGH (5.221 ± 0.8 and 425.1 ± 19.2 ng/mL respectively) and rhGH+Gln (5.507 ± 1.0 and 461.1 ± 49.9 ng/mL respectively) were greater than those with PN alone (3.327 ± 1.7 and 325.8 ± 29.6 ng/mL respectively) and with Gln-supplemented PN (3.433 ± 0.1 and 347.7 ± 55.7 ng/mL respectively), P < 0.01.
CONCLUSION: rhGH significantly improves the anabolism in parenterally fed. Short bowel rats, anabolic effect with Gln is less dramatic, there is no synergistic effect between rhGH and Gln in improvement of whole body anabolism. IGF-1 plays an important part in growth-promoting effects of rhGH.
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Affiliation(s)
- Yan Gu
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Second Medical University, Shanghai 200011, China.
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Abstract
Management of patients with short-bowel syndrome represents a formidable challenge. Aggressive treatment including nutritional care and anticipation of potential complications and rapid treatment of complications enhance outcome. New therapies offer the promise of significantly improving morbidity and mortality. Intestinal transplant is appropriate for infants who would otherwise die from liver disease, recurrent sepsis, or lack of venous access.
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Affiliation(s)
- Sandy T Hwang
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
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