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A Review on the Interactions Between Gutmicrobiota and Innate Inmunity of Fish

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MI NI R E V I E W Areviewontheinteractions betweengut microbiotaandinnate immunityof ¢sh Geovanny D. G´ omez 1 & Jos ´ e Luis Balc ´ azar 2 1 Mariculture Research Laboratory, Ocean University of China, Qingdao, China; and 2 Instituto de Investigaciones Marinas, Consejo Superior de Investigaciones Cient´ıficas (CSIC), Eduardo Cabello, Vigo, Spain Correspondence: Jos ´ e Luis Balc ´ azar, Instituto de Investigaciones Marinas, Consejo Superior de Investigaciones Cient´ıficas (CSIC), Eduardo Cabell
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  MINIREVIEW Areviewontheinteractionsbetweengutmicrobiotaandinnateimmunityof¢sh Geovanny D. G´omez 1 & Jos´e Luis Balc´azar 2 1 Mariculture Research Laboratory, Ocean University of China, Qingdao, China; and  2 Instituto de Investigaciones Marinas, Consejo Superior deInvestigaciones Cient´ ıficas (CSIC), Eduardo Cabello, Vigo, Spain Correspondence:  Jos´ e Luis Balc´ azar,Instituto de Investigaciones Marinas, ConsejoSuperior de Investigaciones Cient´ ıficas (CSIC),Eduardo Cabello 6, 36208 Vigo, Spain.Tel.: 1 34 986 214 457; fax: 1 34 986 292762; e-mail: balcazar@iim.csic.esReceived 20 April 2007; revised 12 September2007; accepted 12 September 2007.First published online 17 December 2007.DOI:10.1111/j.1574-695X.2007.00343.xEditor: Willem van Leeuwen Keywords innate immunity; gut microbiota; probiotics;fish. Abstract Although fish immunology has progressed in the last few years, the contributionof the normal endogenous microbiota to the overall health status has been sofar underestimated. In this context, the establishment of a normal or protectivemicrobiota constitutes a key component to maintain good health, throughcompetitive exclusion mechanisms, and has implications for the developmentand maturation of the immune system. The normal microbiota influences theinnate immune system, which is of vital importance for the disease resistance of fish and is divided into physical barriers, humoral and cellular components. Innatehumoral parameters include antimicrobial peptides, lysozyme, complementcomponents, transferrin, pentraxins, lectins, antiproteases and natural antibodies,whereas nonspecific cytotoxic cells and phagocytes (monocytes/macrophages andneutrophils) constitute innate cellular immune effectors. Cytokines are an integralcomponent of the adaptive and innate immune response, particularly IL-1 b ,interferon, tumor necrosis factor- a , transforming growth factor- b  and severalchemokines regulate innate immunity. This review covers the innate immunemechanisms of protection against pathogens, in relation with the installation andcomposition of the normal endogenous microbiota in fish and its role on health.Knowledge of such interaction may offer novel and useful means designingadequate therapeutic strategies for disease prevention and treatment. Introduction The health status of aquatic organisms is uniquely related totheir immediate environments, which can contain very highconcentrations of microorganisms. Many of these micro-organisms are saprophytic, some are pathogenic and bothtypes are capable of infecting fish when conditions becomefavorable for multiplication. However, under normal condi-tions fish maintain a healthy status by defending themselvesagainst these potential invaders using a repertoire of innateand specific defense mechanisms (Ellis, 2001).The immune systems of fish and higher vertebrates aresimilar and both have two integral components: (1) theinnate, natural or nonspecific defense system formed by aseries of cellular and humoral components, and (2) theadaptive, acquired or specific immune system characterizedby the humoral immune response through the productionof antibodies and by the cellular immune response, which ismediated by T-lymphocytes, capable of reacting specifically with antigens.The innate immune system, unlike the specific immunesystem, lacks the ability to acquire memory and specificrecognition after an encounter with foreign agents. How-ever, this system is quite important in fish since the synthesisof antibodies is relatively slow in comparison with antibody production in the higher vertebrates. An adaptive immuneresponse in ectothermic vertebrates takes considerable time(e.g., antibody production in salmonids takes at least 4–6weeks) to respond and is very temperature-dependent (Ellis,2001).The main function of the innate immune system, i.e., theinnate immune reactions mediated by monocytes/macro-phages, comprises antigen presentation and regulationof the functional balance of immune response related tocytokine and chemokine receptor profiles. Although thehost has evolved various tolerogenic mechanisms allowing FEMS Immunol Med Microbiol  52  (2008) 145–154  c  2007 Federation of European Microbiological SocietiesPublished by Blackwell Publishing Ltd. All rights reserved  a peaceful and productive coexistence with its normalendogenous microbiota, it remains highly responsive toenteropathogenic bacteria. This discriminatory ability re-presents a pivotal feature of efficient tolerance and homeo-static mechanisms.Recently, the use of gnotobiotic animals has shown thatbacteria have a profound impact on the anatomical, physio-logical and immunological development of the host (Rawls et al  ., 2004). Thus, establishing a healthy microbiota plays animportant role in the generation of immunophysiologicregulation in the host by providing crucial signals for thedevelopment and maintenance of the immune system(Salminen  et al  ., 2005).Therefore, the focus of this review will be primarily oninnate immune mechanisms of protection against pathogensas well as on the composition of the gut microbiota in fish,and particularly its role in maintaining health of the host. Innate immune system The primary line of defense in fish is the skin and mucusmembranes. However, when pathogenic microorganismsenter the host, cellular and humoral innate defense mechan-isms are activated (Magnad´ottir, 2006). The most importantmechanism involved in this defense is phagocytic activity,which will be described in detail later. Epithelial barriers Physical and chemical barriers, such as the dermis, epider-mis, scales and mucus, constitute the first line of defenseagainst disease-causing microorganisms in fish. The epider-mal cells are capable of reacting against different aggressorsand the integrity of these cells is fundamental to maintainingosmotic equilibrium, as well as impeding the entrance of foreign agents (Shephard, 1994).Mucus, composed mainly of glycoprotein, prevents thecolonization of foreign agents. The continuously main-tained mucus layer provides a substrate in which the anti-bacterial mechanisms can occur by virtue of biologically active components including antibodies, antibacterial pep-tides, lysozymes, complement proteins, lectinsandpentraxins(Nowak, 1999; Nagashima  et al  ., 2001; Hellio  et al  ., 2002). Innate humoral immunity The body fluids of the fish contain proteins and peptidesthat react against a great variety of microorganisms andmicrobial products. These nitrogenous compounds formpart of the defense of the innate humoral immunity, andconsist of antimicrobial peptides, lysozyme, complement,transferrin, pentraxins, lectins and antiproteases (Ellis,1989). Antimicrobial peptides (AMPs) AMPs are present in tissues exposed to microorganismssuch as mucosal surfaces and skin (Cole  et al  ., 1997) andimmune cells such as mast cells (Silphaduang & Noga, 2001;Murray   et al  ., 2003). One type of AMPs expressed by fishmast cells (also known as eosinophilic granule cells) ispiscidin, which has potent, broad-spectrum antibacterialactivity against fish pathogens (Silphaduang & Noga, 2001).Recently, other AMPs present in gill mast cells have beenidentified such as chrysophsin and pleurocidin, which havebeen isolated from red sea bream ( Chrysophrys major  ) andwinter flounder ( Pleuronectes americanus ), respectively (Iiji-ma  et al  ., 2003; Murray   et al  ., 2003). Lysozyme Lysozyme is a cationic enzyme widely distributed in theserum, mucus, kidney, spleen and intestine of the fish (Lie et al  ., 1989). This enzyme is primarily associated with andsynthesized by monocytes–macrophages and neutrophils(Murray & Fletcher, 1976; Nathan, 1987).Lysozyme has the capacity to hydrolyze the chemicalbond between the  N  -acetylmuramic acid and  N  -acetylglu-cosamine present in the peptidoglycan of bacterial cell walls.Lysozyme is able to lyse certain Gram-positive bacteria and,in conjunction with complement, even some Gram-negativebacteria (Paulsen  et al  ., 2001). Complement The complement system comprises more than 35 solubleplasma proteins that are key to innate and adaptive im-munity. Activation of the complement system initiates acascade of biochemical reactions accompanied by the gen-eration of biologically active mediators that result in antigenelimination via cell membrane lysis and activation of non-specific mediators of inflammation (Holland & Lambris,2002). There are three pathways that can activate thecomplement system: the classical pathway, which requiresthe presence of the antigen–antibody complex; the lectinpathway, which depends on the interaction of lectins such asmannose-binding lectin and ficolins with sugar moietiesfound on the surface of microorganisms, and finally thealternative pathway, which is activated directly by viruses,bacteria, fungi or even tumor cells and is independent of antibody (Boshra  et al  ., 2006). Transferrin Transferrin, a bi-lobed monomeric glycoprotein, is respon-sible for the transport and delivery of iron to cells. Bindingof iron to transferrin creates a bacteriostatic environment by  FEMS Immunol Med Microbiol  52  (2008) 145–154 c  2007 Federation of European Microbiological SocietiesPublished by Blackwell Publishing Ltd. All rights reserved 146  G.D. G´ omez & J.L. Balc´ azar  limiting the availability of iron to replicating pathogens.Transferrin is also an acute phase protein invoked during aninflammatory response to remove iron from damaged tissue(Bayne & Gerwick, 2001) and also functions as an activatorof fish macrophages (Stafford & Belosevic, 2003). Interferon Interferons (IFNs) are secreted by host cells, includingmacrophages, lymphocytes, natural killer cells and fibro-blasts, in response to recognition of viral double-strandedRNA intermediates (Haller  et al  ., 2006).Two families of interferons can be distinguished on thebasis of gene sequences, protein structure and functionalproperties. Type I IFNs, represented by the IFN- a  and theIFN- b , which have a very similar biological activity. TheIFN- a  is synthesized mainly by the leukocytes and IFN- b  by fibroblasts. Both types of interferons are produced inresponse to viral infections.Type II IFN, as represented by IFN- g , is produced by natural killer cells and T-lymphocytes in response to IL-12,IL-18, mitogens or antigens (Robertsen, 2006). In contrastto type I IFNs, IFN- g  is a key activator of macrophages forincreased killing of bacterial, protozoal and viral pathogens. Pentraxins: C-reactive protein (CRP) and serumamyloid protein (SAP) Both CRP and SAP belong to a family of pentamericproteins called the pentraxins that bind their ligands in acalcium-dependent manner. They are commonly associatedwith the acute phase response.CRP was discovered and named because of its reactivity with the phosphorylcholine residues of C-polysaccharide,the teichoic acid of   Streptococcus pneumoniae  (Tillett & Francis, 1930). The main biologic function of CRP is theability to recognize pathogens and damaged cells of the hostand to mediate their elimination by recruiting the comple-ment system and phagocytic cells (Volanakis, 2001). Inrainbow trout, CRP has showed opsonic activity for headkidney cells, resulting in enhanced phagocytic and chemo-kinetic activities (Kodama  et al  ., 1999).CRP is distinguished from SAP by its binding affinity forphosphorylcholine and phosphorylethanolamine. SAP only binds to phosphory-ethanolamine and can be purified as aresult of its affinity for agarose. Lectins Lectins are usually constitutive proteins or glycoproteins,which possess binding activity towards carbohydrate resi-dues. They have been grouped into classes based on thenature of their carbohydrate ligands, the biological processesin which they participate, their subcellular localization andtheir dependence on divalent cations (Drickamer & Taylor,1993). A mannose-binding lectin, isolated from the serumof Atlantic salmon, has been shown to have opsonizingactivity for a virulent strain of   Aeromonas salmonicida (Ottinger  et al  ., 1999). Antiproteases These antienzymes are characterized by their capacity toinhibit the action of proteases that some microorganismsutilize to penetrate the host. In teleost fish, an analogousprotein to  a 1 -antitrypsin was demonstrated (Hjelmeland,1983). Another protein, which was demonstrated as homo-logous to  a 2 -macroglobulin (Starkey   et al  ., 1982), wasreportedly capable of inhibiting several types of proteinases,including serine-, cysteine-, aspartic- and metallo-protei-nases (Alexander & Ingram, 1992).In addition, it has been observed that  a 2 -macroglobulinpresent in the serum of rainbow trout is capable of inhibit-ing  A. salmonicida  protease (Ellis, 1987). The combinedaction of antithrombin and  a 2 -macroglobulin in the plasmaof Atlantic salmon was reported to inhibit the action of a serine protease of   A. salmonicida  (Salte  et al  ., 1992). Thedifferences in the  a 2 -macroglobulin activity between thespecies of rainbow trout and brook trout have been directly correlated with their differing resistance to the infectioncaused by   A. salmonicida  (Freedman, 1991). Natural antibodies (NA) NA are secreted by B-cells without prior antigen-specificactivation or antigen-driven selection. A large proportion of NA is polyreactive to phylogenetically conserved structures,such as nucleic acids, heat shock proteins, carbohydratesand phospholipids (Boes, 2000). The importance of NAfunctions in fish may be even greater than for highervertebrates given that fish have neither appreciable affinity maturation responses nor class switch capabilities (Magor & Magor, 2001).Recently, Sinyakov   et al  . (2002) observed that NA in theserum of goldfish ( Carassius auratus ) can be directly in-volved in the first line of resistance against  A. salmonicida infection. In addition, these authors indicated that NA alsomay influence the level of antibody response since only thelow NA carriers were capable of developing effective anti-body response, and vice versa, the high NA carriers did notpossess potential for active immunization. Innate cellular immunity The adaptive immunity effector function is mediated by T-lymphocytes, whereas nonspecific cytotoxic cells and FEMS Immunol Med Microbiol  52  (2008) 145–154  c  2007 Federation of European Microbiological SocietiesPublished by Blackwell Publishing Ltd. All rights reserved 147 The role of gut microbiota in fish innate immunity  phagocytes (monocytes/macrophages and neutrophils) con-stitute innate cellular immune effectors. Nonspecific cytotoxic cells (NCC) The NCC perform functions very similar to those of thehigher vertebrates, acting on a wide variety of target cells,including allogeneic and xenogeneic tumor cells, virus-infected cells and protozoan parasites. NCC may alsoparticipate in antibacterial immunity by eliciting cytokineproduction and secretion (Jaso-Friedmann  et al  ., 2001). Phagocytosis The innate cellular immune system is formed by a series of cells with essential functions to the host survival. Amongthese cells are the phagocytic cells, monocytes/macrophagesand neutrophils, which play a fundamental role in protec-tion and survival during adverse conditions. For example,antibody production is slow when there is a drop intemperature, therefore the host defense will depend almostexclusively on the phagocytic capacity.Phagocytosis occurs when foreign objects such as bacteriaadhere to the surface of the phagocyte, mediated by hydro-phobic interactions or sugar/lectin interactions (Secombes,1996). However, the most active promoter of phagocytosis isthe C3 component of complement, which is bound to thebacterial surface lipopolysaccharide directly via the alterna-tive pathway or indirectly via lectin or CRP (Ellis, 2001). Antimicrobial response of fish phagocytes Fish macrophages and neutrophils produce bactericidalreactive oxygen species (ROS) during the respiratory burston contact with the particles or during phagocytosis or uponstimulation with a variety of agents. This process involvesreduction of oxygen (O 2 ) to the anionic radical superoxide(O 2  ), which is catalyzed by an NADPH oxidase localized inthe plasma and phagosomal membranes. Production of superoxide anion (O 2  ) results in the spontaneous or en-zyme-catalyzed production of an array of reactive oxygenproducts including hydrogen peroxide (H 2 O 2 ), hydroxylradical (OH  ), hypochlorous acid (OCl  ) and peroxynitrite(ONOO  ), which have potent antimicrobial effects.Production of nitric oxide (NO) constitutes anotherbactericidal mechanism, which is catalyzed by a NOsynthase. Schoor & Plumb (1994) demonstrated inducibleNO production, using enzyme histochemical techniques,from the anterior kidney of channel catfish ( Ictalurus punctatus ) infected with  Edwardsiella ictaluri . Recently,Stafford  et al  . (2001) have characterized the moleculespresent in crude leukocyte supernatants that induce NOproduction in goldfish macrophages, suggesting that trans-ferrin appears to be an important mediator for the activa-tion of both fish macrophages and granulocytes. Integration ofthe immune response -- cytokines Communication within the acquired immune system andbetween the innate and acquired systems is brought about by direct cell-to-cell contact involving adhesion molecules andby theproduction ofchemical messengers.Chiefamongthesechemical messengers are proteins called cytokines, which caninduce a broad range of activities via multiple target cell typesand their redundancy, indicated by the overlap in activitiesamong different cytokines (Engelsma  et al  ., 2002).There are three functional categories of cytokines: (1)cytokines that regulate innate immune response; (2) cyto-kines that regulate adaptive immune response; and (3)cytokines that stimulate hematopoiesis.Cytokines that regulate innate immunity are producedprimarily by macrophages although they can also be pro-duced by lymphocytes, NCC and other cells. They areproduced in response to microbial antigens or compoundsreleased from damaged cells. Among the mediators of inflammation released by activated phagocytes are the cyto-kines, particularly IL-1 b , an important pro-inflammatory cytokine, interferon, tumor necrosis factor- a (TNF- a ), trans-forming growth factor- b  (TGF- b ) and several chemokines.TNF- a  is one of the principal mediators of the inflamma-tory response in mammals, transducing differential signalsthat regulate cellular activation and proliferation, cytotoxicity and apoptosis. When an inflammatory response is induced,the cascade of cytokine secretion begins with the release of TNF- a . This stimulates the release of IL-1 b , which is thenfollowedby thereleaseofIL-6. The initiationofinflammationleads to the release of a myriad of other cytokines, whichinclude chemoattractants that signal neutrophils and macro-phages to migrate to the site of infection (e.g. chemokines). Influence of gut microbiota on thehealth offish As has been indicated previously, fish health status is depen-dent on or conditioned to the immediate environment, sincethey are intimately in contact with a wide variety of micro-organisms, including pathogenic and opportunistic bacteriathat may colonize the external and internal body surfaces(Ellis, 2001). Thus, the establishment of a normal or protec-tive microbiota is a key component in excluding potentialinvaders and maintaining health (Balc´azar  et al  ., 2006a). Thisis accomplished through competitive exclusion mechanismsand facilitates immune system development and maturation.Colonization of the gastrointestinal tract of fish larvaestarts immediately after hatching and is completed within afew hours. Colonizing bacteria can modulate expression of  FEMS Immunol Med Microbiol  52  (2008) 145–154 c  2007 Federation of European Microbiological SocietiesPublished by Blackwell Publishing Ltd. All rights reserved 148  G.D. G´ omez & J.L. Balc´ azar

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