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Cairns CA, Xiao L, Wang JY. Posttranscriptional Regulation of Intestinal Mucosal Growth and Adaptation by Noncoding RNAs in Critical Surgical Disorders. J INVEST SURG 2024; 37:2308809. [PMID: 38323630 PMCID: PMC11027105 DOI: 10.1080/08941939.2024.2308809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Accepted: 01/12/2024] [Indexed: 02/08/2024]
Abstract
The human intestinal epithelium has an impressive ability to respond to insults and its homeostasis is maintained by well-regulated mechanisms under various pathophysiological conditions. Nonetheless, acute injury and inhibited regeneration of the intestinal epithelium occur commonly in critically ill surgical patients, leading to the translocation of luminal toxic substances and bacteria to the bloodstream. Effective therapies for the preservation of intestinal epithelial integrity and for the prevention of mucosal hemorrhage and gut barrier dysfunction are limited, primarily because of a poor understanding of the mechanisms underlying mucosal disruption. Noncoding RNAs (ncRNAs), which include microRNAs (miRNAs), long ncRNAs (lncRNAs), circular RNAs (circRNAs), and small vault RNAs (vtRNAs), modulate a wide array of biological functions and have been identified as orchestrators of intestinal epithelial homeostasis. Here, we feature the roles of many important ncRNAs in controlling intestinal mucosal growth, barrier function, and repair after injury-particularly in the context of postoperative recovery from bowel surgery. We review recent literature surrounding the relationships between lncRNAs, microRNAs, and RNA-binding proteins and how their interactions impact cell survival, proliferation, migration, and cell-to-cell interactions in the intestinal epithelium. With advancing knowledge of ncRNA biology and growing recognition of the importance of ncRNAs in maintaining the intestinal epithelial integrity, ncRNAs provide novel therapeutic targets for treatments to preserve the gut epithelium in individuals suffering from critical surgical disorders.
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Affiliation(s)
- Cassandra A. Cairns
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland 21201
| | - Lan Xiao
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland 21201
| | - Jian-Ying Wang
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland 21201
- Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland 21201
- Baltimore Veterans Affairs Medical Center, Baltimore, Maryland 21201
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Sugita K, Yano K, Onishi S, Tabata Y, Iwamoto Y, Ogata M, Takada L, Kedoin C, Murakami M, Harumatsu T, Matsukubo M, Kawano T, Muto M, Kumagai K, Ido A, Kaji T, Ieiri S. Impact of hepatocyte growth factor on the colonic morphology and gut microbiome in short bowel syndrome rat model. Pediatr Surg Int 2024; 40:185. [PMID: 38997605 DOI: 10.1007/s00383-024-05776-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/06/2024] [Indexed: 07/14/2024]
Abstract
PURPOSE This study aimed to investigate the impact of hepatocyte growth factor (HGF) on colonic morphology and gut microbiota in a rat model of short bowel syndrome (SBS). METHODS SD rats underwent jugular vein catheterization for total parenteral nutrition (TPN) and 90% small bowel resection [TPN + SBS (control group) or TPN + SBS + intravenous HGF (0.3 mg/kg/day, HGF group)]. Rats were harvested on day 7. Colonic morphology, gut microflora, tight junction, and Toll-like receptor-4 (TLR4) were evaluated. RESULTS No significant differences were observed in the colonic morphological assessment. No significant differences were observed in the expression of tight junction-related genes in the proximal colon. However, the claudin-1 expression tended to increase and the claudin-3 expression tended to decrease in the distal colon of the HGF group. The Verrucomicrobiota in the gut microflora of the colon tended to increase in the HGF group. The abundance of most LPS-producing microbiota was lower in the HGF group than in the control group. The gene expression of TLR4 was significantly downregulated in the distal colon of the HGF group. CONCLUSION HGF may enhance the mucus barrier through the tight junctions or gut microbiome in the distal colon.
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Affiliation(s)
- Koshiro Sugita
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan
| | - Keisuke Yano
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan
| | - Shun Onishi
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan
| | - Yumiko Tabata
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan
| | - Yumiko Iwamoto
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan
| | - Masato Ogata
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan
| | - Lynne Takada
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan
| | - Chihiro Kedoin
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan
| | - Masakazu Murakami
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan
| | - Toshio Harumatsu
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan
| | - Makoto Matsukubo
- Department of Pediatric Surgery, Kagoshima City Hospital, Kagoshima, Japan
| | - Takafumi Kawano
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan
| | - Mitsuru Muto
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan
| | - Kotaro Kumagai
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, School of Medical and Dental Sciences, Kagoshima University Graduate, Kagoshima, Japan
| | - Akio Ido
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, School of Medical and Dental Sciences, Kagoshima University Graduate, Kagoshima, Japan
| | - Tatsuru Kaji
- Department of Pediatric Surgery, Kurume University School of Medicine, Kurume, Japan
| | - Satoshi Ieiri
- Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan.
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Norsa L, Goulet O, Alberti D, DeKooning B, Domellöf M, Haiden N, Hill S, Indrio F, Kӧglmeier J, Lapillonne A, Luque V, Moltu SJ, Saenz De Pipaon M, Savino F, Verduci E, Bronsky J. Nutrition and Intestinal Rehabilitation of Children With Short Bowel Syndrome: A Position Paper of the ESPGHAN Committee on Nutrition. Part 1: From Intestinal Resection to Home Discharge. J Pediatr Gastroenterol Nutr 2023; 77:281-297. [PMID: 37256827 DOI: 10.1097/mpg.0000000000003849] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
Short bowel syndrome (SBS) is the leading cause of intestinal failure (IF) in children. The mainstay of treatment for IF is parenteral nutrition (PN). The aim of this position paper is to review the available evidence on managing SBS and to provide practical guidance to clinicians dealing with this condition. All members of the Nutrition Committee of the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) contributed to this position paper. Some renowned experts in the field joined the team to guide with their experience. A systematic literature search was performed from 2005 to May 2021 using PubMed, MEDLINE, and Cochrane Database of Systematic Reviews. In the absence of evidence, recommendations reflect the expert opinion of the authors. Literature on SBS mainly consists of retrospective single-center experience, thus most of the current papers and recommendations are based on expert opinion. All recommendations were voted on by the expert panel and reached >90% agreement. The first part of this position paper focuses on the physiological mechanism of intestinal adaptation after surgical resection. It subsequently provides some clinical practice recommendations for the primary management of children with SBS from surgical resection until discharged home on PN.
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Affiliation(s)
- Lorenzo Norsa
- From the Department of Paediatric Hepatology, Gastroenterology and Transplantation, ASST Papa Giovanni XXIII, Bergamo, Italy
| | - Olivier Goulet
- the Department of Pediatric Gastroenterology-Hepatology-Nutrition, Necker-Enfants Malades Hospital, Université Paris Descartes, Paris, France
| | - Daniele Alberti
- the Department of Pediatric Surgery, ASST Spedali Civili, Brescia, Italy
- the Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Barbara DeKooning
- the Paediatric Gastroenterology, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Magnus Domellöf
- the Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden
| | - Nadja Haiden
- the Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Susan Hill
- the Department of Paediatric Gastroenterology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Flavia Indrio
- the Department of Medical and Surgical Science, University of Foggia, Foggia, Italy
| | - Jutta Kӧglmeier
- the Department of Paediatric Gastroenterology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Alexandre Lapillonne
- the Neonatal Intensive Care Unit, Necker-Enfants Malades Hospital, Paris University, Paris, France
- the CNRC, Department of Pediatrics, Baylor College of Medicine, Houston, TX
| | - Veronica Luque
- Serra Hunter, Universitat Rovira I Virgili, IISPV, Tarragona, Spain
| | - Sissel J Moltu
- the Department of Neonatology, Oslo University Hospital, Oslo, Norway
| | - Miguel Saenz De Pipaon
- the Department of Neonatology, Instituto de Investigación Sanitaria del Hospital Universitario La Paz - IdiPAZ, Hospital Universitario La Paz - Universidad Autónoma de Madrid, Madrid, Spain
| | - Francesco Savino
- the Dipartimento di Patologia e cura del bambino "Regina Margherita", A.U.O. Città delle Salute e della Scienza di Torino, Torino, Italy
| | - Elvira Verduci
- the Department of Pediatrics, Ospedale dei Bambini Vittore Buzzi University of Milan, Milan, Italy
| | - Jiri Bronsky
- the Department of Paediatrics, University Hospital Motol, Prague, Czech Republic
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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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Kounatidis D, Vallianou NG, Tsilingiris D, Christodoulatos GS, Geladari E, Stratigou T, Karampela I, Dalamaga M. Therapeutic Potential of GLP-2 Analogs in Gastrointestinal Disorders: Current Knowledge, Nutritional Aspects, and Future Perspectives. Curr Nutr Rep 2022; 11:618-642. [PMID: 35933503 DOI: 10.1007/s13668-022-00433-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/25/2022] [Indexed: 01/31/2023]
Abstract
PURPOSE OF REVIEW Although Glucagon-like peptide (GLP)-1 receptor agonists have been used for almost two decades in the treatment of diabetes mellitus type 2 and, lately, in obesity, recent years have seen an increasing interest in the pharmacological agonism of other proglucagon-derived peptides, including GLP-2. Herein, we aimed to review the available evidence on the effects of GLP-2 agonism from animal and clinical studies. Furthermore, we summarize the current clinical applications of GLP-2 agonists among patients with intestinal failure associated with short bowel syndrome (SBS-IF) as well as potential future expansion of their indications to other intestinal disorders. RECENT FINDINGS Evidence from preclinical studies has highlighted the cellular trophic and functional beneficial actions of GLP-2 on small intestinal and colonic mucosa. Subsequently, pharmacologic agonism of GLP-2 has gathered interest for the treatment of patients with conditions pertaining to the loss of intestinal anatomical and/or functional integrity to a degree requiring parenteral support, collectively referred to as intestinal failure. GLP-2 analogs positively influence nutrient absorption in animal models and humans, although continued therapy is likely needed for sustained effects. The degradation-resistant GLP-2-analog teduglutide has received approval for the treatment of SBS-IF, in which it may decisively reduce patient dependency on parenteral support and improve quality of life. Another two longer-acting analogs, glepaglutide and apraglutide, are currently undergoing phase III clinical trials. The use of GLP-2 analogs is effective in the management of SBS-IF and may show promise in the treatment of other severe gastrointestinal disorders associated with loss of effective intestinal resorptive surface area.
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Affiliation(s)
- Dimitris Kounatidis
- Departments of Internal Medicine and Endocrinology, Evangelismos General Hospital, 45-47 Ypsilantou Street, 10676, Athens, Greece
| | - Natalia G Vallianou
- Departments of Internal Medicine and Endocrinology, Evangelismos General Hospital, 45-47 Ypsilantou Street, 10676, Athens, Greece.
| | - Dimitrios Tsilingiris
- First Department of Propaedeutic Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, Laiko General Hospital, 17 St Thomas Street, 11527, Athens, Greece
| | - Gerasimos Socrates Christodoulatos
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias, Goudi, 11527, Athens, Greece
| | - Eleni Geladari
- Departments of Internal Medicine and Endocrinology, Evangelismos General Hospital, 45-47 Ypsilantou Street, 10676, Athens, Greece
| | - Theodora Stratigou
- Departments of Internal Medicine and Endocrinology, Evangelismos General Hospital, 45-47 Ypsilantou Street, 10676, Athens, Greece
| | - Irene Karampela
- 2nd Department of Critical Care, Medical School, University of Athens, Attikon General University Hospital, 1 Rimini Street, Chaidari, 12462, Athens, Greece
| | - Maria Dalamaga
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias, Goudi, 11527, Athens, Greece.
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Zorzetti N, D'Andrea V, Lauro A. Proteomic biomarkers in short bowel syndrome : are we ready to use them in clinical activity? Expert Rev Proteomics 2021; 18:285-293. [PMID: 33910424 DOI: 10.1080/14789450.2021.1924063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Introduction: Short bowel syndrome (SBS) is a clinical condition that can affect childhood and adult patients. Biomarker research is expected to be a new frontier in the clinical application, helpful for patients and health-care systems.Areas covered: SBS is usually a consequence of a massive intestinal resection that leads to an intestinal failure because of the reduction of absorptive surface, bacterial overgrowth, and faster intestinal transit. This new condition requires a multidisciplinary expertise to achieve again digestive autonomy. Parental nutrition (PN) supports nutritional status in SBS patients while the new guidelines on intestinal transplantation confirm its strict indication only for patients at actual risk of death on PN. A PubMed literature review from the 1980s up to date was performed, highlighting proteomic biomarkers and growth factor therapies that have shown so far promising results in SBS patients.Expert opinion: Apart from a few specific biomarkers and growth factors, the discovery of specific molecular events is currently under investigation of the proteomic analysis and could potentially represent fundamental, future changes in prevention, diagnosis, therapeutic management, and experimental practices in SBS.
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Affiliation(s)
- Noemi Zorzetti
- Department of General Surgery, "Ospedale Civile Umberto I", Lugo, Ravenna, Italy
| | - Vito D'Andrea
- Department of Surgical Sciences, La Sapienza University, Rome, Italy
| | - Augusto Lauro
- Department of Surgical Sciences, La Sapienza University, Rome, Italy
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Lv YQ, Wu J, Li XK, Zhang JS, Bellusci S. Role of FGF10/FGFR2b Signaling in Mouse Digestive Tract Development, Repair and Regeneration Following Injury. Front Cell Dev Biol 2019; 7:326. [PMID: 31921841 PMCID: PMC6914673 DOI: 10.3389/fcell.2019.00326] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 11/25/2019] [Indexed: 12/18/2022] Open
Abstract
During embryonic development, the rudimentary digestive tract is initially a tube-like structure. It is composed of epithelial cells surrounded by mesenchymal cells. Reciprocal epithelial–mesenchymal interactions progressively subdivide this primitive tube into distinct functional regions: the tongue, the pharynx, the esophagus, the stomach, the duodenum, the small intestine, the cecum, the large intestine, the colon, and the anus as well as the pancreas and the liver. Fibroblast growth factors (Fgfs) constitute a family of conserved small proteins playing crucial roles during organogenesis, homeostasis, and repair after injury. Among them, fibroblast growth factor 10 (Fgf10) has been reported to orchestrate epithelial–mesenchymal interactions during digestive tract development. In mice, loss of function of Fgf10 as well as its receptor fibroblast growth factor receptor 2b (Fgfr2b) lead to defective taste papillae in the tongue, underdeveloped and defective differentiation of the stomach, duodenal, cecal, and colonic atresias, anorectal malformation, as well as underdeveloped pancreas and liver. Fgf signaling through Fgfr2b receptor is also critical for the repair process after gut injury. In the adult mice, a malabsorption disorder called small bowel syndrome is triggered after massive small bowel resection (SBR). In wild-type mice, SBR leads to a regenerative process called gut adaptation characterized by an increase in the diameter of the remaining small intestine as well as by the presence of deeper crypts and longer villi, altogether leading to increased intestinal surface. Intestinal stem cells are key for this regeneration process. Induction of Fgf10 expression in the Paneth cells located in the crypt following SBR suggests a critical role for this growth factor in the process of gut adaptation.
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Affiliation(s)
- Yu-Qing Lv
- Key Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Institute of Life Sciences, Wenzhou University, Wenzhou, China
| | - Jin Wu
- Institute of Life Sciences, Wenzhou University, Wenzhou, China
| | - Xiao-Kun Li
- Key Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Institute of Life Sciences, Wenzhou University, Wenzhou, China
| | - Jin-San Zhang
- Key Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Institute of Life Sciences, Wenzhou University, Wenzhou, China
| | - Saverio Bellusci
- Key Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Institute of Life Sciences, Wenzhou University, Wenzhou, China.,Department of Internal Medicine II, Cardio-Pulmonary Institute, University of Giessen and Marburg Lung Center, Giessen, Germany
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Seiler KM, Waye SE, Kong W, Kamimoto K, Bajinting A, Goo WH, Onufer EJ, Courtney C, Guo J, Warner BW, Morris SA. Single-Cell Analysis Reveals Regional Reprogramming During Adaptation to Massive Small Bowel Resection in Mice. Cell Mol Gastroenterol Hepatol 2019; 8:407-426. [PMID: 31195149 PMCID: PMC6718927 DOI: 10.1016/j.jcmgh.2019.06.001] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 05/29/2019] [Accepted: 06/03/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The small intestine (SI) displays regionality in nutrient and immunological function. Following SI tissue loss (as occurs in short gut syndrome, or SGS), remaining SI must compensate, or "adapt"; the capacity of SI epithelium to reprogram its regional identity has not been described. Here, we apply single-cell resolution analyses to characterize molecular changes underpinning adaptation to SGS. METHODS Single-cell RNA sequencing was performed on epithelial cells isolated from distal SI of mice following 50% proximal small bowel resection (SBR) vs sham surgery. Single-cell profiles were clustered based on transcriptional similarity, reconstructing differentiation events from intestinal stem cells (ISCs) through to mature enterocytes. An unsupervised computational approach to score cell identity was used to quantify changes in regional (proximal vs distal) SI identity, validated using immunofluorescence, immunohistochemistry, qPCR, western blotting, and RNA-FISH. RESULTS Uniform Manifold Approximation and Projection-based clustering and visualization revealed differentiation trajectories from ISCs to mature enterocytes in sham and SBR. Cell identity scoring demonstrated segregation of enterocytes by regional SI identity: SBR enterocytes assumed more mature proximal identities. This was associated with significant upregulation of lipid metabolism and oxidative stress gene expression, which was validated via orthogonal analyses. Observed upstream transcriptional changes suggest retinoid metabolism and proximal transcription factor Creb3l3 drive proximalization of cell identity in response to SBR. CONCLUSIONS Adaptation to proximal SBR involves regional reprogramming of ileal enterocytes toward a proximal identity. Interventions bolstering the endogenous reprogramming capacity of SI enterocytes-conceivably by engaging the retinoid metabolism pathway-merit further investigation, as they may increase enteral feeding tolerance, and obviate intestinal failure, in SGS.
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Affiliation(s)
- Kristen M Seiler
- Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, Missouri
| | - Sarah E Waye
- Department of Developmental Biology, Washington University School of Medicine in St. Louis, St. Louis, Missouri; Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, Missouri; Center of Regenerative Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri
| | - Wenjun Kong
- Department of Developmental Biology, Washington University School of Medicine in St. Louis, St. Louis, Missouri; Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, Missouri; Center of Regenerative Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri
| | - Kenji Kamimoto
- Department of Developmental Biology, Washington University School of Medicine in St. Louis, St. Louis, Missouri; Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, Missouri; Center of Regenerative Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri
| | - Adam Bajinting
- Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, Missouri
| | - William H Goo
- Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, Missouri
| | - Emily J Onufer
- Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, Missouri
| | - Cathleen Courtney
- Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, Missouri
| | - Jun Guo
- Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, Missouri
| | - Brad W Warner
- Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, Missouri
| | - Samantha A Morris
- Department of Developmental Biology, Washington University School of Medicine in St. Louis, St. Louis, Missouri; Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, Missouri; Center of Regenerative Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
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9
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Radiation-induced oxidative injury of the ileum and colon is alleviated by glucagon-like peptide-1 and -2. JOURNAL OF RADIATION RESEARCH AND APPLIED SCIENCES 2019. [DOI: 10.1016/j.jrras.2015.01.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Safety and Efficacy of Teduglutide (Gattex) in Patients With Crohn's Disease and Need for Parenteral Support Due to Short Bowel Syndrome-associated Intestinal Failure. J Clin Gastroenterol 2017; 51:508-511. [PMID: 27433811 PMCID: PMC5243925 DOI: 10.1097/mcg.0000000000000604] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Teduglutide is a GLP-2 analogue indicated for treatment of adults with short bowel syndrome (SBS). Because of the rarity of SBS, real-world safety or efficacy data are not available in patients with Crohn's disease (CD) and SBS treated with teduglutide. AIM To evaluate teduglutide's safety and efficacy in CD patients with SBS. METHODS We conducted a retrospective cohort study at 3 tertiary centers in the United States between 2012 and 2014. Demographic, clinical, and therapeutic data were retrieved from medical record systems. RESULTS Thirteen CD patients were included, 8 (62%) of whom were on concomitant immunosuppression. Median duration of teduglutide therapy was 365 days [interquartile range (IQR), 122 to 482 d] and 9/13 patients (69%) remain on therapy. At teduglutide initiation, 69% were on parenteral nutrition. At conclusion of follow-up, 1 patient was on parenteral nutrition. All patients were on intravenous fluids (IVF) before teduglutide; median IVF were 9000 mL/wk (IQR, 7000 to 14,000 mL/wk). IVF requirements decreased by a median of 3100 mL/wk (IQR, 2400 to 8400 mL/wk). Six patients (46%) ceased IVF. Adverse events attributed to teduglutide were obstructive symptoms (n=1), pancreatitis (n=1), asymptomatic lipase and amylase elevation (n=1), nausea (n=1), and abdominal pain (n=1). Catheter-related sepsis occurred in 4 patients. CONCLUSIONS This is the first report evaluating the safety and efficacy of teduglutide in a cohort of CD patients with SBS requiring parenteral support. More of half the cohort was on concomitant immunosuppression. Teduglutide seemed to be safe and the majority of patients were weaned off parenteral support.
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Danopoulos S, Schlieve CR, Grikscheit TC, Al Alam D. Fibroblast Growth Factors in the Gastrointestinal Tract: Twists and Turns. Dev Dyn 2017; 246:344-352. [PMID: 28198118 DOI: 10.1002/dvdy.24491] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Revised: 02/02/2017] [Accepted: 02/06/2017] [Indexed: 12/15/2022] Open
Abstract
Fibroblast growth factors (FGFs) are a family of conserved peptides that play an important role in the development, homeostasis, and repair processes of many organ systems, including the gastrointestinal tract. All four FGF receptors and several FGF ligands are present in the intestine. They play important roles in controlling cell proliferation, differentiation, epithelial cell restitution, and stem cell maintenance. Several FGFs have also been proven to be protective against gastrointestinal diseases such as inflammatory bowel diseases or to aid in regeneration after intestinal loss associated with short bowel syndrome. Herein, we review the multifaceted actions of canonical FGFs in intestinal development, homeostasis, and repair in rodents and humans. Developmental Dynamics 246:344-352, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Soula Danopoulos
- Developmental Biology and Regenerative Medicine Program, Department of Pediatric Surgery, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA.,Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Christopher R Schlieve
- Developmental Biology and Regenerative Medicine Program, Department of Pediatric Surgery, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA.,Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Tracy C Grikscheit
- Developmental Biology and Regenerative Medicine Program, Department of Pediatric Surgery, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA.,Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Denise Al Alam
- Developmental Biology and Regenerative Medicine Program, Department of Pediatric Surgery, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA.,Keck School of Medicine, University of Southern California, Los Angeles, CA
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12
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Zhang Z, Wu X, Cao L, Zhong Z, Zhou Y. Generation of glucagon-like peptide-2-expressing Saccharomyces cerevisiae and its improvement of the intestinal health of weaned rats. Microb Biotechnol 2016; 9:846-857. [PMID: 27641625 PMCID: PMC5072200 DOI: 10.1111/1751-7915.12412] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Revised: 08/15/2016] [Accepted: 08/20/2016] [Indexed: 02/05/2023] Open
Abstract
We aimed to assess the feasibility of enhancing the intestinal development of weaned rats using glucagon-like peptide-2 (GLP-2)-expressing Saccharomyces cerevisiae (S. cerevisiae). GLP-2-expressing S. cerevisiae (GLP2-SC) was generated using a recombinant approach. The diet of weaned rats was supplemented with the GLP2-SC strain. The average daily gain (ADG), the intestinal morphology and the activities of the digestive enzymes in the jejunum were tested to assess the influence of the GLP2-SC strain on intestinal development. The proliferation of rat enterocytes was also assessed in vitro. The study revealed that the ADG of the weaned rats that received GLP2-SC was significantly greater than that of the controls fed a basal diet (Control) and S. cerevisiae harbouring an empty vector (EV-SC) (P < 0.05) but was equivalent to that of positive control rats fed recombinant human GLP-2 (rh-GLP2) (P > 0.05). Furthermore, GLP2-SC significantly increased villous height (P < 0.01) and digestive enzyme activity (P < 0.05) in the jejunum. Immunohistochemistry analysis further affirmed that enterocyte proliferation was stimulated in rats fed the GLP2-SC strain, as indicated by the greater number of enterocytes stained with proliferative cell nuclear antigen (P < 0.05). In vitro, the proliferation of rat enterocytes was also stimulated by GLP-2 expressed by the GLP2-SC strain (P < 0.01). Herein, the combination of the GLP-2 approach and probiotic delivery constitute a possible dietary supplement for animals after weaning.
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Affiliation(s)
- Zhongwei Zhang
- Department of Intensive Care Unit, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Xiaodong Wu
- Hospital of Chengdu Office of People's Government of Tibetan Autonomous Region, Chengdu, Sichuan, 610041, China
| | - Lili Cao
- Medical School, Chengdu University, Chengdu, Sichuan, 610041, China
| | - Zhengdong Zhong
- Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan, 610041, China
| | - Yan Zhou
- Department of Intensive Care Unit, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
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13
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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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14
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Wiśniewski K, Sueiras-Diaz J, Jiang G, Galyean R, Lu M, Thompson D, Wang YC, Croston G, Posch A, Hargrove DM, Wiśniewska H, Laporte R, Dwyer JJ, Qi S, Srinivasan K, Hartwig J, Ferdyan N, Mares M, Kraus J, Alagarsamy S, Rivière PJM, Schteingart CD. Synthesis and Pharmacological Characterization of Novel Glucagon-like Peptide-2 (GLP-2) Analogues with Low Systemic Clearance. J Med Chem 2016; 59:3129-39. [DOI: 10.1021/acs.jmedchem.5b01909] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Kazimierz Wiśniewski
- Ferring
Research Institute Inc., 4245 Sorrento
Valley Boulevard, San Diego, California 92121, United States
| | - Javier Sueiras-Diaz
- Ferring
Research Institute Inc., 4245 Sorrento
Valley Boulevard, San Diego, California 92121, United States
| | - Guangcheng Jiang
- Ferring
Research Institute Inc., 4245 Sorrento
Valley Boulevard, San Diego, California 92121, United States
| | - Robert Galyean
- Ferring
Research Institute Inc., 4245 Sorrento
Valley Boulevard, San Diego, California 92121, United States
| | - Mark Lu
- Ferring
Research Institute Inc., 4245 Sorrento
Valley Boulevard, San Diego, California 92121, United States
| | - Dorain Thompson
- Ferring
Research Institute Inc., 4245 Sorrento
Valley Boulevard, San Diego, California 92121, United States
| | - Yung-Chih Wang
- Ferring
Research Institute Inc., 4245 Sorrento
Valley Boulevard, San Diego, California 92121, United States
| | - Glenn Croston
- Ferring
Research Institute Inc., 4245 Sorrento
Valley Boulevard, San Diego, California 92121, United States
| | - Alexander Posch
- Ferring
Research Institute Inc., 4245 Sorrento
Valley Boulevard, San Diego, California 92121, United States
| | - Diane M. Hargrove
- Ferring
Research Institute Inc., 4245 Sorrento
Valley Boulevard, San Diego, California 92121, United States
| | - Halina Wiśniewska
- Ferring
Research Institute Inc., 4245 Sorrento
Valley Boulevard, San Diego, California 92121, United States
| | - Régent Laporte
- Ferring
Research Institute Inc., 4245 Sorrento
Valley Boulevard, San Diego, California 92121, United States
| | - John J. Dwyer
- Ferring
Research Institute Inc., 4245 Sorrento
Valley Boulevard, San Diego, California 92121, United States
| | - Steve Qi
- Ferring
Research Institute Inc., 4245 Sorrento
Valley Boulevard, San Diego, California 92121, United States
| | - Karthik Srinivasan
- Ferring
Research Institute Inc., 4245 Sorrento
Valley Boulevard, San Diego, California 92121, United States
| | - Jennifer Hartwig
- Ferring
Research Institute Inc., 4245 Sorrento
Valley Boulevard, San Diego, California 92121, United States
| | - Nicky Ferdyan
- Ferring
Research Institute Inc., 4245 Sorrento
Valley Boulevard, San Diego, California 92121, United States
| | - Monica Mares
- Ferring
Research Institute Inc., 4245 Sorrento
Valley Boulevard, San Diego, California 92121, United States
| | - John Kraus
- Ferring
Research Institute Inc., 4245 Sorrento
Valley Boulevard, San Diego, California 92121, United States
| | - Sudarkodi Alagarsamy
- Ferring
Research Institute Inc., 4245 Sorrento
Valley Boulevard, San Diego, California 92121, United States
| | - Pierre J. M. Rivière
- Ferring
Research Institute Inc., 4245 Sorrento
Valley Boulevard, San Diego, California 92121, United States
| | - Claudio D. Schteingart
- Ferring
Research Institute Inc., 4245 Sorrento
Valley Boulevard, San Diego, California 92121, United States
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15
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Chen J, Qin Z, Shan H, Xiao Y, Cai W. Early Adaptation of Small Intestine After Massive Small Bowel Resection in Rats. IRANIAN JOURNAL OF PEDIATRICS 2015; 25:e530. [PMID: 26396708 PMCID: PMC4575806 DOI: 10.5812/ijp.530] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Accepted: 12/22/2014] [Indexed: 02/08/2023]
Abstract
BACKGROUND It is important that the residual bowel adapts after massive resection. The necessary intestinal adaptation is a progressive recovery from intestinal failure through increase in absorptive surface area and functional capacity and includes both morphological and functional adaptations. OBJECTIVES The aim of this study was to investigate intestinal morphological and functional adaptations of small bowel syndrome (SBS) model rats (SBS1W) 7 days after bowel resection. MATERIALS AND METHODS Male sprague-dawley rats (n = 20/group) underwent either a 75% proximal small bowel resection (SBS1W group) or a control operation (control group). Markers of morphological adaptation were revealed by TEM analysis of H&E-stained tissue samples. The intestinal barrier condition was assessed by BT, and sIgA concentration in intestinal mucus was measured by ELISA. Contractility and the slow wave rhythm of the entire intestinal remnant were measured and recorded. RESULTS The SBS1W group experienced more weight loss than control group and had a clearly different intestinal morphology as revealed in TEM images. Compared with control rats, the SBS1W group had a lower sIgA concentration in intestinal mucus and higher BT to lymph nodes (70% vs 40%; level I), portal blood (40% vs 10%; level II), and peripheral blood (60% vs 30%; level III). Disorder of spontaneous rhythmic contraction, irregular amplitude, and slow frequency were detected in the SBS1W group by a muscle strips test. Similarly, the slow wave of the entire intestinal remnant in the SBS1W group was irregular and uncoordinated. CONCLUSIONS The finding of intestinal adaptation following massive SBR in SBS1W rats provides more understanding of the mechanisms of progressive recovery from the intestinal failure that underlies SBS. The mechanical, chemical, immunological, and biological barriers were all impaired at 7 days following bowel resection, indicating that the SBS model rats were still in the intestinal adaptation phase.
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Affiliation(s)
- Jie Chen
- Department of Pediatric Surgery, Xin Hua Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Zhen Qin
- Department of Pediatric Surgery, Xin Hua Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Hongmei Shan
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute of Pediatric Research, Shanghai Jiao Tong University, Shanghai, China
| | - Yongtao Xiao
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute of Pediatric Research, Shanghai Jiao Tong University, Shanghai, China
| | - Wei Cai
- Department of Pediatric Surgery, Xin Hua Hospital, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute of Pediatric Research, Shanghai Jiao Tong University, Shanghai, China
- Corresponding author: Wei Cai, Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute of Pediatric Research, Shanghai Jiao Tong University, Shanghai, China. Tel: +86-2125078425, E-mail:
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16
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Wu J, Qi K, Xu Z, Wan J. Glucagon-like peptide-2-loaded microspheres as treatment for ulcerative colitis in the murine model. J Microencapsul 2015. [PMID: 26218715 DOI: 10.3109/02652048.2015.1065923] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Glucagon-like peptide-2 (GLP-2) is an intestinal hormone that promotes intestinal growth, but the rapid degradation by dipeptidyl peptidase-IV limits its applications. PLGA microsphere is a well-developed drug delivery system, while seldom been studied as a solution for prolonging in vivo effects of GLP-2. In this study, we encapsulated porcine GLP-2 (pGLP-2) into microspheres and investigated its therapeutic effects in dextran sulfate sodium (DSS)-treated mice. pGLP-2 microspheres showed 20.36% in initial burst and constant release for at least 9 d. In the DSS-treated mice, a single injection of GLP-2 microspheres significantly increased the body weight, colonic length, small intestinal weight and mRNA expression of Occludin, decreased the colonic damage score, mRNA expression of IL-6, IL-10, TNF-α and IFN-γ. In conclusion, pGLP-2 microspheres were resistant to degradation and decreased the severity of DSS-induced ulcerative colitis which suggested that GLP-2-loaded microspheres could be a proper candidate for the treatment of ulcerative colitis.
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Affiliation(s)
- Jie Wu
- a Institute of Animal Husbandry and Veterinary Science, Zhejiang Academy of Agricultural Sciences , Hangzhou , People's Republic of China
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17
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He S, Liang XF, Li L, Sun J, Wen ZY, Cheng XY, Li AX, Cai WJ, He YH, Wang YP, Tao YX, Yuan XC. Transcriptome analysis of food habit transition from carnivory to herbivory in a typical vertebrate herbivore, grass carp Ctenopharyngodon idella. BMC Genomics 2015; 16:15. [PMID: 25608568 PMCID: PMC4307112 DOI: 10.1186/s12864-015-1217-x] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2014] [Accepted: 01/02/2015] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Although feeding behavior and food habit are ecologically and economically important properties, little is known about formation and evolution of herbivory. Grass carp (Ctenopharyngodon idella) is an ecologically appealing model of vertebrate herbivore, widely cultivated in the world as edible fish or as biological control agents for aquatic weeds. Grass carp exhibits food habit transition from carnivory to herbivory during development. However, currently little is known about the genes regulating the unique food habit transition and the formation of herbivory, and how they could achieve higher growth rates on plant materials, which have a relatively poor nutritional quality. RESULTS We showed that grass carp fed with duckweed (modeling fish after food habit transition) had significantly higher relative length of gut than fish before food habit transition or those fed with chironomid larvae (fish without transition). Using transcriptome sequencing, we identified 10,184 differentially expressed genes between grass carp before and after transition in brain, liver and gut. By eliminating genes potentially involved in development (via comparing fish with or without food habit transition), we identified changes in expression of genes involved in cell proliferation and differentiation, appetite control, circadian rhythm, and digestion and metabolism between fish before and after food habit transition. Up-regulation of GHRb, Egfr, Fgf, Fgfbp1, Insra, Irs2, Jak, STAT, PKC, PI3K expression in fish fed with duckweed, consistent with faster gut growth, could promote the food habit transition. Grass carp after food habit transition had increased appetite signal in brain. Altered expressions of Per, Cry, Clock, Bmal2, Pdp, Dec and Fbxl3 might reset circadian phase of fish after food habit transition. Expression of genes involved in digestion and metabolism were significantly different between fish before and after the transition. CONCLUSIONS We suggest that the food habit transition from carnivory to herbivory in grass carp might be due to enhanced gut growth, increased appetite, resetting of circadian phase and enhanced digestion and metabolism. We also found extensive alternative splicing and novel transcript accompanying food habit transition. These differences together might account for the food habit transition and the formation of herbivory in grass carp.
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Affiliation(s)
- Shan He
- Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, College of Fisheries, Huazhong Agricultural University, Hubei Collaborative Innovation Center for Freshwater Aquaculture, 430070, Wuhan, China.
| | - Xu-Fang Liang
- Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, College of Fisheries, Huazhong Agricultural University, Hubei Collaborative Innovation Center for Freshwater Aquaculture, 430070, Wuhan, China.
| | - Ling Li
- Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, College of Fisheries, Huazhong Agricultural University, Hubei Collaborative Innovation Center for Freshwater Aquaculture, 430070, Wuhan, China.
| | - Jian Sun
- Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, College of Fisheries, Huazhong Agricultural University, Hubei Collaborative Innovation Center for Freshwater Aquaculture, 430070, Wuhan, China.
| | - Zheng-Yong Wen
- Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, College of Fisheries, Huazhong Agricultural University, Hubei Collaborative Innovation Center for Freshwater Aquaculture, 430070, Wuhan, China.
| | - Xiao-Yan Cheng
- Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, College of Fisheries, Huazhong Agricultural University, Hubei Collaborative Innovation Center for Freshwater Aquaculture, 430070, Wuhan, China.
| | - Ai-Xuan Li
- Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, College of Fisheries, Huazhong Agricultural University, Hubei Collaborative Innovation Center for Freshwater Aquaculture, 430070, Wuhan, China.
| | - Wen-Jing Cai
- Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, College of Fisheries, Huazhong Agricultural University, Hubei Collaborative Innovation Center for Freshwater Aquaculture, 430070, Wuhan, China.
| | - Yu-Hui He
- Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, College of Fisheries, Huazhong Agricultural University, Hubei Collaborative Innovation Center for Freshwater Aquaculture, 430070, Wuhan, China.
| | - Ya-Ping Wang
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, 430072, Wuhan, China.
| | - Ya-Xiong Tao
- Department of Anatomy, Physiology, and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, 36849-5519, USA.
| | - Xiao-Chen Yuan
- Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, College of Fisheries, Huazhong Agricultural University, Hubei Collaborative Innovation Center for Freshwater Aquaculture, 430070, Wuhan, China.
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18
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Sangild PT, Ney DM, Sigalet DL, Vegge A, Burrin D. Animal models of gastrointestinal and liver diseases. Animal models of infant short bowel syndrome: translational relevance and challenges. Am J Physiol Gastrointest Liver Physiol 2014; 307:G1147-68. [PMID: 25342047 PMCID: PMC4269678 DOI: 10.1152/ajpgi.00088.2014] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Intestinal failure (IF), due to short bowel syndrome (SBS), results from surgical resection of a major portion of the intestine, leading to reduced nutrient absorption and need for parenteral nutrition (PN). The incidence is highest in infants and relates to preterm birth, necrotizing enterocolitis, atresia, gastroschisis, volvulus, and aganglionosis. Patient outcomes have improved, but there is a need to develop new therapies for SBS and to understand intestinal adaptation after different diseases, resection types, and nutritional and pharmacological interventions. Animal studies are needed to carefully evaluate the cellular mechanisms, safety, and translational relevance of new procedures. Distal intestinal resection, without a functioning colon, results in the most severe complications and adaptation may depend on the age at resection (preterm, term, young, adult). Clinically relevant therapies have recently been suggested from studies in preterm and term PN-dependent SBS piglets, with or without a functional colon. Studies in rats and mice have specifically addressed the fundamental physiological processes underlying adaptation at the cellular level, such as regulation of mucosal proliferation, apoptosis, transport, and digestive enzyme expression, and easily allow exogenous or genetic manipulation of growth factors and their receptors (e.g., glucagon-like peptide 2, growth hormone, insulin-like growth factor 1, epidermal growth factor, keratinocyte growth factor). The greater size of rats, and especially young pigs, is an advantage for testing surgical procedures and nutritional interventions (e.g., PN, milk diets, long-/short-chain lipids, pre- and probiotics). Conversely, newborn pigs (preterm or term) and weanling rats provide better insights into the developmental aspects of treatment for SBS in infants owing to their immature intestines. The review shows that a balance among practical, economical, experimental, and ethical constraints will determine the choice of SBS model for each clinical or basic research question.
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Affiliation(s)
- Per T. Sangild
- 1Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Frederiksberg, Denmark; ,2Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark;
| | - Denise M. Ney
- 3Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin;
| | | | - Andreas Vegge
- 1Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Frederiksberg, Denmark; ,5Diabetes Pharmacology, Novo Nordisk, Måløv, Denmark; and
| | - Douglas Burrin
- 6USDA-ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas
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Finch PW, Mark Cross LJ, McAuley DF, Farrell CL. Palifermin for the protection and regeneration of epithelial tissues following injury: new findings in basic research and pre-clinical models. J Cell Mol Med 2014; 17:1065-87. [PMID: 24151975 PMCID: PMC4118166 DOI: 10.1111/jcmm.12091] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2013] [Revised: 05/06/2013] [Accepted: 05/15/2013] [Indexed: 02/06/2023] Open
Abstract
Keratinocyte growth factor (KGF) is a paracrine-acting epithelial mitogen produced by cells of mesenchymal origin, that plays an important role in protecting and repairing epithelial tissues. Pre-clinical data initially demonstrated that a recombinant truncated KGF (palifermin) could reduce gastrointestinal injury and mortality resulting from a variety of toxic exposures. Furthermore, the use of palifermin in patients with hematological malignancies reduced the incidence and duration of severe oral mucositis experienced after intensive chemoradiotherapy. Based upon these findings, as well as the observation that KGF receptors are expressed in many, if not all, epithelial tissues, pre-clinical studies have been conducted to determine the efficacy of palifermin in protecting different epithelial tissues from toxic injury in an attempt to model various clinical situations in which it might prove to be of benefit in limiting tissue damage. In this article, we review these studies to provide the pre-clinical background for clinical trials that are described in the accompanying article and the rationale for additional clinical applications of palifermin.
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20
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Chen J, Du L, Xiao YT, Cai W. Disruption of interstitial cells of Cajal networks after massive small bowel resection. World J Gastroenterol 2013; 19:3415-3422. [PMID: 23801833 PMCID: PMC3683679 DOI: 10.3748/wjg.v19.i22.3415] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2012] [Revised: 02/22/2013] [Accepted: 04/16/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the disruptions of interstitial cells of Cajal (ICC) in the remaining bowel in rats after massive small bowel resection (mSBR).
METHODS: Thirty male Sprague-Dawley rats fitting entry criteria were divided randomly into three experimental groups (n = 10 each): Group A rats underwent bowel transection and re-anastomosis (sham) and tissue samples were harvested at day 7 post-surgery. Group B and C rats underwent 80% small bowel resection with tissue harvested from Group B rats at day 7 post-surgery, and from Group C rats at day 14 post-surgery. The distribution of ICC at the site of the residual small bowel was evaluated by immunohistochemical analysis of small intestine samples. The ultrastructural changes of ICC in the remnant ileum of model rats 7 and 14 d after mSBR were analyzed by transmission electron microscopy. Intracellular recordings of slow wave oscillations were used to evaluate electrical pacemaking. The protein expression of c-kit, ICC phenotypic markers, and membrane-bound stem cell factor (mSCF) in intestinal smooth muscle of each group were detected by Western blotting.
RESULTS: After mSBR, immunohistochemical analysis indicated that the number of c-kit-positive cells was dramatically decreased in Group B rats compared with sham tissues. Significant ultrastructural changes in ICC with associated smooth muscle hypertrophy were also observed. Disordered spontaneous rhythmic contractions with reduced amplitude (8.5 ± 1.4 mV vs 24.8 ± 1.3 mV, P = 0.037) and increased slow wave frequency (39.5 ± 2.1 cycles/min vs 33.0 ± 1.3 cycles/min, P = 0.044) were found in the residual intestinal smooth muscle 7 d post mSBR. The contractile function and electrical activity of intestinal circular smooth muscle returned to normal levels at 14 d post mSBR (amplitude, 14.9 ± 1.6 mV vs 24.8 ± 1.3 mV; frequency, 30.7 ± 1.7 cycles/min vs 33.0 ± 1.3 cycles/min). The expression of Mscf and c-kit protein was decreased at 7 d (P = 0.026), but gradually returned to normal levels at 14 d. The ICC and associated neural networks were disrupted, which was associated with the phenotype alterations of ICC.
CONCLUSION: Massive small bowel resection in rats triggered damage to ICC networks and decreased the number of ICC leading to disordered intestinal rhythmicity. The mSCF/c-kit signaling pathway plays a role in the regulation and maintenance of ICC phenotypes.
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MESH Headings
- Animals
- Biomarkers/metabolism
- Blotting, Western
- Gastrointestinal Motility
- Hypertrophy
- Immunohistochemistry
- Interstitial Cells of Cajal/metabolism
- Interstitial Cells of Cajal/pathology
- Interstitial Cells of Cajal/ultrastructure
- Intestine, Small/innervation
- Intestine, Small/metabolism
- Intestine, Small/pathology
- Intestine, Small/physiopathology
- Intestine, Small/surgery
- Male
- Microscopy, Electron, Transmission
- Muscle, Smooth/pathology
- Muscle, Smooth/physiopathology
- Phenotype
- Proto-Oncogene Proteins c-kit/metabolism
- Rats
- Rats, Sprague-Dawley
- Signal Transduction
- Stem Cell Factor/metabolism
- Time Factors
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21
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Janssen P, Rotondo A, Mulé F, Tack J. Review article: a comparison of glucagon-like peptides 1 and 2. Aliment Pharmacol Ther 2013; 37:18-36. [PMID: 23121085 DOI: 10.1111/apt.12092] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2012] [Revised: 07/09/2012] [Accepted: 09/29/2012] [Indexed: 12/18/2022]
Abstract
BACKGROUND Recent advancements in understanding the roles and functions of glucagon-like peptide 1 (GLP-1) and 2 (GLP-2) have provided a basis for targeting these peptides in therapeutic strategies. AIM To summarise the preclinical and clinical research supporting the discovery of new therapeutic molecules targeting GLP-1 and GLP-2. METHODS This review is based on a comprehensive PubMed search, representing literature published during the past 30 years related to GLP-1 and GLP-2. RESULTS Although produced and secreted together primarily from L cells of the intestine in response to ingestion of nutrients, GLP-1 and GLP-2 exhibit distinctive biological functions that are governed by the expression of their respective receptors, GLP-1R and GLP-2R. Through widespread expression in the pancreas, intestine, nervous tissue, et cetera, GLP-1Rs facilitates an incretin effect along with effects on appetite and satiety. GLP-1 analogues resistant to degradation by dipeptidyl peptidase-IV and inhibitors of dipeptidyl peptidase-IV have been developed to aid treatment of diabetes and obesity. The GLP-2R is expressed almost exclusively in the stomach and bowel. The most apparent role for GLP-2 is its promotion of growth and function of intestinal mucosa, which has been targeted for therapies that promote repair and adaptive growth. These are used as treatments for intestinal failure and related conditions. CONCLUSIONS Our growing understanding of the biology and function of GLP-1, GLP-2 and corresponding receptors has fostered further discovery of fundamental biological function as well as new categories of potent therapeutic medicines.
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Affiliation(s)
- P Janssen
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Belgium
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Matarese LE. Nutrition and Fluid Optimization for Patients With Short Bowel Syndrome. JPEN J Parenter Enteral Nutr 2012; 37:161-70. [DOI: 10.1177/0148607112469818] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Arda-Pirincci P, Oztay F, Bayrak BB, Yanardag R, Bolkent S. Teduglutide, a glucagon-like peptide 2 analogue: a novel protective agent with anti-apoptotic and anti-oxidant properties in mice with lung injury. Peptides 2012; 38:238-47. [PMID: 23059393 DOI: 10.1016/j.peptides.2012.09.030] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2012] [Revised: 09/27/2012] [Accepted: 09/27/2012] [Indexed: 12/31/2022]
Abstract
Teduglutide is a long-acting synthetic analogue of human glucagon-like peptide-2 (GLP-2). GLP-2 regulates cell proliferation and apoptosis as well as normal physiology in the gastrointestinal tract. In the present study, possible cytoprotective and reparative effects of teduglutide were analyzed on a mouse model with lung injury induced by tumor necrosis factor-alpha (TNF-α) and actinomycin D (Act D). BALB/c mice were divided into six groups: control mice (I), mice injected intraperitoneally with 15 μg/kg TNF-α (II), 800 μg/kg Act D (III), Act D 2 min prior to TNF-α administration with the same doses (IV), mice injected subcutaneously with 200 μg/kg teduglutide every 12h for 10 consecutive days (V), and mice given Act D 2 min prior to TNF-α administration on day 11 after receiving teduglutide for 10 days (VI). The TNF-α/Act D administration made the lung a sensitive organ to damage. Mice lung subjected to TNF-α/Act D were characterized by the disruption of alveolar wall, induced pulmonary endothelial/epithelial cell apoptosis and expression of active caspase-3. These mice exhibited an increase in lipid peroxidation, glutathione levels, and activities of myeloperoxidase, superoxide dismutase, catalase, glutathione peroxidase and xanthine oxidase, as well as reduced tissue factor and sodium-potassium/ATPase activities. Teduglutide pretreatment regressed the structural damage, cell apoptosis and oxidative stress by reducing lipid peroxidation in mice received TNF-α/Act D. GLP-2 receptors were present on the cell membrane of type II pneumocytes and interstitial cells. Thus, teduglutide can be suggested as a novel protective agent, which possesses anti-apoptotic and anti-oxidant properties, against lung injury.
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Affiliation(s)
- Pelin Arda-Pirincci
- Department of Biology, Faculty of Science, Istanbul University, 34134 Vezneciler, Istanbul, Turkey.
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Chen J, Wen J, Cai W. Smooth muscle adaptation and recovery of contractility after massive small bowel resection in rats. Exp Biol Med (Maywood) 2012; 237:578-84. [PMID: 22581812 DOI: 10.1258/ebm.2012.011338] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Previous studies have suggested that massive small bowel resection (mSBR) compromises the normal intestinal processes of digestion and absorption, and requires an adaptive response to regain full function and reinstate coordinated contractile activity of the circular smooth muscle. This study was designed to investigate spontaneous contractile activity of circular smooth muscle using the mSBR rat model and to determine the functional role of M(2) and M(3) muscarinic acetylcholine receptors (mAChR) in this process. Male Sprague-Dawley rats underwent an 80% proximal SBR or sham operation. Markers of adaptation, including villus and microvillus height, were analyzed by hematoxylin and eosin staining and transmission electron microscopy. Contractility was measured by attaching the distal ileum strips to strain gauge transducers and exposing the tissue to varying doses of the cholinergic agonist carbachol. Protein expressions of M(2)- and M(3)-mAChR in intestinal smooth muscle (ISM) were detected by Western blot. Following mSBR, the ISM showed perturbed spontaneous rhythmic contraction, irregular amplitude and slow frequency by muscle strip test. However, by two weeks after mSBR, the contractile function of circular smooth muscle was found to have returned to normal levels. Protein expression of M(2)-mAChR was down-regulated following mSBR but up-regulated during the adaptive process when contractile activity of circular smooth muscle was regained. These results indicate that smooth muscle contractility was spontaneously restored in rats following mSBR, and involved the acetylcholine receptors M(2) and M(3). Thus, the disrupted contractile response of smooth muscle in short bowel syndrome may be corrected by therapeutic intervention to restore the expressions of M(2)- and M(3)-mAChR to pre-mSBR levels.
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Affiliation(s)
- Jie Chen
- Department of Pediatric Surgery, School of Medicine, Xin Hua Hospital, Shanghai Institute of Pediatric Research, Shanghai Jiao Tong University, 1665 Kong Jiang Road 200092, Shanghai, China
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Vipperla K, O'Keefe SJ. Teduglutide for the treatment of short bowel syndrome. Expert Rev Gastroenterol Hepatol 2011; 5:665-78. [PMID: 22017694 DOI: 10.1586/egh.11.82] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Extensive resection of the intestine impairs its absorptive capacity and results in short bowel syndrome when the nutritional equilibrium is compromised. The remnant intestine adapts structurally to compensate, but nutritional autonomy cannot be achieved in patients with intestinal failure, requiring intravenous fluids and parenteral nutrition (PN) for sustenance of life. PN is expensive and associated with serious complications. Efforts to minimize or eliminate the need for PN heralded research focusing on the therapeutic utility of intrinsic gut factors involved in the postresection adaptation process. With the breakthrough recognition of the intestinotrophic properties of glucagon-like peptide-2, teduglutide, a recombinant analogue of glucagon-like peptide-2, is being investigated as a promising hope to mitigate the requirement of PN. Clinical studies to date have demonstrated a desirable benefit-to-risk profile in regards to its safety and efficacy. If approved for marketing, it will be the first of its class in short bowel syndrome management, offering an innovative therapeutic modality for this debilitating condition.
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Affiliation(s)
- Kishore Vipperla
- Division of General Internal Medicine, University of Pittsburgh Medical Center, 200 Lothrop Street, 933W MUH, Pittsburgh, PA 15213, USA
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Wulkersdorfer B, Kao KK, Agopian VG, Dunn JC, Wu BM, Stelzner M. Growth Factors Adsorbed on Polyglycolic Acid Mesh Augment Growth of Bioengineered Intestinal Neomucosa. J Surg Res 2011; 169:169-78. [DOI: 10.1016/j.jss.2009.11.719] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2009] [Revised: 10/07/2009] [Accepted: 11/18/2009] [Indexed: 01/18/2023]
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Rowland KJ, Brubaker PL. The "cryptic" mechanism of action of glucagon-like peptide-2. Am J Physiol Gastrointest Liver Physiol 2011; 301:G1-8. [PMID: 21527727 DOI: 10.1152/ajpgi.00039.2011] [Citation(s) in RCA: 104] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Glucagon-like peptide-2 (GLP-2) is a peptide hormone with multiple beneficial effects on the intestine, including expansion of the mucosal surface area through stimulation of crypt cell proliferation, as well as enhancement of nutrient digestion and absorption. Recent advances in clinical trials involving GLP-2 necessitate elucidation of the exact signaling pathways by which GLP-2 acts. In particular, the GLP-2 receptor has been localized to several intestinal cell types that do not include the proliferating crypt cells, and the actions of GLP-2 have thus been linked to a complex network of indirect mediators that induce diverse signaling pathways. The intestinotropic actions of GLP-2 on the colon have been shown to be mediated through the actions of keratinocyte growth factor and insulin-like growth factor (IGF)-2, whereas small intestinal growth has been linked to IGF-1, IGF-2, and ErbB ligands, as well as the IGF-1 receptor and ErbB. The cellular source of these mediators remains unclear, but it likely includes the intestinal subepithelial myofibroblasts. Conversely, the anti-inflammatory and blood flow effects of GLP-2 are dependent on vasoactive intestinal polypeptide released from submucosal enteric neurons and nitric oxide, respectively. Finally, recent studies have suggested that GLP-2 not only modulates intestinal stem cell behavior but may also promote carcinogenesis in models of sporadic colon cancer. Further consideration of the molecular cross-talk and downstream signaling pathways mediating the intestinotropic effects of GLP-2 is clearly warranted.
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Effects of probiotics on experimental short-bowel syndrome. Am J Surg 2011; 202:461-8. [PMID: 21722874 DOI: 10.1016/j.amjsurg.2011.03.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2010] [Revised: 03/13/2011] [Accepted: 03/13/2011] [Indexed: 12/27/2022]
Abstract
BACKGROUND This study was performed to analyze the potential benefits of probiotics on experimental short-bowel syndrome (SBS). METHODS Forty-eight male Wistar-Albino rats were used in the study. The animals were divided into 6 groups as follows: control, rats that received probiotics, rats that underwent intestinal transection and anastomosis, rats that underwent anastomosis and received probiotics, rats that underwent 75% intestinal resection, and rats that underwent 75% intestinal resection plus received probiotics. Body weight monitoring, intestinal bowel diameter, villus length and crypt depth measurements, goblet cell count, mitosis, and immunohistochemical evaluation were used for the assessment of intestinal proliferation ability. RESULTS Statistical analysis showed a significant difference in villus length, crypt depth, goblet cell count in villus and crypt, mitosis, and immunohistochemical evaluation in the jejunum when the SBS group was compared with the SBS group that received probiotics. There was no significant difference in these parameters in ileum. CONCLUSIONS This trial clearly has shown that probiotics had a positive impact on jejunum in the experimental SBS.
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Taqi E, Wallace LE, de Heuvel E, Chelikani PK, Zheng H, Berthoud HR, Holst JJ, Sigalet DL. The influence of nutrients, biliary-pancreatic secretions, and systemic trophic hormones on intestinal adaptation in a Roux-en-Y bypass model. J Pediatr Surg 2010; 45:987-95. [PMID: 20438940 DOI: 10.1016/j.jpedsurg.2010.02.036] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2010] [Accepted: 02/03/2010] [Indexed: 01/04/2023]
Abstract
PURPOSE 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.
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Affiliation(s)
- Esmaeel Taqi
- Faculty of Medicine, Division of Pediatric General Surgery, Department of Surgery, University of Calgary, Calgary, Alberta, Canada AB T3B 6A8
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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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Shyntum Y, Iyer SS, Tian J, Hao L, Mannery YO, Jones DP, Ziegler TR. Dietary sulfur amino acid supplementation reduces small bowel thiol/disulfide redox state and stimulates ileal mucosal growth after massive small bowel resection in rats. J Nutr 2009; 139:2272-8. [PMID: 19828685 PMCID: PMC2777475 DOI: 10.3945/jn.109.105130] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Following massive small bowel resection in animal models, the remnant intestine undergoes a dynamic growth response termed intestinal adaptation. Cell growth and proliferation are intimately linked to cellular and extracellular thiol/disulfide redox states, as determined by glutathione (GSH) and GSH disulfide (GSSG) (the major cellular redox system in tissues), and cysteine (Cys) and its disulfide cystine (CySS) (the major redox system in plasma), respectively. The study was designed to determine whether dietary supplementation with sulfur amino acids (SAA) leads to a greater reduction in thiol/disulfide redox state in plasma and small bowel and colonic mucosa and alters gut mucosal growth in an established rat model of short bowel syndrome (SBS). Adult rats underwent 80% jejunal-ileal resection (RX) or small bowel transection (surgical control) and were pair-fed either isonitrogenous, isocaloric SAA-adequate (control) or SAA-supplemented diets (218% increase vs. control diet). Plasma and gut mucosal samples were obtained after 7 d and analyzed for Cys, CySS, GSH, and GSSG concentrations by HPLC. Redox status (E(h)) of the Cys/CySS and GSH/GSSG couples were calculated using the Nernst equation. SAA supplementation led to a greater reduction in E(h) GSH/GSSG in jejunal and ileal mucosa of resected rats compared with controls. Resected SAA-supplemented rats showed increased ileal adaptation (increased full-thickness wet weight, DNA, and protein content compared with RX control-fed rats; increased mucosal crypt depth and villus height compared with all other study groups). These data suggest that SAA supplementation has a trophic effect on ileal adaptation after massive small bowel resection in rats. This finding may have translational relevance as a therapeutic strategy in human SBS.
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Affiliation(s)
- Yvonne Shyntum
- Graduate Program in Molecular and Systems Pharmacology, Graduate Program in Nutrition and Health Sciences, Department of Medicine, and Center for Clinical and Molecular Nutrition, Emory University, Atlanta GA 30322
| | - Smita S. Iyer
- Graduate Program in Molecular and Systems Pharmacology, Graduate Program in Nutrition and Health Sciences, Department of Medicine, and Center for Clinical and Molecular Nutrition, Emory University, Atlanta GA 30322
| | - Junqiang Tian
- Graduate Program in Molecular and Systems Pharmacology, Graduate Program in Nutrition and Health Sciences, Department of Medicine, and Center for Clinical and Molecular Nutrition, Emory University, Atlanta GA 30322
| | - Li Hao
- Graduate Program in Molecular and Systems Pharmacology, Graduate Program in Nutrition and Health Sciences, Department of Medicine, and Center for Clinical and Molecular Nutrition, Emory University, Atlanta GA 30322
| | - Yanci O. Mannery
- Graduate Program in Molecular and Systems Pharmacology, Graduate Program in Nutrition and Health Sciences, Department of Medicine, and Center for Clinical and Molecular Nutrition, Emory University, Atlanta GA 30322
| | - Dean P. Jones
- Graduate Program in Molecular and Systems Pharmacology, Graduate Program in Nutrition and Health Sciences, Department of Medicine, and Center for Clinical and Molecular Nutrition, Emory University, Atlanta GA 30322
| | - Thomas R. Ziegler
- Graduate Program in Molecular and Systems Pharmacology, Graduate Program in Nutrition and Health Sciences, Department of Medicine, and Center for Clinical and Molecular Nutrition, Emory University, Atlanta GA 30322,To whom correspondence should be addressed. E-mail:
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Drozdowski L, Thomson ABR. Intestinal hormones and growth factors: effects on the small intestine. World J Gastroenterol 2009; 15:385-406. [PMID: 19152442 PMCID: PMC2653359 DOI: 10.3748/wjg.15.385] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
There are various hormones and growth factors which may modify the intestinal absorption of nutrients, and which might thereby be useful in a therapeutic setting, such as in persons with short bowel syndrome. In part I, we focus first on insulin-like growth factors, epidermal and transferring growth factors, thyroid hormones and glucocorticosteroids. Part II will detail the effects of glucagon-like peptide (GLP)-2 on intestinal absorption and adaptation, and the potential for an additive effect of GLP2 plus steroids.
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McClave SA, Martindale RG, Vanek VW, McCarthy M, Roberts P, Taylor B, Ochoa JB, Napolitano L, Cresci G. Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr 2009; 33:277-316. [PMID: 19398613 DOI: 10.1177/0148607109335234] [Citation(s) in RCA: 980] [Impact Index Per Article: 61.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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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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Affiliation(s)
- Dileep N Lobo
- Division of Gastrointestinal Surgery, E Floor, West Block, Wolfson Digestive Diseases Centre, Nottingham University Hospitals, Queen's Medical Centre, Nottingham, NG7 2UH, UK.
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Effect of Dietary Fiber and Growth Hormone on Colonic Adaptation in Short Bowel Syndrome Treated by Enteral Nutrition. World J Surg 2008; 32:1832-9. [DOI: 10.1007/s00268-008-9611-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Abstract
Glucagon-like peptide-2 (GLP-2) is a pleiotropic hormone that affects multiple facets of intestinal physiology, including growth, barrier function, digestion, absorption, motility, and blood flow. The mechanisms through which GLP-2 produces these actions are complex, involving unique signaling mechanisms and multiple indirect mediators. As clinical trials have begun for the use of GLP-2 in a variety of intestinal disorders, the elucidation of such mechanisms is vital. The GLP-2 receptor (GLP-2R) is a G protein-coupled receptor, signaling through multiple G proteins to affect the cAMP and mitogen-activated protein kinase pathways, leading to both proliferative and antiapoptotic cellular responses. The GLP-2R also demonstrates unique mechanisms for receptor trafficking. Expression of the GLP-2R in discrete sets of intestinal cells, including endocrine cells, subepithelial myofibroblasts, and enteric neurons, has led to the hypothesis that GLP-2 acts indirectly through multiple mediators to produce its biological effects. Indeed, several studies have now provided important mechanistic data illustrating several of the indirect pathways of GLP-2 action. Thus, insulin-like growth factor I has been demonstrated to be required for GLP-2-induced crypt cell proliferation, likely involving activation of beta-catenin signaling. Furthermore, vasoactive intestinal polypeptide modulates the actions of GLP-2 in models of intestinal inflammation, while keratinocyte growth factor is required for GLP-2-induced colonic mucosal growth and mucin expression. Finally, enteric neural GLP-2R signaling affects intestinal blood flow through a nitric oxide-dependent mechanism. Determining how GLP-2 produces its full range of biological effects, which mediators are involved, and how these mediators interact is a continuing area of active research.
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Affiliation(s)
- Philip E Dubé
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
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Shroyer NF, Helmrath MA, Wang VYC, Antalffy B, Henning SJ, Zoghbi HY. Intestine-specific ablation of mouse atonal homolog 1 (Math1) reveals a role in cellular homeostasis. Gastroenterology 2007; 132:2478-88. [PMID: 17570220 DOI: 10.1053/j.gastro.2007.03.047] [Citation(s) in RCA: 231] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2006] [Accepted: 03/08/2007] [Indexed: 12/25/2022]
Abstract
BACKGROUND & AIMS Math1 (Atoh1) is a basic helix-loop-helix transcription factor important for intestinal secretory cell differentiation. We hypothesized that Math1 is important in cell fate commitment, and therefore mediates proliferative homeostasis and the adaptive response following intestinal resection in the adult intestine. METHODS We generated mice with an intestine-specific mosaic deletion of Math1 (Math1(Delta intestine)) using the Cre/loxP system. Histologic analysis in adult Math1(Delta intestine) and wild-type littermates at baseline and following small bowel resection or sham surgery was performed. RESULTS We observed loss of Paneth, goblet, and enteroendocrine cells in Math1-null crypts. In addition, aberrant activation of the Math1 promoter occurred in absorptive enterocytes derived from Math1-null crypts, suggesting a change in cell fate. Proliferation was increased but apoptosis unchanged in Math1-mutant crypts compared to adjacent wild-type crypts. Math1(Delta intestine) mice and wild-type littermates displayed similar physiologic adaptive responses to small bowel resection as measured by changes in body weight and ileal wet weight. In contrast, Math1-mutant crypts displayed a blunted adaptive response compared to adjacent wild-type crypts. CONCLUSIONS We show that Math1 is essential for adult intestinal secretory cell production, and in its absence cells destined to a secretory phenotype instead adopt an absorptive phenotype. Subtle abnormalities of proliferation within Math1-null crypts in Math1(Delta intestine) mice were identified, together with a substantial defect in the adaptive response of Math1-null crypts following small bowel resection. Our results suggest that Math1 is critical for both cell fate determination within the intestinal epithelium and for regulation of the response to intestinal resection.
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Affiliation(s)
- Noah F Shroyer
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA
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Wang L, Tang Y, Rubin DC, Levin MS. Chronically administered retinoic acid has trophic effects in the rat small intestine and promotes adaptation in a resection model of short bowel syndrome. Am J Physiol Gastrointest Liver Physiol 2007; 292:G1559-69. [PMID: 17307727 DOI: 10.1152/ajpgi.00567.2006] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Following the loss of functional small bowel surface area, the intestine undergoes a compensatory adaptive response. The observation that adaptation is inhibited in vitamin A-deficient rats following submassive intestinal resection suggested that vitamin A is required for this response and raised the possibility that exogenous vitamin A could augment adaptation. Therefore, to directly assess whether chronically administered retinoic acid could stimulate gut adaptation in a model of short bowel syndrome and to address the mechanisms of any such effects, Sprague-Dawley rats were implanted with controlled release retinoic acid or control pellets and then subjected to mid-small bowel or sham resections. At 2 wk postoperation, changes in gut morphology, crypt cell proliferation and apoptosis, enterocyte migration, the extracellular matrix, and gene expression were assessed. Retinoic acid had significant trophic effects in resected and sham-resected rats. Retinoic acid markedly inhibited apoptosis and stimulated crypt cell proliferation and enterocyte migration postresection. Data presented indicate that these proadaptive effects of retinoic acid may be mediated via changes in the extracellular matrix (e.g., by increasing collagen IV synthesis, decreasing E-cadherin expression, and reducing integrin beta(3) levels), via affects on Hedgehog signaling (e.g., by reducing expression of the Hedgehog receptors Ptch and Ptch2 and the Gli1 transcription factor), by increasing expression of Reg1 and Pap1, and by modulation of retinoid and peroxisome proliferator-activated receptor signaling pathways. These studies are the first to demonstrate that retinoic acid can significantly enhance intestinal adaptation and suggest it may be beneficial in patients with short bowel syndrome.
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MESH Headings
- Adaptation, Physiological/drug effects
- Adaptation, Physiological/genetics
- Animals
- Apoptosis/drug effects
- Cell Movement/drug effects
- Cell Proliferation/drug effects
- Disease Models, Animal
- Drug Implants
- Enterocytes/drug effects
- Enterocytes/pathology
- Extracellular Matrix Proteins/metabolism
- Gene Expression/drug effects
- Hedgehog Proteins/metabolism
- Intestine, Small/drug effects
- Intestine, Small/metabolism
- Intestine, Small/pathology
- Intestine, Small/physiopathology
- Intestine, Small/surgery
- Male
- Pancreatitis-Associated Proteins
- Peroxisome Proliferator-Activated Receptors/drug effects
- Peroxisome Proliferator-Activated Receptors/metabolism
- RNA, Messenger/metabolism
- Rats
- Rats, Sprague-Dawley
- Receptors, Retinoic Acid/agonists
- Receptors, Retinoic Acid/genetics
- Receptors, Retinoic Acid/metabolism
- Short Bowel Syndrome/drug therapy
- Short Bowel Syndrome/genetics
- Short Bowel Syndrome/metabolism
- Short Bowel Syndrome/pathology
- Short Bowel Syndrome/physiopathology
- Signal Transduction/drug effects
- Time Factors
- Tretinoin/administration & dosage
- Tretinoin/pharmacology
- Tretinoin/therapeutic use
- Wnt Proteins/metabolism
- beta Catenin/metabolism
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Affiliation(s)
- Lihua Wang
- Washington Univ. School of Medicine, Campus Box 8124, 660 South Euclid Ave., St. Louis, MO 63110, USA
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Tian J, Washizawa N, Gu LH, Levin MS, Wang L, Rubin DC, Mwangi S, Srinivasan S, Gao Y, Jones DP, Ziegler TR. Stimulation of colonic mucosal growth associated with oxidized redox status in rats. Am J Physiol Regul Integr Comp Physiol 2007; 292:R1081-91. [PMID: 17095654 DOI: 10.1152/ajpregu.00050.2006] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Limited data in animal models suggest that colonic mucosa undergoes adaptive growth following massive small bowel resection (SBR). In vitro data suggest that intestinal cell growth is regulated by reactive oxygen species and redox couples [e.g., glutathione (GSH)/glutathione disulfide (GSSG) and cysteine (Cys)/cystine (CySS) redox]. We investigated the effects of SBR and alterations in redox on colonic growth indexes in rats after either small bowel transection (TX) or 80% midjejunoileal resection (RX). Rats were pair fed +/- blockade of endogenous GSH synthesis with buthionine sulfoximine (BSO). Indexes of colonic growth, proliferation, and apoptosis and GSH/GSSG and Cys/CySS redox potentials (E(h)) were determined. RX significantly increased colonic crypt depth, number of cells per crypt, and epithelial cell proliferation [crypt cell bromodeoxyuridine (BrdU) incorporation]. Administration of BSO markedly decreased colonic mucosal GSH, GSSG, and Cys concentrations in both TX and RX groups, with a resultant oxidation of GSH/GSSG and Cys/CySS E(h). BSO did not alter colonic crypt cell apoptosis but significantly increased all colonic mucosal growth indexes (crypt depth, cells/crypt, and BrdU incorporation) in both TX and RX groups in a time- and dose-dependent manner. BSO significantly decreased plasma GSH and GSSG, oxidized GSH/GSSG E(h), and increased plasma Cys and CySS concentrations. Collectively, these data provide in vivo evidence indicating that oxidized colonic mucosal redox status stimulates colonic mucosal growth in rats. The data also suggest that GSH is required to maintain normal colonic and plasma Cys/CySS homeostasis in these animal models.
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Affiliation(s)
- Junqiang Tian
- General Clinical Research Center, Emory University Hospital, 1364 Clifton Road, Atlanta, GA 30322, USA
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Helmrath MA, Fong JJ, Dekaney CM, Henning SJ. Rapid expansion of intestinal secretory lineages following a massive small bowel resection in mice. Am J Physiol Gastrointest Liver Physiol 2007; 292:G215-22. [PMID: 16920699 DOI: 10.1152/ajpgi.00188.2006] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Following massive small bowel resection (SBR) in mice, there are sustained increases in crypt depth and villus height, resulting in enhanced mucosal surface area. The early mechanisms responsible for resetting and sustaining this increase are presently not understood. We hypothesized that expansion of secretory lineages is an early and sustained component of the adaptive response. This was assessed in the ileum by quantitative morphometry at 12 h, 36 h, 7 days, and 28 days and by quantitative RT-PCR of marker mRNAs for proliferation and differentiated goblet, Paneth cell, and enterocyte genes at 12 h after 50% SBR or sham operation. As predicted, SBR elicited increases of both crypt and villus epithelial cells, which were sustained though the 28 days of the experiment. Significant increases in the overall number and percentage of both Paneth and goblet cells within intestinal epithelium occurred by 12 h and were sustained up to 28 days after SBR. The increases of goblet cells after SBR were initially observed within villi at 12 h, with marked increases occurring in crypts at 36 h and 7 days. Consistent with this finding, qRT-PCR demonstrated significant increases in the expression of mRNAs associated with proliferation (c-myc) and differentiated goblet cells (Tff3, Muc2) and Paneth cells (lysozyme), whereas mRNA associated with differentiated enterocytes (sucrase-isomaltase) remained unchanged. From these data, we speculate that early expansion of intestinal secretory lineages within the epithelium of the ileum occurs following SBR, possibly serving to amplify the signal responsible for initiating and sustaining intestinal adaptation.
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Affiliation(s)
- Michael A Helmrath
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
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Abstract
Multiple peptide hormones produced within the gastrointestinal system aid in the regulation of energy homeostasis and metabolism. Among these is the intestinotrophic peptide glucagon-like peptide-2 (GLP-2), which is released following food intake and plays a significant role in the adaptive regulation of bowel mass and mucosal integrity. The discovery of GLP-2's potent growth-promoting and cytoprotective effects in the gastrointestinal (GI) tract stimulated interest in its use as a therapeutic agent for the treatment of GI diseases involving malabsorption, inflammation, and/or mucosal damage. Current research has focused on determining the physiological mechanisms contributing to the effects of GLP-2 and factors regulating its biological mechanisms of action. This chapter provides an overview of the biology of GLP-2 with a focus on the most recent findings on the role of this peptide hormone in the normal and diseased GI tract.
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Affiliation(s)
- Jennifer L Estall
- Department of Laboratory Medicine and Pathobiology, The Banting and Best Diabetes Center, Toronto General Hospital, University of Toronto, Ontario, Canada, M5G 2C4
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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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Abstract
PURPOSE OF REVIEW This review aims to cover the methods and techniques currently used by researchers to evaluate intestinal trophism. RECENT FINDINGS Although subjected to criticisms, conventional gut trophism evaluation by both morphological and histological parameters continues to be largely reported. The metaphase arrest technique and the detection of H-tymidine have been used less frequently in recent years due to increasing interest in the immunohistochemical methods such as 5-bromo-2'deoxy-uridine, Ki-67, and proliferating cell nuclear antigen. Along with common techniques for the evaluation of intestinal trophism, the combination of methods that includes a measurement of cell proliferation and an apoptotic index in the same study are most valuable and are increasing in the current literature. SUMMARY Evaluation of intestinal trophism is an important issue for both clinical and experimental nutritional studies. The immunohistochemical techniques are the gold standard to access cell proliferation. Evaluation of proliferation and apoptosis at the same time may offer a more reliable evaluation of the actual status of gut trophism.
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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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Ziegler TR, Leader LM. Parenteral nutrition: transient or permanent therapy in intestinal failure? Gastroenterology 2006; 130:S37-42. [PMID: 16473070 DOI: 10.1053/j.gastro.2005.09.063] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2005] [Accepted: 09/21/2005] [Indexed: 12/02/2022]
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