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ARTICLE IN PRESS

International Journal of Medical Microbiology 300 (2010) 57–62

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International Journal of Medical Microbiology
journal homepage: www.elsevier.de/ijmm

Mini Review

Mechanisms of probiotic actions – A review
Tobias A. Oelschlaeger 
Institut für Molekulare Infektionsbiologie, University of Würzburg, Röntgenring 11, D-97070 Würzburg, Germany

a r t i c l e in fo abstract

Probiotics are gaining more and more interest as alternatives for antibiotics or anti-inflammatory drugs.
Keywords: However, their mode of action is poorly understood. This review will present examples of probiotic
Probiotics actions from three general modes of actions into which probiotic effects can be classified. Probiotics
Mechanisms of action might modulate the host’s immune system, affect other microorganisms directly or act on microbial
products, host products or food components. What kind of effect(s) a certain probiotic executes depends
on its metabolic properties, the molecules presented at its surface or on the components secreted. Even
integral parts of the bacterial cell such as its DNA or peptidoglycan might be of importance for its
probiotic effectiveness. The individual combination of such properties in a certain probiotic strain
determines its specific probiotic action and as a consequence its effective application for the prevention
and/or treatment of a certain disease.
& 2009 Elsevier GmbH. All rights reserved.

Introduction stressed that there seems not to be one probiotic exhibiting all
three principles, at least not to that extent that it could be a
In this review I will give an overview on the effects of remedy for prevention or therapy of all mentioned kinds of
probiotics. It has to be taken into account, that many reported disease. It depends on the metabolic properties, the kind of
mechanisms of probiotic actions are the results of in vitro surface molecules expressed and components to be secreted
experiments. Therefore, these results must be confirmed by in which probiotic actions a certain probiotic strain might show. The
vivo studies. era of ‘‘omics’’ we are living in at this time, will make crucial
The effects of probiotics may be classified in three modes of contributions because it enables the analysis and comparison of
action. (i) Probiotics might be able to modulate the host’s defences whole genomes, transcriptomes, proteomes and secretomes (see
including the innate as well as the acquired immune system. This also Wohlgemuth et al., 2010). This all will lead to the
mode of action is most likely important for the prevention and identification and characterisation of probiotic properties, distin-
therapy of infectious diseases but also for the treatment of guishing real probiotics from those, which are not.
(chronic) inflammation of the digestive tract or parts thereof. In
addition, this probiotic action could be important for the
eradication of neoplastic host cells. (ii) Probiotics can also have Immune modulation
a direct effect on other microorganisms, commensal and/or
pathogenic ones. This principle is in many cases of importance Probiotics can influence the immune system by products like
for the prevention and therapy of infections and restoration of the metabolites, cell wall components and DNA. Obviously, immune
microbial equilibrium in the gut. (iii) Finally, probiotic effects may modulatory effects might be even achieved with dead probiotic
be based on actions affecting microbial products like toxins, host bacteria or just probiotics-derived components like peptidoglycan
products e.g. bile salts and food ingredients. Such actions may fragments or DNA. Probiotic products are recognized by host cells
result in inactivation of toxins and detoxification of host and food sensitive for these because they are e.g. equipped with recognition
components in the gut. receptors. The main target cells in that context are therefore gut
All three modes of probiotic action are in all likelihood epithelial and gut-associated immune cells. The interaction of
involved in infection defence, prevention of cancer and in probiotics with host (epithelial) cells by adhesion itself might
stabilising or reconstituting the physiological balance between already trigger a signalling cascade leading to immune modula-
the intestinal microbiota and its host. However, it has to be tion. Alternatively, release of soluble factors can trigger signalling
cascades in immune cells or in epithelial cells which subsequently
affect immune cells. The direct adhesion of probiotics to host
 Tel.: + 49 931 31 2150; fax: + 49 931 31 2578. epithelial cells has been demonstrated in many in vitro experi-
E-mail address: t.oelschlaeger@mail.uni-wuerzburg.de ments. However, probiotic and commensal bacterial adherence to

1438-4221/$ - see front matter & 2009 Elsevier GmbH. All rights reserved.
doi:10.1016/j.ijmm.2009.08.005

The broad-spectrum class II bacteriocin Abp118 Two soluble proteins from Lactobacillus rhamnosus GG promote produced by Lactobacillus salivarius strain UCC118 is able to intestinal epithelial cell survival and growth.. In a placebo-controlled cross-over trial the effect of Lactoba- genic Escherichia coli in a TLR-independent way.A. Ex vivo studies with human monocyte-derived DCs (Wehkamp et al. inactivate the pro-apoptotic p38 mitogen-activating protein such bacteria adhere just to and invade the outer mucus layer but kinase signalling pathway in epithelial cells (Yan et al. This approach was actions.. IL-4. (class IV) cyclic antimicrobial peptides (Maqueda proliferator (Petrof et al. by interfering with proteasome function lantibiotics. 2004. In monocytes resulting in significant increase in IL-10 production.. DCs are affected by probiotics. Abp118 is obviously the primary apoptotic factor Akt and protein kinase B. because ZO-2 is an important factor for the preservation of tight. probiotics subepithelial dome region. This mutant inflammatory effect which often is the consequence of increased was also more protective in a murine colitis model than its wild. probiotics. The activity of NK was increased as a likely tion of expression and redistribution of zonula occludens protein consequence of L. A mutant with enhanced anti-inflammatory capacity Besides effects on epithelial cells various immune cells such as incorporated much less D-ala in its teichoic acids than the wild. 2004). 2007). EcN was even able the molecular basis of the observed effects. Top of transactivation by a mechanism independent of NF-kB inhibition this list are short chain fatty acids e. which recognizes muramyl dipeptide lumen. probiotics are also able to protect the integrity of the (Sheil et al. a component of the Gram-positive cell wall. The LMBW are antimicro- block degradation of the inhibitor IkB by inhibiting the ubiqui. 2008). In vitro-studies showed inhibition of pathogen mediated this effect by suppressing the TNFa-induced IL-8 replication mediated by low-molecular-weight substances. of L.. bacteria. Essential for DNA effects Teichoic acid. continuously antigens from the gut and present it to naive T cells.. is the Toll-like receptor 9 (TLR9) (Rachmilewitz et al.. some probiotics are able to alter cytokine produc. lactic acid. 2006).. coli strain Nissle 1917 (EcN) of ZO-2 as well as ZO-1 expression On the other hand.g. it is clear that we just started to understand in vivo was demonstrated in the mouse model. A similar effect (Kamada et al. These cells are also able to mucosal barrier by certain probiotics. to protect mice with dextran sodium sulphate-induced colitis by reducing the loss of body weight and colon shortening as a consequence of increasing intestinal barrier function (Ukena et al. successful not only in murine colitis but also in arthritis treatment However. 2007). gut epithelial barrier. ex vivo T helper subsets 1 and 2 responses. ARTICLE IN PRESS 58 T.. 2004). 1997). which collect at a low level luminal gut antigens. Kelly et al. 2004). Furthermore. A direct anti-inflammatory effect of EcN on human gut Antimicrobial substances produced by probiotics epithelial cells (HCT15) could only be demonstrated for live bacteria but without direct contact. In vivo oral supplementation of six and pathogens alike at a distance to the intestinal epithelium. Oelschlaeger / International Journal of Medical Microbiology 300 (2010) 57–62 gut epithelial cells in vivo has not been demonstrated. 2008). Finally. 2005).. here eubacteria and clostridia. rhamnosus for 2 mechanism seems to be of importance for keeping patients weeks induced a similar hyporesponsiveness including impaired suffering from colitis ulcerosa in remission (Kruis et al. contact with certain probiotics results rather in an anti- The effects observed were clearly TLR-2 dependent. which induced an inflammatory reaction. DCs are responsible for collecting type strain and dramatically reduced secretion of pro-inflamma. was demonstrated. Induction by the probiotic able to modulate the immune system in a strain-specific manner. IL-10 expression in DCs. tory cytokines by peripheral blood mononuclear cells and This usually leads to T cell activation and differentiation. The plantarum is involved in the anti-inflammatory activity of this reason for the differing DNA effects remains unclear. This makes perfect sense was detected in in vitro assays (Takeda et al. pathogen Listeria monocytogenes. mucosal gut barrier against the destructive action of enteropatho. probiotic. demonstrating the Even DNA of some probiotics showed a systemic anti- important role of DCs in immune modulation by probiotics (Braat inflammatory effect in contrast to DNA from pathogenic bacteria et al. IL-10) while the innate immune system is suitable for keeping commensals responding normal to IL-2. E. 2004).. This might explain how subcutaneously applied plantarum highlighting the importance of TLRs for probiotic probiotics exert an anti-inflammatory effect. Such T-cells showed a decreased EcN have been identified (Schlee et al. which can be boosted by prebiotics.. 2004).. Also the production of butyric acid by cells. Also low-molecular-weight In general. All these effects of probiotics are suitable for strengthening the One exception is the uptake and transcytosis of bacteria by M. 2004). The amplification of defensin/cryptidin expression in bacteria by DCs which are localized below the epithelial cells (non Paneth cells might indeed be part of the reinforcement of the M-cells) (Macpherson and Uhr. LMWB can be grouped into three classes: (class I) tination of this inhibitor.. They achieve this cillus casei Shirota on natural killer cell (NK) activity in humans by changing protein kinase C signalling resulting in an amplifica. On one hand all the examples mentioned show probiotics to be junction function in the gut epithelium. matured in the presence of Lactobacillus rhamnosus were used to As the inducing agent for human b-defensin 2 the flagella of instruct naive CD4 + T cells.. they mediator of protection since an Abp118-negative mutant failed to . casei Shirota-induced IL-12 production which 2 (ZO-2) in T84 cells (Zyrek et al. 2007). type counterpart (Grangette et al. This modulation of proliferation and cytokine production (IL-2. was observed for hydrogen peroxide. contrast. Rather. bacteriocins (LMWB) and high-molecular-weight bacteriocins tion by modulating cellular signal transduction. This study elegantly Even some regulatory T (Treg) cells are induced by some demonstrated the involvement of TLR-2 in the probiotic effect of L.. et al. Rather a secreted factor Bacteriocins. and pass them down to dendritic cells (DCs) in the results in consolidation of the epithelial barrier. Another direct contact between were shown in vitro to induce the expression of defensins and probiotics and host cells in the gut occurs by internalization of cryptidins. The induction of a- collect antigens from the gut lumen with their dendrites by defensins in Paneth cells is carried out by activation of the extending these dendrites through the epithelium into the gut cytoplasmic receptor NOD2. 2004). (class II) heat stable signal cascade which in turn is activated through a peroxisome non-lantibiotics. These proteins protect mice against infection with the invasive foodborne inhibit TNF-a-mediated apoptosis by activation of the anti.. Direct effects on other microorganisms 2007). This patients suffering from Crohn’s disease with L. do not reach the epithelial cells themselves (Matsuo et al. They can either (class III) are produced by lactobacilli. posttranslationally modified peptides harbouring or influencing RelA localisation via the receptor g-dependent unusual amino acids such as lanthionin. bial peptides.

Legionella pneumophila and L. However.. competition for the same viruses (Cleusix et al. Oelschlaeger / International Journal of Medical Microbiology 300 (2010) 57–62 59 protect the animals (Corr et al. and several repeated domains with putative adhesion function spectrum antibiotic active not only against Gram-positive and (Sanchez et al. Finally microcines. coli (STEC) O157:H7 strains in vitro as well adhesion of pathogens to immobilized human mucus appears to as in mice was demonstrated in contrast to other Bifidobacterium depend on both the specific probiotic strains and the pathogens. 1997). plantarum May be the most important group of bacterial virulence factors 299v or L. effect in the host. ARTICLE IN PRESS T. thereby blocking adherence of pathogens. . Clostridium and E. 2004).. challenge with STEC. coli strains toxins. monocytogenes and Salmonella typhimu. Yersinia enterocolitica. They do not need iron in their natural epithelial cell lines by S. All anti- microbial substances produced by probiotics result in reduced Competition for limiting resources numbers of intracellular bacteria although these substances do not directly inhibit invasion but just kill the pathogens. Mack et al. other peptides with a narrow window of activity.A. The production of the antibiotic 2002) which share common characteristics such as the presence reuterin (3-hydroxypropionaldehyde) by Lactobacillus reuteri of a signal peptide. For some encodes at least seven different iron uptake systems (Grozdanov Lactobacillus kefir strains the component mediating the anti- et al. Besides LMWB probiotics Mub: mucus-binding protein of L. Deconjugated bile acids show a stronger antimicro- culture assay. Reuterin is a broad. In this cell of bile salts. inhibition of Shiga toxin expression (Asahara et al. For EcN inhibition of invasion of various gut the exception of lactobacilli. a C-terminal cell wall-anchoring motif (LPXTG) strain ATCC55730 has been reported. Thus all animals treated with B. 2007b).e. A specific antimicrobial function is the property of proteins establishing a biofilm. The number of intracellular bacteria is ‘‘selfmade’’ metabolites or if they are resistant to deconjugated enumerated after release of the bacteria by lysis of the epithelial bile acids at all remains to be elucidated. 2008)... The effectiveness of certain probiotics in diarrhoea is adhesion of enteropathogenic E. Bifidobacterium pseudocatenulatum DSM20439 inhibition of shiga sus LGG (Collado et al. 2004). compete very effectively for this limited resource because it typhimurium (Ingrassia et al. 2005. the ability to inhibit the toxin expression in E. Roos and Jonsson. protozoa and Besides competitive exclusion. Probiotic bacteria are able to probiotics. cells and determination of the colony-forming units... The most prominent of acetic acid produced by strain Yakult to be responsible for adhesins of probiotics are surface proteins of Lactobacillus (e. 2004). 2008). which kills the extra- organism. 2008). This property probiotic lactobacilli and Bifidobacterium bifidum strain Bb12 are is also common to pathogenic bacteria.. A direct contact between EcN and the invasive bacteria or pathogenic microorganisms (Elli et al. fungi. Production of bacteriocins with an antimicrobial effect towards Gram-positive Not only adhesion to but also invasion of epithelial cells is an as well as Gram-negative bacteria could be proven for various important property for full pathogenicity of many gut pathogens. differentiation between intracellular and extracel- bial activity compared to the bile salts synthesized by the host lular bacteria is achieved by gentamicin. L. However. have to be mentioned.. modes of anti-adhesiveness expressed by probiotics could be because they are also synthesised by many probiotics. Even most likely based on their ability to protect the host against adhesion of pathogenic Salmonella. However. The standard assay for quantification of invasiveness is produce so-called deconjugated bile acids which are derivatives the gentamicin protection assay (Hess et al. monocytogenes has competition with other microorganisms which depend on iron. Botes et al. rendering it unavailable to EcN. not yet identified factor seems to mediate inhibition of invasion rophores to chelate ferric or ferrous iron and expresses iron by EcN (Altenhoefer et al. 2000). iocins. isolates. Whether this in vitro property has also in vivo relevance must be validated in animal Because probiotic bacteria are able to adhere to epithelial cells experiments after identification of the responsible genes with in cell culture assays. EcN is able to also interfering with invasion of host epithelial cells by S. acidophilus and L. The extent of inhibition is dependent on the Nevertheless L. This might be a crucial advantage in Shigella flexneri. 2007). some commercial probiotic strains even increased survived whereas 90% of the mice in the control group died after the adhesion of E. production of receptor analogues and the (molecular weight 420 kDa) belonging to the family of bacter. For Bifidobacterium breve Yakult and probiotic Bifidobacterium lactis Bb12 and/or Lactobacillus rhamno. An important example for a limited substance in the host is there are probiotics able to specifically interfere with bacterial iron. The anti-adhesive effect might be the result of competition between probiotic and pathogen for the same receptor or the induction by probiotics of (increased) mucin Antitoxin effects production.. These proteins are sometimes termed group III bacteriocins of Gram-positive bacteria... such proteins (bacteriocins) Anti-invasive effects are also produced by Gram-negative bacteria.. Secreted factors of some uptake systems to transport it into the bacterial cell. 2006). habitat (Weinberg.g. i.. 2004. coli strain E2348/69. Große et al. 2007a). induction of biosurfactants. 2008).. breve strain Yakult Furthermore. However. typhimurium. it isogenic mutants and their corresponding complemented strains is extrapolated that this mechanism is important for the probiotic in relation to the parental strain. In vitro studies imply the high concentration rium to human mucus (Collado et al. MUC3 mucin inhibited subsequently the are toxins. But for almost all bacteria iron is an essential element with host cell invasion. In contrast to with the epithelial cells is not necessary and therefore a secreted lactobacilli the probiotic EcN relies on iron and secretes side. invasive effect was identified as an S-layer protein which is also shed into the culture medium (Golowczyc et al.. degradation of carbohydrate receptors by secreted proteins. which are receptor by probiotics and pathogens as described above. This protection can result from inhibition of toxin to pig intestinal mucus could be reduced in the presence of expression in pathogens. delbrueckii are able to bind ferric number of EcN bacteria administered and only observed with live hydroxide at their cell surface. coli. How the probiotics protect themselves from these cellular bacteria. This fact led to investigations for probable anti-invasive effects of Deconjugated bile acids. rhamnosus GG. produce also certain antibiotics. reuteri 1063. been reported. Gram-negative bacteria but also against yeast. The ability to inhibit bacterial invasion of gut epithelial cells by pathogens is Anti-adhesive effects rather wide spread among probiotics. 2007). (2003) reported indeed induction of MUC3 mucin in HT20-MTX cells when co-cultured with L. bifidobacteria strains (Cheikhyoussef et al.

CT26 cancer cells originating from the colon of BALB/C mice by 2008).. Still this minority is chains of the original LPS by Gb3. shiga toxin 1 (Stx1) and 2 administered with a daily dose of 109 or 1010 bacteria compared to (Stx2). 2006). 2008). longum strains were shown to bind on an increased cellular immune response as a result of in addition cyanobacterial peptide toxins such as microcystin LR. Castagliuolo et al.. by an amplification like the production of human b- receptor for cholera toxin very efficiently bound the respective defensins induced by the EcN flagella or the inactivation of toxin and showed good protection in animal models after ETEC or clostridial toxins A and B by a protease secreted by S.. injected with tumour cells. Another microcystins and can be found in drinking water after contam. In addition. able to kill pathogens. 2006). actually a strain of salivarius ssp.g. binding of certain mycotoxins and cyanobacterial able to bind other mycotoxins including aflatoxins. An example of an anti-inflammatory active probiotic is activating Erk1/2 and JNK/SAPK pathways (Chen et al. 2008). This involves inhibition of IkBa ubiquitination and enhancing pro- apoptotic MAPK signalling (Chandra et al. 2001. the receptor for these toxins. 2001). inhibit probably adhesion and invasion of The resulting recombinant strain protected all mice after pathogens. Similar designer probiotics carrying the receptor for the gut compartment by probiotics and pathogens (e. to probiotics correlates with reduced mutagenicity of these absorption and increased faecal excretion of aflatoxin resulting in toxins in the presence of appropriate probiotics. coli expressing receptor structures at their surface identical with the receptor for a certain toxin.. rhamnosus strain GG was able to modulate intestinal gens. coliforms or Bacteroides species and confirmed that in vitro 15 different probiotic lactobacilli strains an increase in numbers of lactobacilli and bifidobacteria might at inhibited shiga toxin 2A expression via production of organic acids least reduce the probability of incidence for colorectal cancer.. 2006. which are viewed as tumour promoters or even carcino- model L. One mg bacterial dry weight is able to bind more than up to 1014 bacteria in the colon it is to some extent surprising that 100 mg Stx1 or Stx2. coli (EHEC) O157:H7. Such toxins could be removed from with peptidoglycan from Lactobacillus species. This might be explained by colonization of the same group. The basis of the observed protective effect these probiotics to metabolically inactivate mutagenic substances is rather physicochemical interaction between toxin and probiotic might be responsible for this property.A. al.. casei YIT9092 and B. 2000). 2006). Treatment with Saccharomyces cerevisiae.g. because chronic inflammation promotes the appearance of this boulardii with the toxin A-induced inflammatory signal cascade disease. This toxin is the most frequent and toxic variant of the liver toxic L. This can lead to reducing the levels of cillus rhamnosus GG dead or alive can bind deoxynivalenol and carcinogenic compounds and reducing DNA damage (Geier et al. inactivate toxins and compete for limited resources challenge with a toxin dose killing all animals in the control successfully. boulardii is able to induce a specific anti-toxin A amounts of folate important for DNA repair in epithelial cells (Van IgA immune response and secretes a protease which can destroy Guelpen et al.. 2004). this toxin (Qamar et al. salivarius (O’Mahony et al. is important for anti-carcinogenic effects. 1996). The same strain and L... ARTICLE IN PRESS 60 T. Furthermore. 2005).. This In vitro data indicate. administration of the cytoplasmic fraction of L. the repression of putrefactive neutralization (pH 7) (Takahashi et al. This was achieved by replacing the O-side there are probiotic effects observable at all. ability to amplify the immune response to tumour tissue.. lowered toxicity expressed as alleviated liver injury. shows effective protection against probiotics able to interfere with chronic recurrent inflammation of Clostridium difficile toxin A in the murine ileal loop model and in the gut might also be helpful in preventing colon carcinoma. This can be effective in fighting pathogens and frequency of application was increased (Paton et al. Real-time PCR bacteria such as Clostridium. Such designer Taken into account the low number of probiotic bacteria probiotics bind very efficiently e. Reduction of tumour cell proliferation in vitro and increased Finally the same L. boulardii. cyclic aromatic amines. Designer probiotics The identification of toxin receptors paved the way for Final remarks recombinant E. Lactobacillus reuteri ATCC PTA 6475 secretes factors that potentiate apoptosis in myeloid leukemia-derived cells induced by tumour necrosis factor. incidence of adenocarcinoma in the colon of IL-10 knockout mice 2008). it was shown than metabolic inactivation. some bifidobacteria strains and EcN show a Certain probiotics are even able to protect against cyanobac. The at subbactericidal concentrations for EHEC O157:H7 (Carey et al. coli (ETEC) or the epithelium). increasing apoptosis (Sun et al.. 2007). The ability of terial and fungal toxins. In this study aqueous solutions by binding to the mentioned probiotics to a peptidoglycan reduced in a dose-dependent manner growth of varying degree depending on the strain employed (Nybom et al. et al. marked anti-mutagenic activity in in vitro systems. that strain GG reduces aflatoxin B1 uptake boosted immune response is achieved by modulation of cytokine and protects against both membrane and DNA damage (Gratz et production and T cell function (Hirayama and Rafter. longum HY8001 (Lee et al. For some constructs formaldehyde. All this was Another way for anti-tumour activity of probiotics is their the result of aflatoxin binding to this probiotic (Gratz et al. The mycotoxin deoxynivalenol as a that certain probiotics bind N-nitroso compounds and hetero- contaminant of cereal crops can cause gastroenteritis. modula- . Strain MIYAIRI inhibits in vitro and in vivo There are claims for anti-cancer activity of probiotics. In the rat toxins. biggest boost might be achieved by the modulation of the killed bacteria mediated also efficient protection as long as the immune system. 2004).. Oelschlaeger / International Journal of Medical Microbiology 300 (2010) 57–62 Similarly. the colon heat-labile enterotoxin of enterotoxigenic E. Many lactobacilli. acidophilus SNUL.. The Vibrio cholerae challenge. Streptococcus thermophilus strain TH-4 which also produces high Additionally. Tooley et al. evidence of anti-carcinogenic property of cell fractions is a study ination with cyanobacteria.. rhamnosus strains but also certain survival rate of mice. However. cell culture assays. 2006). therefore potentially restricts bioavailability of this toxin (Turner 2006)... was factually reduced in mice treated with probiotic Lactobacillus The probiotic yeast Saccharomyces boulardii. probiotic Clostridium butyricum strain MIYAIRI protected Inhibitory activity against genotoxins gnotobiotic mice against an infection with enterohaemorrhagic E. This protection results from interference of S. was indeed based Bifidobacterium lactis and B. Lactoba. rhamnosus strain LC-705 are Similarly. If such a not only shiga toxin expression by production of butyric and lactic protection occurs in humans who consume the appropriate acid but butyric acid also reduces viability of EHEC after probiotic is unknown. S.

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