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      Intestinal epithelial cell apoptosis and loss of barrier function in the setting of altered microbiota with enteral nutrient deprivation

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          Abstract

          Total parenteral nutrition (TPN), a commonly used treatment for patients who cannot receive enteral nutrition, is associated with significant septic complications due in part to a loss of epithelial barrier function (EBF). While the underlying mechanisms of TPN-related epithelial changes are poorly understood, a mouse model of TPN-dependence has helped identify several contributing factors. Enteral deprivation leads to a shift in intestinal microbiota to predominantly Gram-negative Proteobacteria. This is associated with an increase in expression of proinflammatory cytokines within the mucosa, including interferon-γ and tumor necrosis factor-α. A concomitant loss of epithelial growth factors leads to a decrease in epithelial cell proliferation and increased apoptosis. The resulting loss of epithelial tight junction proteins contributes to EBF dysfunction. These mechanisms identify potential strategies of protecting against TPN-related complications, such as modification of luminal bacteria, blockade of proinflammatory cytokines, or growth factor replacement.

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          Most cited references50

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          Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy.

          The PI3K/Akt signal transduction cascade has been investigated extensively for its roles in oncogenic transformation. Initial studies implicated both PI3K and Akt in prevention of apoptosis. However, more recent evidence has also associated this pathway with regulation of cell cycle progression. Uncovering the signaling network spanning from extracellular environment to the nucleus should illuminate biochemical events contributing to malignant transformation. Here, we discuss PI3K/Akt-mediated signal transduction including its mechanisms of activation, signal transducing molecules, and effects on gene expression that contribute to tumorigenesis. Effects of PI3K/Akt signaling on important proteins controlling cellular proliferation are emphasized. These targets include cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitors. Furthermore, strategies used to inhibit the PI3K/Akt pathway are presented. The potential for cancer treatment with agents inhibiting this pathway is also addressed.
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            Perioperative total parenteral nutrition in surgical patients. The Veterans Affairs Total Parenteral Nutrition Cooperative Study Group.

            G. Buzby (1991)
            We undertook this study to test the hypothesis that perioperative total parenteral nutrition (TPN) decreases the incidence of serious complications after major abdominal or thoracic surgical procedures in malnourished patients. We studied 395 malnourished patients (99 percent of them male) who required laparotomy or noncardiac thoracotomy. They were randomly assigned to receive either TPN for 7 to 15 days before surgery and 3 days afterward (the TPN group) or no perioperative TPN (the control group). The patients were monitored for complications for 90 days after surgery. The rates of major complications during the first 30 days after surgery in the two groups were similar (TPN group, 25.5 percent; control group, 24.6 percent), as were the overall 90-day mortality rates (13.4 percent and 10.5 percent, respectively). There were more infectious complications in the TPN group than in the controls (14.1 vs. 6.4 percent; P = 0.01; relative risk, 2.20; 95 percent confidence interval, 1.19 to 4.05), but slightly more noninfectious complications in the control group (16.7 vs. 22.2 percent; P = 0.20; relative risk, 0.75; 95 percent confidence interval, 0.50 to 1.13). The increased rate of infections was confined to patients categorized as either borderline or mildly malnourished, according to Subjective Global Assessment or an objective nutritional assessment, and these patients had no demonstrable benefit from TPN. In contrast, severely malnourished patients who received TPN had fewer noninfectious complications than controls (5 vs. 43 percent; P = 0.03; relative risk, 0.12; 95 percent confidence interval, 0.02 to 0.91), with no concomitant increase in infectious complications. The use of preoperative TPN should be limited to patients who are severely malnourished unless there are other specific indications.
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              Early enteral feeding, compared with parenteral, reduces postoperative septic complications. The results of a meta-analysis.

              This two-part meta-analysis combined data from eight prospective randomized trials designed to compare the nutritional efficacy of early enteral (TEN) and parenteral (TPN) nutrition in high-risk surgical patients. The combined data gave sufficient patient numbers (TEN, n = 118; TPN, n = 112) to adequately address whether route of substrate delivery affected septic complication incidence. Phase I (dropouts excluded) meta-analysis confirmed data homogeneity across study sites, that TEN and TPN groups were comparable, and that significantly fewer TEN patients experienced septic complications (TEN, 18%; TPN, 35%; p = 0.01). Phase II meta-analysis, an intent-to-treat analysis (dropouts included), confirmed that fewer TEN patients developed septic complications. Further breakdown by patient type showed that all trauma and blunt trauma subgroups had the most significant reduction in septic complications when fed enterally. In conclusion, this meta-analysis attests to the feasibility of early postoperative TEN in high-risk surgical patients and that these patients have reduced septic morbidity rates compared with those administered TPN.
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                Author and article information

                Journal
                Front Cell Infect Microbiol
                Front Cell Infect Microbiol
                Front. Cell. Infect. Microbiol.
                Frontiers in Cellular and Infection Microbiology
                Frontiers Media S.A.
                2235-2988
                23 December 2013
                2013
                : 3
                : 105
                Affiliations
                Section of Pediatric Surgery, Department of Surgery, University of Michigan Health System Ann Arbor, MI, USA
                Author notes

                Edited by: Yongqun He, Virginia Tech, USA

                Reviewed by: Glen C. Ulett, Griffith University, Australia; Eric Ghigo, CNRS, France

                *Correspondence: Daniel H. Teitelbaum, Section of Pediatric Surgery, Mott Children's Hospital, University of Michigan, 1540 E. Hospital Dr., SPC 4211, Ann Arbor, MI 48109-4211, USA e-mail: dttlbm@ 123456umich.edu

                This article was submitted to the journal Frontiers in Cellular and Infection Microbiology.

                Article
                10.3389/fcimb.2013.00105
                3870295
                24392360
                b4592873-e80b-431b-985c-e3949bf6cfb3
                Copyright © 2013 Demehri, Barrett, Ralls, Miyasaka, Feng and Teitelbaum.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 19 October 2013
                : 09 December 2013
                Page count
                Figures: 4, Tables: 0, Equations: 0, References: 64, Pages: 7, Words: 6215
                Categories
                Microbiology
                Review Article

                Infectious disease & Microbiology
                small intestine,parenteral nutrition,epithelial barrier function,microbiome,epithelial cell apoptosis,epithelial call proliferation

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