advances in food and nutrition research volume 56

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  • ADVISORY BOARDSKEN BUCKLEUniversity of New South Wales, Australia

    MARY ELLEN CAMIREUniversity of Maine, USA

    ROGER CLEMENSUniversity of Southern California, USA

    HILDEGARDE HEYMANNUniversity of California, Davis, USA

    ROBERT HUTKINSUniversity of Nebraska, USA

    RONALD JACKSONQuebec, Canada

    HUUB LELIEVELDGlobal Harmonization Initiative, The Netherlands

    DARYL B. LUNDUniversity of Wisconsin, USA

    CONNIE WEAVERPurdue University, USA


  • Academic Press is an imprint of Elsevier30 CorporateDrive, Suite 400, Burlington,MA01803, USA525 B Street, Suite 1900, San Diego, CA 92101-4495, USA32 Jamestown Road, LondonNW1 7BY, UKRadarweg 29, POBox 211, 1000AEAmsterdam, TheNetherlandsLinacreHouse, JordanHill, OxfordOX2 8DP,UK

    First edition 2009

    Copyright# 2009 Elsevier Inc. All rights reserved.

    No part of this publication may be reproduced, stored in a retrievalsystem or transmitted in any form or by any means electronic, mechan-ical, photocopying, recording or otherwise without the prior writtenpermission of the publisher.

    Permissions may be sought directly from Elseviers Science & Technol-ogy Rights Department in Oxford, UK: phone (+44) (0) 1865 843830;fax (+44) (0) 1865 853333; email: Alterna-tively you can submit your request online by visiting the Elsevier website at, and selecting Obtainingpermission to use Elsevier material.

    NoticeNo responsibility is assumed by the publisher for any injury and/ordamage to persons or property as a matter of products liability,negligence or otherwise, or from any use or operation of any methods,products, instructions or ideas contained in thematerial herein. Becauseof rapid advances in the medical sciences, in particular, independentverification of diagnoses and drug dosages should bemade.

    ISBN: 978-0-12-374439-5ISSN: 1043-4526For information on all Academic Press publicationsvisit ourwebsite at elsevierdirect.comPrinted and bound inUSA

    09 10 11 12 10 9 8 7 6 5 4 3 2 1


  • CONTRIBUTORSNumbers in parentheses indicate the pages on which the authors' contributions begin.

    Abby K. van den BergProctor Maple Research Center, University of Vermont, Harvey Road,Underhill Center, Vermont, USA (101)

    Sinead C. CorrDepartment of Biochemistry and Immunology, Trinity College Dublin,Ireland (1)

    Susan E. DuncanVirginia Polytechnic Institute and State University (Virginia Tech),Blacksburg, Virginia, USA (17)

    A. DunnGalvinDepartment of Paediatrics and Child Health, Cork University Hospital,Ireland (65)

    Cormac G. M. GahanDepartment of Microbiology, School of Pharmacy and AlimentaryPharmabiotic Centre, University College Cork, Ireland (1)

    Colin HillDepartment of Microbiology, University College Cork, Ireland (1)

    J O. B. HourihaneDepartment of Paediatrics and Child Health, Cork University Hospital,Ireland (65)

    Timothy D. PerkinsProctor Maple Research Center, University of Vermont, Harvey Road,Underhill Center, Vermont, USA (101)

    R. T. RileyToxicology & Mycotoxin Research Unit, USDA Agricultural ResearchService, Athens, Georgia, USA (145)

    M. C. SpeerCenter for Human Genetics, Duke University Medical Center, Durham,North Carolina, USA (145)vii

  • viii Contributors V. L. StevensDepartment of Epidemiology and Surveillance Research, AmericanCancer Society, Atlanta, Georgia, USA (145)

    K. A. VossToxicology & Mycotoxin Research Unit, USDA Agricultural ResearchService, Athens, Georgia, USA (145)

    J. Gelineau-van WaesDepartment of Genetics, Cell Biology & Anatomy, University ofNebraska Medical Center, Omaha, Nebraska, USA (145)

    Janet B. WebsterVirginia Polytechnic Institute and State University (Virginia Tech),Blacksburg, Virginia, USA (17)

  • CHAPTER 1Advances in Food and NISSN 1043-4526, DOI: 10Understanding the Mechanismsby Which Probiotics InhibitGastrointestinal Pathogens

    Sinead C. Corr,* Colin Hill, and Cormac G. M. GahanContents I. Introduction 2II. Evidence for Potential Mechanisms of Action 4

    A. Epithelial barrier function and

    probiotic signaling 4

    B. Production of acid and secretion of

    inhibitory substances 7

    C. Immunomodulation 8

    D. Inhibition of virulence factor expression 10

    III. Conclusions 11

    Acknowledgment 12

    References 12Abstract In recent years, there has been a growing interest in the use ofprobiotic bacteria for the maintenance of general gastrointestinal

    health and the prevention or treatment of intestinal infections.

    Whilst probiotics are documented to reduce or prevent specific

    infectious diseases of the GI tract, the mechanistic basis of this

    effect remains unclear. It is likely that diverse modes-of-action

    contribute to inhibition of pathogens in the gut environment and

    proposed mechanisms include (i) direct antimicrobial activity

    through production of bacteriocins or inhibitors of virulence gene

    * Department of Biochemistry and Immunology, Trinity College Dublin, Ireland{ Department of Microbiology, University College Cork, Ireland{ Department of Microbiology, School of Pharmacy and Alimentary Pharmabiotic Centre, University CollegeCork, Irelandutrition Research, Volume 56 # 2009 Elsevier Inc..1016/S1043-4526(08)00601-3 All rights reserved.


  • 2 Sinead C. Corr et al.expression; (ii) competitive exclusion by competition for binding

    sites or stimulation of epithelial barrier function; (iii) stimulation of

    immune responses via increases of sIgA and anti-inflammatory

    cytokines and regulation of proinflammatory cytokines; and

    (iv) inhibition of virulence gene or protein expression in gastroin-

    testinal pathogens. In this review, we discuss the modes of action

    by which probiotic bacteria may reduce gastrointestinal infections,

    and highlight some recent research which demonstrates the mech-

    anistic basis of probiotic cause and effect.I. INTRODUCTION

    The gastrointestinal tract is a complex ecosystem which can be a reservoirof both beneficial and harmful bacteria. Recently, there has been interestin the role of the gut microbiota in health, and also in the deliberate use ofbacterial supplements to influence this microbial community in a mannerwhich could potentially assist in maintaining health and in diseaseprevention (Holzapfel et al., 1998; Senok et al., 2005). Probiotics (definedas any live microorganism, that when administered to human or animalhosts, has health-promoting benefits) could potentially offer an alterna-tive to conventional therapies such as antibiotics for the prophylaxis ortreatment of intestinal infections (Bourlioux et al., 2003; Rolfe, 2000).From various in vitro and in vivo studies to date, it is clear that probioticsoffer great potential in prevention and treatment of infections (Table 1.1).However, a thorough understanding of their mechanisms of action isrequired to ensure their efficient use. Probiotics are presumed to modu-late the indigenous intestinal flora and improve health via a plethora ofpotential mechanisms of action, such as immunomodulation, directantagonism, or competitive exclusion (summarized in Fig. 1.1)(Gotteland et al., 2006; Sartor, 2004; Venturi et al., 1999). Probiotics caninhibit growth of enteric pathogens by decreasing luminal pH, the secre-tion of bactericidal peptides/proteins, or the stimulation of defensinproduction by epithelial cells (Toure et al., 2003; Zhu et al., 2000). Probio-tics can also block attachment to or invasion of the intestinal epitheliumby pathogens through blocking of epithelial surface receptors or induc-tion of mucins, large carbohydrate molecules which form a barrier alongthe epithelial monolayer (Mack et al., 1999; Mattar et al., 2002).

    A number of in vivo studies have been performed which have deter-mined the probiotic capabilities of such strains. While these studies havebeen important in demonstrating probiotic efficacy against various infec-tious diseases, few have specifically identified the mechanistic basis behindthe observed benefits, and many rely on in vitro data to decipher thepossible mechanism of action. However, what has emerged to date is that

  • TABLE 1.1 A list of potential probiotic strains and their observed beneficial effects

    Organism Effect Mechanism Reference

    E. coli strain Nissle 1917 Improves epithelial

    barrier function

    Increases tight junction protein

    expression, ZO-2

    Zyrek et al. (2007)

    L. rhamnosus R0011 Improves epithelial

    barrier function

    Prevents the pathogen-induced drop in

    transepithelial resistance

    Sherman et al.


    L. plantarum 299v Improves epithelial

    barrier function

    Increases extracellular secretion of mucin,


    Mack et al. (2003)

    VSL#3 probiotic


    Improves epithelial

    barrier function

    Induces human b-defensin, hBD-2 geneexpression

    Schlee et al. (2008)

    B. breve Yakult Secretion of inhibitory


    Production of acetic acid and thus

    lowering of pH

    Asahara et al.


    L. johnsonii NCC533 Secretion of inhibitory


    Production of hydrogen peroxide Pridmore et al.


    L. salivarius UCC118 Secretion of inhibitory


    Production of bacteriocin Corr et al. (2007b)

    L. casei NCDO1205 Immunomodulation Decrease IL-8 and


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