MINIREVIEW

Probiotics: multifarious oral vaccine against infectious traumas

Sarika Amdekar, Deepak Dwivedi, Purabi Roy, Sapna Kushwah & Vinod Singh
Department of Microbiology, Barkatullah University, Bhopal, Madhya Pradesh, India

Correspondence: Vinod Singh, Department of Microbiology, Barkatullah University, Bhopal 462026, Madhya Pradesh, India. Tel.: 191 0755 645 8209; fax: 191 0755 249 1824; e-mail: vsingh3@rediff.com

Abstract Microorganisms have been used for a long time in food and alcoholic fermentation. In the last few years they have undergone scientic scrutiny of their preventative and therapeutic aspects. This has led to the discovery of a new term, probiotics. Lactic acid bacteria (LAB) are microbial communities normally present in the intestine of most animals. They play an important role in humans and other animals, and act as immunomodulators. They are helpful in the treatment and prevention of disease as well as improving the digestion and absorption of nutrients. Probiotic microorganisms include the LAB Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus casei, Lactobacillus plantarum and Lactobacillus rhamnosus. Use of these live bacteria to elicit an immune response or to carry a vaccine component is a new invention in vaccine development. The advantage of live bacterial vaccines is that they mimic natural infection, have intrinsic adjuvant properties and can be given orally. Components of pathogenic and nonpathogenic food-related microorganisms are currently being evaluated as candidates for oral vaccines.

IMMUNOLOGY & MEDICAL MICROBIOLOGY

Received 3 September 2009; revised 27 October 2009; accepted 27 October 2009. Final version published online 19 January 2010. DOI:10.1111/j.1574-695X.2009.00630.x Editor: Willem van Leeuwen Keywords probiotics; oral vaccine; immunomodulation.

Introduction
Live vaccines have played an important role from the beginning of vaccinology, despite safety problems associated with the risk of reversion to a virulent organism and the threat of causing disease in immunocompromised individuals (Dietrich et al., 2003). Within the last two decades the concept of live vaccines has engendered a lot of interest due to our increased immunological understanding and the availability of various techniques that make the construction of live vaccines safer (Lindberg, 1995). The term probiotics was originally used by Lilly and Stillwell (1965) for a substance that stimulates the growth of other microorganisms. The meaning of this term has now changed and is restricted to a viable microbial agent that, when used for other organisms like animal or man, benecially affects the host by improving the balance of the normal microbial communities (Fuller, 1991). The benecial effects of probiotics were rst reported by Methnikoff in the early 1900s (Salimen et al., 1996), in which study he demonstrated the useful effects of fermented milk in humans. It was also reported that the consumption of live microorganisms such as lactic acid bacteria (LAB) in sour milk may help to improve the balance of the intestinal microbial communities. Probiotic bacteria must survive in
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the oral cavity and be resistant to pH, bile acid, proteolytic enzymes, antimicrobial peptides and intestinal peristalsis. Pathogenic and nonpathogenic food-related bacteria are currently being evaluated as live vaccines (Methnikoff, 1908). Lindberg has provided an excellent review of the history of live bacterial vaccines (Kajikawa et al., 2007). The rst live bacterial vaccine was used in Spain in 1884, a subcutaneous injection of weakened Vibrio cholerae (Detme & Glenting, 2006). A few years later, eld trials were carried out in India with a more effective V. cholerae as a vaccine, using a parenteral route (Table 1).

Probiotics as antibiotics or lactobiotics

Probiotic microorganisms are harmless and are assigned a generally regarded as safe (GRAS) status in animal and human systems (Underdahl et al., 1982). The safety of probiotic strains is evaluated as follows: 1 Ability of cells to produce secondary metabolites, such as sakacin, salivaricin, enterocin, formicacid, diacetyl, hydrogen peroxide and acetoin, and enzymes, such as a-galactosidase, a-glucosidase, nitroreductase and b-glucosidase. 2 Adhesion properties such as a-enolase, which help them to adhere to epithelium.
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Table 1. Microbial probiotics and their safety status Organisms Lactobacillus Lactococcus Streptococcus Enterococcus Bacillus Bidobacterium Propionibacterium Saccharomyces Infection potential Mainly nonpathogens; a few opportunistics reported in AIDS patients Mainly nonpathogens Opportunistics; only S. thermophilus is used in dairy products Opportunistics; some strains exhibit antibiotic resistance Only B. subtilis, GRAS status, is reported in probiotics use Mainly nonpathogens; some strains are isolated from human infection Dairy propionibacterial group is a potential candidate for probiotics Mainly nonpathogens; some strains are isolated from human infection

Table 2. Probiotic bacteria and their effects Strain Lactobacillus acidophilus LA1 Lactobacillus GG Benecial effect Adherence to human intestinal cells Balances intestinal microbial communities Immune enhancement Prevention of antibiotic-associated diarrhea Treatment of rotavirus diarrhea Treatment of diarrhea caused by Clostridium difcile Stabilization of Crohns disease Prevention of intestinal microbiota disturbance Positive effects on bladder cancer Carcinogenic-associated enzyme reduction Prevention of viral diarrhea Growth stimulation of other friendly bacteria

Lactobacillus casei Shirota

Lactobacillus gasseri Bidobacterium bidum Propionibacterium freudenreichii

Reproduced from Donohue & Salminen (1996).

3 Factors that inuence the strain survival. 4 Interactions with the host body, particularly in terms of prevention of pathogenic microorganisms (Chukeatirote, 2003). LAB are gram-positive bacteria of various genera: Lactobacillus, Lactococcus, Leuconostoc, Pediococcus, Aerococcus, Bidobacterium and Weissela. Lactobacillus is the most widely used probiotic (Khansari et al., 1990; Havenaar et al., 1992; Reid et al., 1993; Bernet et al., 1994; Greene & Klaenhammer, 1994; Jack et al., 1994; Gonzalez et al., 1995; Sarem-Damerdjii et al., 1995; Casas & Dobrogosz, 1997; Holzapfel et al., 1998; Kirjavainen et al., 1998; Netherwood et al., 1999; Ouwehand et al., 1999; Reid, 1999; Reid & Burton, 2002; Table 2).

For detailed references, see Salminen et al. (1998).

LAB as an immune enhancer

Consumption of Lactobacillus as a probiotic has been suggested to have disease resistance benets including immune enhancement [interleukin-6 (IL-6) and IL-10 production] and resistance to malignant growth [tumour necrosis factor-a (TNF-a) production] and other infectious diseases. Malfunctioning of the immune system in ageing, stress and infectious diseases (e.g. AIDS), and in the undernourished is well established (Goodwin, 1995; Pawelec et al., 1995; Woodward, 1998; Lin & Chen, 2000). The above deciencies can be overcome by immunomodulation using suitable natural and chemical agents and/or products. Currently, available immunostimulatory products are associated with dreadful side-effects (Lin et al., 1989; Tahri et al., 1996). The development of natural products with immunomodulatory properties, devoid of side-effects, is therefore important for large population groups with impaired immune function (Dietrich et al., 2003).
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The development of oral live vaccines for pathogens is the challenge for the application of current life sciences in infectious diseases. Easy administration in a host is crucial when considering continued drug treatments in a population exceeding hundreds and millions of people with limited health care resources. The use of bacteria to induce an immune response to itself or to a carried vaccine component is an attractive vaccine strategy (Lindberg, 1995). Advantages of live vaccines are that they mimic the pathogen (or antigen) adjuvant properties and, of course, that they can be administered orally (Kotloff et al., 1996). Derivatives of pathogenic and nonpathogenic food-related bacteria are also used as a source of oral vaccine (Donohue & Salminen, 1996; Lindberg, 1998). Vaccination is an efcient and cost-effective method of preventing infectious diseases, but available vaccines are delivered by injection, which has made mass immunization more expensive and hazardous. Oral vaccines have several merits compared with parenteral vaccines, but they have been used almost solely against mucosally transmitted pathogens (Benyacoub et al., 1999). Their potential for controlling nonmucosally transmitted diseases has not been accepted. The use of live attenuated bacteria as an oral vaccine is not a new concept (Kochi et al., 2003). Previously attenuated Salmonella enterica serovar of Typhi has been administered as an acid-resistant capsule and marketed for use as a vaccine against typhoid. In addition, attenuated V. cholerae is the basis of a marketed vaccine against cholera. However, there is a possibility of using attenuated bacteria as a vehicle for delivering heterogeneous antigens, i.e. antigens against pathogens other than themselves.
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Derivatives of both pathogenic and nonpathogenic bacteria can be used as live vaccines. These include Salmonella typhi, Shigella exineri, Listeria monocytogenes, V. cholerae and Escherichia coli as well as some nonpathogenic bacteria such as Lactobacillus and Bidobacterium (McGhee et al., 1992; Klijn et al., 1995; Nardelli-Haeiger et al., 1996). These probiotic bacteria target inductive sites of the host immune system such as mucosal surfaces and antigenpresenting cells (APCs) on macrophages. Use of LAB for the delivery of vaccine is less exploited than attenuated pathogens (Fuller, 1989). These bacteria are safe and the availability of genetic tools for recombinant gene expression in LAB is attractive for use as a vaccine candidate. LAB are not pathogenic and the vaccine delivery to APCs may be less effective than that of invasive bacteria. However, specic immune responses have been obtained with several LAB. Some of the benecial effects claimed for probiotics include improvement of the indigenous microbial communities, prevention of infectious diseases and allergies, diminishing of the serum cholesterol level, anticancer activity, stabilization of the gut mucosal barrier, immune adjuvant properties, alleviation of intestinal bowel disease symptoms and improvement in the digestion of lactose in intolerant hosts (Strobel, 1995).

Probiotics and gut-associated lymphoid tissue (GALT) immunity

The functioning of the gut mucosal immune system requires a complex network of signals with multiple interactions

between commensal and foreign antigens and with the host cell. These host cells include epithelial cells, macrophages, dendritic cells and other cells that belong to the nonspecic barriers, mucus-producing cells, such as goblet cells and Paneth cells, which secrete antimicrobial peptides and produce cryptidins and defensins (Phillips-Quagliata & Lamm, 1988). The mucosal epithelial cells are important because they coordinate the defense mechanisms by releasing chemokines and cytokines (IL-2, IL-10 and IL-6) that prevent both the specic and the nonspecic immune responses of the immune cells. It is important that these responses are not triggered by harmless intestinal commensal bacteria, and that the inammatory response is controlled. Probiotic bacteria produce luminal secretory immunoglobulin A (IgA) (Link-Amster et al., 1994). It is obvious that these nonpathogenic probiotic bacteria must interact with the epithelial cells and GALT (Fig. 1). The increase in the number of IgA-producing cells was the most remarkable property induced by probiotic microorganisms and by fermented milk yogurt. The physiological role of IgA on the mucosal surface is unquestionable. Some probiotic bacteria can act as adjuvants of the mucosal and & Alvarez, 1992). systemic immune response (Perdigon Probiotic microorganisms are able to induce a gut mucosal immune response, which requires bacteria to interact with the epithelial and immune cells in the gut to induce the network of signals involved in an immune response. In the gastrointestinal tract, LAB communicates with the different pathways to interact with antigens (Neutra &

Fig. 1. The local immune response in the gut induced by the interaction between probiotic bacteria and the epithelial and immune cells associated with the lamina propria of the small intestine. BL, B lymphocyte; DC, dendritic cells; EC, epithelial cells; MC, M cells; MQ, macrophages; MS, mast cells; PC, plasma cells; TL, T lymphocyte.

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Krahenbuhl, 1996). These bacteria (as whole cells or as antigenic fragments) interact with the M cells in Peyers patches, with gut epithelial cells, and with the associated immune cells. Cells release cytokines that up- or downregulate the immune response (Mattingly & Waksman, 1978). Bacterial vaccine vectors induce the production of multiple cytokines, including TNF-a, interferon-g and IL12 and proinammatory mediators such as reactive nitric oxide, which enhance early innate immunity and create a local environment favorable for antigen presentation. Mucosal epithelial cells form an efcient barrier, which prevents antigens of environmental pathogens from affecting the host mucosal immunity itself; these antigens are responsible for more than two-thirds of the activity of the entire immune system, based on the numbers of immunocompetent cells, the extent of the mucosal tissues and the quantities of immunoglobulins produced at these sites. Mucosal immunity is distinguished from systemic immunity by the abundance of secretory immunoglobulin, (sIgA). Dedicated cellular agellated microorganisms, including commensals, trigger epithelial homeostatic chemokine responses that recruit immune cells of the innate immune system to the gut epithelium and lamina propria of the intestine to form a link between the humoral and cell-mediated immune responses. Recognition of Toll-like receptor (TLR) by LAB can activate the TLR signals, mainly TLR 2 and TLR 4. These peptides are dominant receptors of the lipopolysaccharides of bacterial species. TLR 2 mediates signals from other bacterial components, including lipoteichoic acid, peptidoglycan and lipoproteins and/or lipopeptides (Singh et al., 2008). Although the exact location of these receptors in the intestinal epithelial cells is still controversial, TLR signals are

essential not only for the response against pathogens but also to maintain the functions of the intestinal barrier. For an effective application there should be multiple consequences of the cross-talk between the probiotic bacteria and the intestinal mucosa. Probiotic bacteria may provide benecial effects through colonization and/or release of some of bioactive compounds (enzymes, peptides, bacteriocins, etc.). This translates into a reinforcement of the intestinal barrier as well as direct modulation of epithelial cell functions, including cytokine and chemokine release [IL-6, IL-10, IL-2, IL-8 and transforming growth factor-b], which elicits innate and adaptive immunity and production of cytokines by monocytes/macrophages and thus increases the signals to the epithelial cells and other immune cells and provides microbial antigens to naive T cells in Peyers patches and mesenteric lymph nodes (MLN). IgA antibody-mediated mucosal response is thereby activated to prevent overgrowth and spread of the bacteria beyond MLN (Weissman et al., 2000). There is evidence that nonpathogenic bacteria or their fragments are taken up by macrophages or dendritic cells in the lamina propria and, it is possible, through direct sampling of luminal antigen for dendritic cells, by TLRs and CD-206 mannose receptor (Akira et al., 2001). These bacteria can be cleared or transported to the MLNs, where they interact with T and B cells to induce specic mucosal IgA or suppress T cells (Th3, Tr1 and CD251; Holder & Freeman, 1981) (Fig. 2).

The demise of the needle

Probiotic bacteria have long been considered useful because of the changes they induce in the intestinal ora. Oral vaccines from probiotic strain Lactobacillus are active

Fig. 2. Schematic diagram showing cross-talk between the probiotic bacteria and the intestinal mucosa. FAE, follicle associated epithelium.

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against many diseases caused by bacteria, viruses and protozoa. They can be used against various diseases.

Malaria
Merozoite surface protein 1 (MSP1) is a common surface protein layer, which is found in most of the Plasmodium species. MSP1 has been studied as an important candidate for vaccine against malaria (Blackman et al., 1991). Highlevel expression of MSP1 by Plasmodium in the asexual stage plays an important role in its entry in red blood cells. MSP1 can be proteolytically cleaved into ve fragments, two steps after the maturation of merozoites, with the carboxylterminal 19-kU fragment (MSP119) remaining on the surface of merozoites (Miller et al., 1993). These protective antigens can be delivered to the mucosal surfaces using live bacteria with plasmids that are responsible for the expression of specic antigens. These antigens are derived from attenuated pathogenic microorganisms such as S. typhi and Salmonella chlorella. As an alternative, harmless food-grade bacteria such as LAB are being used for their efcacy as a live antigen candidate. LAB can survive in the gastrointestinal tract of human beings and other animals for 23 days, they do not destroy or colonize mucus and do not elicit strong host immune responses. The immunogenicity of soluble protein is low when administered orally, but this can be enhanced using genetically engineered bacteria, so that low-level expression of MSP119 in Lactococcus lactis was still able to confer strong protection against the malarial parasite (Mercenier et al., 2000).

expressing vaccinia virus challenge in mice (Aldovini & Young, 1991). Oral administration of recombinant L. lactis-associated vaccine with the V2V4 loop of the HIV virus can protect against AIDS, and also signicantly reduce viral load. These ndings make recombinant L. lactis an appropriate candidate for HIV vaccine development.

Infantile diarrhea
Rota virus is the major cause of severe infantile diarrhea, responsible for over 2 million diarrheal episodes. The rst Rota virus vaccine, RotaShield, was used in the United States. Its efcacy was up to 80100%. However, in 1999 the US Centers for Disease Control and Prevention found an association between RotaShield and a potentially fatal bowel obstruction, intussusception. RotaShield was therefore withdrawn from the market in 1999. In 2004, a new vaccine, Rortarix, was developed. Although it is 70% efcient, Rotarix had side-effects such as low-grade fever and therefore it did not become popular. Another vaccine, RotaTeq, is a live attenuated vaccine. Passively produced antibodies provide protection against rotavirus (Anderson & Weber, 2004). Over the last few years their role in probiotics, especially Lactobacillus species, for the prevention of rotavirus diarrhea has been recognized. Combination of species of Lactobacilli with antirotavirus antibodies produced in animals was checked in mouse pups along with rotavirus (Velazquez et al., 1996). Lactobacillus rhamnosus GG, a wellknown probiotic, was found to synergize with antiviral antibodies and helped in early recovery from diarrhea in mice, saving up to 90% of antibodies. Lactobacillus casei GG isolated from human samples, now popularly known as L. rhamnosus, has been used in Finland for recovery from acute rotavirus diarrhea in children (Gomboova et al., 1986). The probiotic is given in the form of powder or as a fermented milk product. Children with rotavirus diarrhea recovered 1.5 days after treatment with Lactobacillus reuteri vs. 2.5 days in matched control infants (Korik et al., 1968). Lactobacillus reuteri also reinforces the local immune defenses through a specic IgA response to rotavirus.

AIDS
AIDS is a deadly disease, or rather, a collection of diseases. A safe, powerful and cost-effective vaccine, which can induce both mucosal and systemic immunity may be required to limit the spread of HIV. In the past few years, multiple strategies to produce an immunogenic HIV vaccine have been developed (Ke-Qin et al., 2003): HIV subunit peptide vaccines, DNA as a vaccine, recombinant virus-vector vaccines (using viral vectors such as vaccinia virus, adenovirus, rabies virus, avivirus, Friend murine leukemia virus, Venezuelan equine encephalitis virus and adenoassociated virus), and bacteria as a vector, such as Bacille CalmetteGuerin. Each of these strategies showed some promise in animal models (Schnell et al., 2000), for use either alone or in combination. Yet there is still a great need for a safe and highly effective HIV vaccine. A study conducted in mice demonstrated that oral administration of recombinant L. lactis encoding the V2V4 loop of the HIV env gene can induce HIV-specic mucosal and systemic immunity. Induced humoral and cell-mediated immune response is sufcient to provide immunity against an HIV EnvFEMS Immunol Med Microbiol 58 (2010) 299306

Trichomoniasis
Trichomoniasis is commonly known as urinary tract infection or urinogenital tract infection. It is a sexually transmitted disease. The immunotherapeutic effect in trichomoniasis is accomplished by stimulation of the humoral/ B-cell immune response in the serum and probably also in the cervical secretion of the host (Tatyana et al., 2000). Until 1959, topical vaginal preparations were available against trichomoniasis, which provided relief but did not cure. Azomycin was used for the treatment of trichomoniasis, marketed as Flagyl. It was ineffective against Trichomonas
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vaginalis. Solco Trichovac is the only vaccine available against these bacteria in the market. The mode of action of the bacterial vaccines prepared for trichomoniasis is not satisfactory; however, vaccines made up of LAB induce cross-reacting antibodies against abnormal Lactobacillus and T. vaginalis without adversely affecting the growth of normal Lactobacilli in the vagina. This concept of antigenic similarity of two unrelated and serologically variable groups of organisms such as Lactobacilli and Trichomonas is rather surprising, and probably also exists in the cervical secretion of the host (Classen et al., 1995). This mode of action of induction of antibodies against aberrant L. acidophilus, which cross-react with T. vaginalis but not with LAB is a new concept for a vaccine candidate.

its colonization on mucosal surfaces is best prevented by enhancement of immunity following local stimulation. Different delivery systems satisfying this requirement are currently under development, with various avenues being explored for oral administration (Isolauri et al., 1991). One such delivery system is based on live bacterial vectors, including nonpathogenic, noninvasive (LAB) strains (Shornikova et al., 1997). These do not induce pronounced proinammatory responses, which renders them particularly suitable for immunocompromised subjects, infants and elderly individuals.

Conclusion
The rationale behind the development of dietary LAB as a live mucosal delivery system is that they have been used from time immemorial in the preparation of fermented foods and feeds and, thus, are consumed worldwide by humans and animals. Moreover, specic LAB strains have been shown to exert benecial health, that is, probiotic effects and to be particularly adapted to immunization by the oral route, as they are quite acid-resistant. Administering vaccines orally, through drinking water, provides excellent disease protection while eliminating the problems associated with injections. Oral vaccination offers numerous benets including convenience and efciency in treating hundreds, even thousands, of patients. The vaccines are safe, noninvasive, nonpathogenic and have good adherent properties. Lactobacillus is a noted vaccine candidate. LAB is capable of delivering antigens to the mucosal and systemic immune systems, eliciting specic antibody responses in serum and secretions. Notably, this carrier seems to induce a mixed Th1/Th2-type immune response.

Ischemic heart diseases

The protection of the heart and prevention of ischemia is a difcult and multifaceted phenomenon with potential clinical applications. Previous reports suggest that heat-shock proteins and proteins with antioxidative activity are helpful in myocardial infarction. Hormone-mediated signaling mechanisms may also be involved. Myocardial tolerance to a subsequent challenge against ischemia and reperfusion by sublethal doses of gram-negative bacterial endotoxin (lipopolysaccharides) is well known (Morimoto & Santoro, 1998). However, the toxic nature of endotoxin has precluded its clinical application. Use of an endotoxin analog with reduced toxicity, the 48-monophosphoryl derivative of lipid A (MLA), opened up new possibilities for studying protective mechanisms (Kukreja et al., 1996). Despite the reduced toxicity of MLA, such agents are always given in limited doses due to the risk to and toxic effects on the host. Lactobacillus preparation is used as a nontoxic bacteriaderived agent utilized for the formulation of new drugs that have no toxic effects (Goldin et al., 1992). Increased myocardial tolerance to ischemia-reperfusion damage, similar to that demonstrated with gram-negative bacteria (endotoxin), might be obtained using different bacterial strains capable of enhancing nonspecic resistance (Elmer, 2001). Lactobacillus is generally recognized as a safe organism, as it is devoid of lipopolysaccharides and lipid A in its cell walls, and it also stimulates the hosts nonspecic immunity (adjuvanticity).

Acknowledgement
This research was supported by a Grant from Madhya Pradesh Council of Science and Technology (MPCST), Bhopal, Madhya Pradesh, India.

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