Gut ecosystem: how microbes help us.

Wageningen Academic P u b l i s h e r s

Beneficial Microbes, 2014; 5(3): 219-233

http://www.wageningenacademic.com/doi/pdf/10.3920/BM2013.0057 - Tuesday, October 10, 2017 5:35:21 AM - Göteborgs Universitet IP Address:130.241.16.16

Gut ecosystem: how microbes help us R. Martín1,2, S. Miquel1,2, J. Ulmer1,2, P. Langella1,2 and L.G. Bermúdez-Humarán1,2 1INRA, UMR1319 Micalis, Domaine de Vilvert, 78350 Jouy-en-Josas, France; 2AgroParisTech, UMR Micalis, Domaine de

Vilvert, 78350 Jouy-en-Josas, France; [email protected]

Received: 25 September 2013 / Accepted: 7 November 2013 © 2014 Wageningen Academic Publishers

REVIEW PAPER Abstract The human gut houses one of the most complex and abundant ecosystems composed of up to 1013-1014 microorganisms. Although the anthropocentric concept of life has concealed the function of microorganisms inside us, the important role of gut bacterial community in human health is well recognised today. Moreover, different microorganims, which are commonly present in a large diversity of food products, transit through our gut every day adding in some cases a beneficial effect to our health (probiotics). This crosstalk is concentrated mainly in the intestinal epithelium, where microbes provide the host with essential nutrients and modulation of the immune system. Furthermore, microorganisms also display antimicrobial activities maintaining a gut ecosystem stable. This review summarises some of the recent findings on the interaction of both commensal and probiotic bacteria with each other and with the host. The aim is to highlight the cooperative status found in healthy individuals as well as the importance of this crosstalk in the maintenance of human homeostasis. Keywords: microbiota, immunomodulation, crosstalk bacteria-host, human health

1. Introduction A vast number of bacteria, archaea, viruses, and unicellular eukaryotes inhabit the human body. In particular, the gastrointestinal tract (GIT) is by far the most greatly colonised organ. The GIT is a microenvironment for a varied and dynamic microbial population, whose structure and functions are of capital importance to human health. Despite this dynamism, the core of dominant species is stable in long-term analysis (Martinez et al., 2013). In addition, the human GIT has an estimated surface area of around 200 m2 thus representing a major surface for microbial colonisation (Gebbers and Laissue, 1989). Furthermore, the GIT is rich in molecules that can be used as nutrients by the microorganisms, favouring the colonisation. The interaction between gut microbiota and the host, among others, is essential for the maturation of the immune system and for the developmental regulation of intestinal physiology. Alterations in the process of microbial colonisation of the human GIT in early life have been shown to influence the risk of disease afterward in life (Sekirov et al., 2010). In addition, a deregulation of this microbial ecosystem may happen by the growth of subdominant opportunistic bacteria; this dysbiosis can lead to a situation

of illness (Martin et al., 2013). Thus, when commensal bacteria are partial or completely depleted, an abnormal situation occurs due to a lack of beneficial effects of these bacteria rather than the overgrowth of pathobionts (Miquel et al., 2013). To fully understand the human gut ecosystem it would be necessary to combine the analysis of both the host and its surrounding environment (geolocalisation, season, lifestyle, etc.). This includes the bacteria ingested everyday, such as those present in fermented foods and probiotics: ‘live microorganisms which when administered in adequate amounts confer a health benefit on the host’ (FAO/WHO, 2002) and the relationship between them and other possible bacteria present in the intestinal environment. For example, complex relations have been found among diet, gastrointestinal transit, and gut microbiota in humanised mice (i.e. germ-free mice colonised by human microbiota) (Kashyap et al., 2013). Both commensal and probiotic microorganisms offer a wide range of benefits to the host. This crosstalk can be classified into three major categories depending on which component of the ecosystem is regulated: the intestinal epithelium, the intestinal pathogenic bacteria and the immune response (Figure 1).

ISSN 1876-2833 print, ISSN 1876-2891 online, DOI 10.3920/BM2013.0057219

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Probiotic Vitamins SCFA Metabolites Free amino acids GABA

Comm

IgA

en

Direct exclusion and competition

β-defensins Heat shock proteins

Mucus layer Absorption of nutrients

Antimicrobial substances Lactic acid H2O2 Bactericins

Pathog

Modification of gene expression

M cell

Tight junction

IEC Lamina propria

Dendric cell

IL-12 IL-6 IL-23

Sub-epithelial macrophage

IgA Killing of commensal bacteria

IL-12 IL-10 TGF-β TNF-α

Plasma cell IEC

Microbial signals (MAMPS)

Native T cell

TH2 IL-4 IL-5

TH1 IL-12 IFN-γ

TLR 2/1/6

TLR 4

MyD88

TIRAP

TRIF

TRAF6

Treg IL-10 TGF-β

TLR 3

ERK/p38/JNK NFκB

Proper TH1/TH2 ratio

Endosome

MAPK

Cytokines and chemokines

Figure 1. Mechanisms of action of resident bacteria. Probiotic and commensal bacteria are able to communicate with M cells, dendritic cells and IECs activating signalling pathways leading to the production of different cytokines and inmunoglobulines. They induce IECs to produce defence molecules, such as β-defensins and heat shock proteins, and enhance their absorption of nutrients by producing vitamins, GABA and free amino acids, among others. Finally, they abolish pathogen development and establishment by means of direct exclusion and the production of antimicrobial substances. Abbreviations used: ERK = extracellular-signal-regulated kinase; GABA = gamma-aminobutyric acid; IEC = intestinal epithelial cell; IFN = interferon; IgA = immunoglobulin A; IL = interleukin; JNK = c-Jun N-terminal kinase; MAMPS = microbe-associated molecular patterns; MAPK = mitogen-activated protein kinase; NFκβ = nuclear factor kappa beta; SCFA = short chain fatty acid; TGF = tumour growth factor; TH = T helper cell; TIR = Toll/interleukin-1 receptor; TLR = Toll-like regulator; TNF = tumour necrosis factor; TRAF = TNF-receptor-associated factor; TRIF = TIR-domain-containing adapter-inducing interferon-β. 220

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Human microbiota and health

2. Regulating intestinal epithelial cells development and functions

Human microbiota is part of the mammalian nutrition system

The GIT microbiota has a major influence on the host epithelium. Although life without microbiota is possible, its absence interferes with the normal development of the GIT as shown in the case of germ-free animals that have morphological and physiological characteristics differing from conventional ones (Leser and Molbak, 2009). Compared with conventional animals, germ-free animals have an immature and underdeveloped lymphoid system, a decreased number of secretory goblets and enteroendocrine cells, and epithelial cell turnover (Bates et al., 2007; Chowdhury et al., 2007; Smith et al., 2007). The use of gnotobiotic animals (i.e. germ-free animals colonised by one or a few bacterial species) can help us understand the role of the different members of the microbiota in the maturation of host epithelium as well as the main pathways of action. Studies with these animals have demonstrated that bacteria modify host glycosylation patterns and gene expression, and take part in epithelial maturation and proliferation (Bry et al., 1996; Cherbuy et al., 2010; Hooper et al., 2001; Reikvam et al., 2011). In fact, bacteria can have an impact on the colon epithelium development in part due to their metabolite production. For example, lactate has been proposed as the signal produced by Streptococcus thermophilus to modulate colon epithelium (Rul et al., 2011) and acetate produced by Bacteroides thetaiotamicron to induce cell differentiation (Wrzosek et al., 2013). Furthermore, mono-associated mice with one species of Bacteroides have recently allowed the detection of a locus responsible for commensal colonisation (named ccf for commensal colonisation factors) that confers resistance to colonisation by the same species (Lee et al., 2013).

Most of the absorption and digestion of food takes place in the small intestine where bacteria have been reported to produce vitamins essential to the host (Conly and Stein, 1992; Mcconnell and Tannock, 1993; Tannock et al., 1988, 1994). In addition, the bacterial formation of short-chain fatty acids (SCFA) in the intestine enables the host to use some energy of the dietary fibre that would not be used otherwise. Strikingly, it has been demonstrated that 70% of the energy obtained by intestinal epithelial cells (IECs) is derived from butyrate (Roediger, 1980). Claus et al. (2011) have demonstrated that during gut colonisation of germfree animals there is a rapid weight gain associated with the stimulation of hepatic glycogenesis and triglyceride synthesis. Intestinal bacterial transformation of some plantderived non-nutritive substances, such as flavonoids, leads to the formation of a large variety of metabolites (Blaut and Clavel, 2007). Gut microbiota has also been found to modify mouse bile acid metabolite profiles modulating the hepatic expression of 12-alpha hydroxylase, an enzyme which controls the hydrophobicity of the bile acid pool, an important component in cholesterol absorption and biosynthesis in the liver (Claus et al., 2011).

One of the main functions of the GIT epithelium is to absorb nutrients, water and electrolytes, but it also represents the main barrier between pathogens (and other undesirable compounds) and the host (Leser and Molbak, 2009). Microbiota take part in these processes, modifying epithelial expression of genes involved in nutrient uptake and metabolism, mucosal barrier function, xenobiotic metabolism, enteric nervous system and motility, hormonal and maturational responses, angiogenesis, cytoskeleton and extracellular matrix, signal transduction, cell turnover, mucus biosynthesis, and priming of the immune system (Chowdhury et al., 2007; Leser and Molbak, 2009). Interestingly, these modifications depend on microbiota composition, since the host responds to each bacterium in a specific way (Leser and Molbak, 2009).


In addition, the production of some biogenic compounds by microorganisms in functional foods improves their nutritional composition in free amino acids, vitamins, bioactive peptides and γ-amino butyric acid (GABA). These components protect the producing bacteria from acidic pH and have physiological roles, such as neurotransmission, induction of hypotension, and diuretic and tranquiliser effects (Gobbetti et al., 2010). From this perspective, microbial metabolism of bacteria present in cheese and kefir (a fermented dairy product) enhances their nutritional properties due to the increase in concentration of free amino acids during processing (Mangia et al., 2008; Milesi et al., 2008; Simova et al., 2006). This also occurs in fermented milk that contains bioactive peptides having antioxidative, antimutagenic or antihypertensive effects (Hayes et al., 2006; Matar et al., 1996; Minervini et al., 2003). This role can also be played by bacterial compounds, for instance, butyrate modulates enterocyte differentiation, proliferation and restitution (Augeron and Laboisse, 1984; Bocker et al., 2003; Tsao et al., 1982), fatty acid oxidation, electron transport chain, oxidative stress and apoptosis (Vanhoutvin et al., 2009) (Figure 2). Butyrate has also been associated with specific modulation of muc gene expression in intestinal epithelial goblet cells deprived of glucose (Gaudier et al., 2004). This compound acts at transcriptional level, stimulating or inhibiting gene expression mainly by hyperacteylating histones (Mohana Kumar et al., 2007; Sealy and Chalkley, 1978).

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en

Butyrate

Mucus layer

Fatty acid oxidation Electron transport Oxidative stress

Energy

IEC

Cytokines

Goblet cell

Differentiation Proliferation Restitution Apoptosis

Lamina propria muc genes expression

Figure 2. Butyrate effects. Butyrate is a short chain fatty acid (SCFA) that interacts with the intestinal epithelial cell (IEC) leading to the activation of different genes involved in the differentiation, proliferation and restitution of enterocytes. It is also involved in the regulation of fatty acid oxidation, electron transport chain, oxidative stress and apoptosis. In goblet cells, it has been described to stimulate muc genes, allowing a high production of mucus. Finally, this SCFA is an energy source for the cells and stimulates the production of different cytokines in a time-, cell type- and dose-dependent way.

Keeping the protective role of the epithelium The intestinal barrier is an effective defence mechanism that depends on the integrity of the tight junction complex between cells (Figure 1). Several microorganisms have shown to protect this integrity and repair it when it has suffered damage. Among them, Lactobacillus acidophilus

and B. thetaiotaomicron prevent the cytokine-induced increase in permeability (Resta-Lenert and Barrett, 2006). Different probiotic bacteria also protect the intestinal barrier by other mechanisms, such as enhancing membrane translocation of tight junction complex proteins, either increasing or stabilising transepithelial resistance (TER) (Table 1).

Table 1. Some bacteria involved in stabilising transepithelial resistance. Microorganism

Model1

Effect1

Reference

Escherichia coli Nissle 1917

infection with EPEC strain E2348/69 in polarised T84 intestinal human epithelial cells Salmonella dublin induced alterations hydrogen peroxide-induced damage in Caco-2 cells monolayers

restores barrier disfunction

Zyrek et al., 2007

E. coli Nissle 1917 and VLS#3 Lactobacillus rhamnosus GG and its soluble proteins (p40 and p75) Lactobacillus casei DN-114001

both co-culture and post-infection models of EPEC (strain E2348/69) in T84 cells

restores barrier disfunction Otte and Podolsky, 2004 protects intestinal epithelial tight junctions Seth et al., 2008 and barrier function by PKC- and MAPK-dependent mechanism decreases E. coli-induced TER and ZO-1 Parassol et al., 2005 redistribution in a dose dependent way

1

Abbreviations used: EPEC = enteropathogenic E. coli; MAPK = mitogen-activated protein kinase; PKC = protein kinase C; TER = transepithelial resistance; ZO-1 = zonula occludens-1.

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In the intestinal epithelium, some microorganisms can induce the production of cytoprotective substances or molecules. These molecules, such as heat-shock proteins (Hsp), are constitutively expressed in IECs, and their expression is increased when a stress arrives in order to maintain homeostasis. Bacteroides fragilis ATCC23745 plays a role in maintaining physiological expression of Hsp25 and Hsp72 colonocytes (Kojima et al., 2003). Likewise, it has been demonstrated that some soluble factors present in the culture supernatant of the probiotic Lactobacillus rhamnosus GG (LGG) strain also induce the expression of these Hsp in a p38- and c-Jun N-terminal kinase (JNK)/ mitogen-activated protein kinase (MAPK)-dependent way (Tao et al., 2006). Additionally, LGG also prevents cytokine-induced apoptosis activating anti-apoptotic Akt in a phosphatidylinositol-3-kinase dependent manner and inhibiting pro-apoptotic p38/MAPK activation (Yan and Polk, 2002). This activity has been found to be induced by two soluble factors, proteins p75 and p40, present in the LGG culture supernatant (Yan et al., 2007). The intestinal epithelium also contributes to host defence by producing antimicrobial peptides. In particular, the defensins (small cationic peptides) inhibit the entry of enteric bacteria and other potential pathogen microorganisms (Ganz and Lehrer, 1994). In this way, some probiotic lactobacilli as well as VLS#3 (a mixture of Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, L. acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus bulgaricus and S. thermophilus) and Escherichia coli Nissle 1917 induce the expression of the antimicrobial peptide human beta-defensin-2 (hBD2) in the human line Caco-2 in vitro. All these probiotic bacteria strengthen intestinal barrier function by inducing pro-inflammatory pathways, including nuclear factor kappa beta (NF-κB) and activator protein-1, as well as MAPKs (Schlee et al., 2007; Wehkamp et al., 2004). This effect has been also demonstrated in vivo, where faecal hBD-2 peptide was increased by 78% after three weeks of E. coli Nissle 1917 administration (Mondel et al., 2009). The epithelial barrier also consists of a dense mucous layer containing secretory immunoglobulin A (IgA) (Ohland and MacNaughton, 2010) and antimicrobial peptides (Antoni et al., 2013). Normal human colon has an inner mucus layer that is impenetrable to bacteria (Johansson et al., 2013). Mucus is continuously secreted into the GIT lumen by goblet cells and is mainly composed of heavily O-glycosylated proteins called mucins (Kim and Ho, 2013). Microbiota is able to influence the globet cell number and function modulating the mucus layer (Wrzosek et al., 2013) (Comelli et al., 2008; Tomas et al., 2013). This mucus layer covering the epithelial surface serves as the first line of protection against the luminal contents and plays a key role in the establishment and activity of the commensal microbiota.



Inhibition of pathogen growth Production of antimicrobial substance H

O

– H2O2

O

Competition for the nutrients

H

– Lactic acid

– Bacteriocins: Class I, II, III and IV

Gut microbiota and probiotic bacteria

Adhesion to: – epithelium – mucus – fibronectin

Co-aggregation

Inhibition of pathogen colonisation

Figure 3. Antimicrobial effect of gut microbiota and probiotics. Gut microbiota make use of two mechanisms to protect the mucosa from the settlement of undesirable microorganisms: (1) exclusion (inhibition of pathogen colonisation), driven by the formation of a biofilm that masks the epithelial cell receptors and (2) inhibition of growth, due to generation of lactic acid from the fermentative catabolism of sugars, hydrogen peroxide (H2O2) and bacteriocins, among others.

3. Blocking effects of intestinal pathogenic bacteria Another of the proposed benefits of both commensal and probiotic bacteria to human health includes antimicrobial activities (Figure 3). In vitro studies have shown that probiotics display their antimicrobial effect mainly by means of production of antibacterial substances (Cotter et al., 2005; Servin, 2004) and their competitive effects. Among these molecules, the most important antimicrobial compounds are lactic acid, hydrogen peroxide (H2O2 ) and bacteriocins. Lactic acid production is a defining trait of the lactic acid bacteria group (LAB), which are the most representative probiotics up to date (Holt, 1994; Riley and Wertz, 2002) and form part of the autochthonous microbiota of the human gut. The main effect of the lactic acid is to inhibit bacterial growth due to the decrease in pH, although new antimicrobial functions are being attributed to it (Kolling et al., 2013). H2O2 exerts its bactericidal effect through generation of oxidising metabolites such as the radical OHthat introduces breaks in the DNA of the cell (Klebanoff and Belding, 1974). This effect is notably enhanced in the acid vaginal environment (Martin and Suarez, 2010).

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Bacteriocins are antimicrobial peptides that are generally active against bacteria related to the producing strain but are not toxic to it (Konisky, 1982; Tagg et al., 1976). Although bacteriocins have been found to have many distinct mechanism of action (Cotter et al., 2013), their principal mechanism is forming pores in the cytoplasmic membrane of sensitive bacteria, for example nisin target lipid II, a key intermediate in peptidoglycan biosynthesis (Bierbaum and Sahl, 2009). They have been found to be produced by both Gram positive and Gram-negative microorganisms, including commensal and probiotic bacteria. Classically, they can be classified into four different groups: (Class I) low molecular weight bacterocins, called lantibiotics, which are post-translationally modified and contain unusual amino acids; (Class II) low molecular weight bacteroicins heat stable non-lantibiotics; (Class III) high molecular weight bacteriocins; and (Class IV) cyclic antimicrobial peptides (Oelschlaeger, 2010). The analysis of the currently known genomic sequences of Lactobacillus strains predicts a broad group of bacteriocins with highly divergent sequences active against Gram-positive bacteria, such as Lactococcus, Streptococcus, Staphylococcus, Listeria and Mycobacteria (Altermann et al., 2005; Chaillou et al., 2005; Makarova et al., 2006; Pridmore et al., 2004). For instance, it is well known that a Class II bacteriocin produced by Lactobacillus salivarius UCC118 has the ability to protect mice against infection with Listeria monocytogenes (Corr et al., 2007). In the same vein, the board spectrum antibiotic activity of reuterin, a potent antimicrobial multi-compound produced by Lactobacillus reuteri ATCC55730, is active not only against Gram-positive and Gram-negative bacteria but also against yeast, fungi, protozoa and viruses (Cleusix et al., 2007). Bacteriocins have been found in almost every bacterial species studied, and within a species tens or even hundreds of different kinds of bacteriocins are produced (James et al., 1991; Riley and Wertz, 2002). Their presence is frequently related to probiotic properties (Awaisheh et al., 2013; Messaoudi et al., 2013). Other anti-microbial mechanisms carried out by microorganisms are direct exclusion or competition. For instance, bacteria can directly antagonise limiting resources (e.g. iron; Oelschlaeger, 2010) or competitively inhibit pathogen and toxin adherence to the intestinal epithelium. Several strains of lactobacilli and bifidobacteria are able to inhibit the adhesion of the following pathogenic bacteria to IECs: Bacteroides vulgates, Clostridium histolyticum, Staphylococcus aureus, Salmonella enterica, Yersinia enterocolitica, and enterotoxigenic and enteropathogenic E. coli (Candela et al., 2005; Collado et al., 2007; Roselli et al., 2006; Sherman et al., 2005). These strains are also able to displace pathogens already attached to the epithelial surface before their administration (Candela et al., 2005; Collado et al., 2007). Besides competitive exclusion, probiotics can also interfere with pathogenic bacteria through degradation of receptors via secreted proteins, establishment of a 224

biofilm, production of receptor analogues, induction of biosurfactants and increasing mucin production (Mack et al., 2003; Oelschlaeger, 2010). Finally, some bacteria have been also able to inhibit the invasion of epithelial cells or the expression of toxins in some pathogens. Secreted factors of Bifidobacterium breve CNCM I-4035 interfere with the invasion of host cells by Salmonella typhi (Bermudez-Brito et al.,2013) Tien et al. (2006) reported that a strain of Lactobacillus casei could attenuate the pro-inflammatory signalling induced by Shigella flexneri after invasion of human IECs. These effects are due, at least in part, to a down-regulation of proinflammatory cytokines and chemokines and adherence molecules induced by invasive S. flexneri resulting in an anti-inflammatory effect, apparently mediated by the inhibition of NF-κB pathway (Tien et al., 2006). Similar effects have been described in E. coli Nissle 1917, which is able to inhibit the invasion of various gut epithelial cells lines by the following bacteria: adherent-invasive E. coli (AIEC), S. typhi, Y. enterocolitica, S. flexneri, Legionella pneumophila and L. monocytogenes (Altenhoefer et al., 2004; Boudeau et al., 2003). Moreover, B. breve Yakult, Bifidobacterium pseudocatenulatum DSM20439 and Clostridium butyricum MIYAIRI inhibit Shiga toxin expression by E. coli O157:H7 (Asahara et al., 2004; Takahashi et al., 2004), and Saccharomyces cerevisiae protects against Clostridium difficile toxin A-associated enteritis by blocking the activation of Erk1/2 MAP kinases (Chen et al., 2006).

4. Regulating mucosal immune responses Stable (commensal) or temporary (probiotics) resident bacteria in the GIT play a fundamental role in the development and maintenance of the right immune functions. The intimate relationship between commensal bacteria and the host immune system (crosstalk) is increasingly clear (Macpherson and Harris, 2004; Noverr and Huffnagel, 2004). Furthermore, probiotic and commensal microbiota regulate the balance between pro- and anti-inflammatory mucosal responses leading to intestinal homeostasis and protecting from pathogen damage and inflammation. On the other hand, the temporal stability of the gut microbiota depends on innate and adaptive immunity (Dimitriu et al., 2013).

Enhancing host innate immunity The gut-associated lymphoid tissue, which is formed in the intestine by Peyer’s patches, isolated lymphoid follicles (ILFs) and the mesenteric lymph nodes (MLNs), is in active communication with intestinal microbiota and directly interacts with orally administered antigens or bacteria, such as probiotics. Their development also depends on the microbiota, as can be deduced by the fact that germBeneficial Microbes 5(3)


free mice have underdeveloped Peyer’s patches and MLNs (Macpherson and Harris, 2004) as well as lower ratio of CD4+ T cells compared to conventional mice (Mazmanian et al., 2005). B. fragilis NCTC 9343 presents a polysaccharide (PSA)-promoting lymphoid organogenesis that increases CD4+T cells in germ-free rodents (Mazmanian et al., 2005). Additionally, Lactobacillus gasseri, Lactobacillus johnsonii and L. reuteri can also upregulate host immune Th1 responses through dendritic cells (DCs)-directed T cell activation to defend against infection (Mohamadzadeh et al., 2005). Gram-negative peptidoglycan also has an important role in this phenomenon, being necessary and sufficient to induce formation of ILFs (Bouskra et al., 2008). All these factors among others, also called symbiosis factors, are the molecular demonstration of the environmental interactions between bacteria and host. Bacteria are internalised by M cells (Figure 1) allowing the interaction with DCs and follicle-associated epithelial cells, which is the initial step in various responses mediated by macrophages and T- and B-lymphocytes (Kraehenbuhl and Corbet, 2004; Winkler et al., 2007). Interestingly, intestinal DCs can retain commensal bacteria selectively, activating B lymphocytes to produce IgA that leads to the reduction of mucosal penetration by bacteria and also the prevention of absorption of antigens from mucosal surfaces (Lamm et al., 1996). In this context, Bifidobacterium animalis strain Bb12 (Bakker-Zierikzee et al., 2006) and LGG (He et al., 2005) have been found to increase faecal IgA levels. Additionally, LAB can interact at different levels with the immune system, through M cells at Peyer’s patches or directly with the IECs. The following immune pathways have been previously described (Perdigon et al., 1999): (1) L. acidophilus and L. plantarum increase the number of immonuglobulin M cells in the lamina propria; (2) L. rhamnosus and Streptococcus salivarius ssp. thermophilus, increase IgA cells present in the MLNs after interacting with IECs and being processed and presented as antigens; and (3) Lactobacillus delbrueckii ssp. bulgaricus and Lactococcus lactis increase IgA cells interacting with IECs without being processed as antigens. Furthermore, the potential systemic immune responses are avoided by the restricted localisation of DCs carrying commensals to the intestinal mucosal lymphoid tissues (Macpherson and Harris, 2004).

Balancing the ratio of pro- and anti-inflammatory cytokine production The human immune system is dynamic, being able to adapt to different situations. The proper balance Th1/Th2 is critical to maintain human health (Neurath et al., 2002). The indigenous microbiota is responsible for at least part of this equilibrium (Mazmanian et al., 2005). On one hand, there are some probiotics that have been shown to increase the production of anti-inflammatory cytokines by DCs (including interleukin (IL)-10), which in turn suppress Beneficial Microbes 5(3)


the Th1 response, such as L. reuteri, L. casei and VSL#3 (Drakes et al., 2004; Hart et al., 2004; Smits et al., 2005). Interestingly, another study demonstrated that beneficial effects of VSL#3 may also result from native DNA carrying specific unmethylated CpG motifs (Rachmilewitz et al., 2004). In fact, DNA isolated from this probiotic mixture was able to reduce IL-8 production by IECs exposed to a pro-inflammatory stimulus via a mechanism involving I-κB stabilisation. Other probiotics seem to block the production of these inflammatory cytokines in an IL-10independent manner. In this group, we can find B. infantis and Lactobacillus spp. that inhibit IL-12 and tumour necrosis factor (TNF)-α in IL-10 knockout mice (Pena et al., 2005; Sheil et al., 2006), and L. salivarius Ls33 that induces local mucosal IL-10 production in an NOD-like receptor (NLR) protein 2-peptoglycan-dependent way, protecting mice from chemically induced colitis (Fernandez et al., 2011). This NLR interaction has also been proposed in cell signalling after host cell internalisation of peptidoglycan fragments, mainly with the NLR protein 1 that interacts with the gamma-D-glutamyl-mesodiaminopimelic acid present in all Gram-negative bacteria (i.e. E. coli Nissle 1917) and some Gram-positive bacteria, such as L. plantarum, but also with MLR protein 2 that detects muramyl dipeptides present in all peptidoglycan (Bron et al., 2012). Probiotics and commensal bacteria can also modulate the ratio of Th2/Th1 cytokines by suppressing proinflammatory cytokine production. Thus, different bacteria, conditioned media (i.e. supernatant) or symbiosis factors are postulated as mediators of this process (Table 2). Although most of the factors mediating this process are still unknown, the role of PSA from B. fragilis correcting the Th1/Th2 balance has been proved in cellular and animal models (Mazmanian et al., 2005, 2008) as well as the anti-inflammatory character of the lipoteichoic acid (LTA) of L. plantarum KCTC10887BP (Kim et al., 2007, 2008a,b, 2011). In fact, purified LTA from L. plantarum WCFS1, L. plantarum KCTC10887BP, L. plantarum L-137, L. casei YIT9029, LGG and L. acidophilus NCFM have been found to modulate TNF through a Toll-like receptor (TLR)-2 mechanism (Bron et al., 2012). Other cell wall components, such as capsular polysaccharide (CPS), are also recognised by host specific receptors, such as the CPS of L. casei Shirota that mediates the suppression of proinflammatory responses in macrophages (Yasuda et al., 2008). Some other metabolites have also been proposed to counterbalance this ratio. For instance, butyrate has immunoregulatory effects on IECs in vivo and in vitro (Kamitani et al., 1999). These effects seem to be dose- and time-dependent and also different in each cellular type. In fact, butyrate decreases the secretion of IL-8 in Caco-2 and HIPEC cells but enhances IL-8 production in HT-29 and HT-29 MTX cells all from intestinal origin (Bocker et al., 2003). Additionally, butyrate enhances IL-10 and IL-4 secretion by human monocytes, and reduces IL-2 and 225

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Table 2. Examples of some bacteria found to regulate the Th1/Th2 cytokine ratio. Microorganism

Activity localisation

Anti-inflammatory Cellular factor models

Animal models

Reference

Actinobacillus actinomycetemcomitans Bacteroides fragilis Bacteroides thetaiotamicron Bifidobacterium animalis MB5 Bifidobacterium bifidum B536 Bifidobacterium breve BbC50 B. breve C50 B. breve NumRes 204 Escherichia coli Nissle 1917 Faecalibacterium prausnitzzi Lactobacillus bulgaricus KCT3188 Lactobacillus casei L. casei CRL 431 L. casei KCTC L. casei LOCK 0900, 0908, Lactobacillus paracasei LOCK 0919 Lactobacillus helveticus KCT3545 Lactobacillus johnsonii Ncc533 Lactobacillus paraplantarum BGCG11 Lactobacillus plantarum L. plantarum KCTC10887BP L. plantarum BMCM12 L. plantarum, Lactobacillus acidophilus and Bifidobacterium infantis Lactobacillus reuteri Lactobacillus rhamnosus GG

cell surface cell surface unknown cells conditioned medium conditioned medium conditioned medium cells conditioned medium conditioned medium, cells cell (heat killed) unknown cells cell (heat killed) cell (heat-killed)

unknown (peptide) polysaccharide psa unknown unknown unknown unknown unknown unknown unknown unknown unknown unknown unknown unknown unknown

yes yes yes yes yes yes yes yes yes yes yes yes no yes yes

no yes yes no no no no no no yes no no yes no no

Reddi et al., 1995 Mazmanian et al., 2005, 2008 Kelly et al., 2004 Roselli et al., 2006 Menard et al., 2004 Menard et al., 2004 Heuvelin et al., 2009, 2010 Plantinga et al., 2011 Sturm et al., 2005 Sokol et al., 2008 Kim et al., 2011 Tien et al., 2006 Castillo et al., 2011 Kim et al., 2011 Cukrowska et al., 2010

cell (heat killed) cells cell (uv-irradiated) conditioned medium cell wall extracellular proteins conditioned medium

unknown unknown exopolysaccharide unknown lipoteichoic acid peptide stp unknown

yes no yes yes yes yes yes

no yes no no no no yes

Kim et al., 2011 Yang et al., 2011 Nikolic et al., 2012 Petrof et al., 2009 Kim et al., 2007 Bernardo et al., 2012 Shiou et al., 2013

biofilm supernatants cells and soluble factors

unknown unknown

yes yes

no no

L. rhamnosus CRL1505 L. rhamnosus GG NCIMB 8824, Lactobacillus salivarius NCIMB 41606, L. plantarum NCIMB 41605, Lactobacillus fermentum MS15 and B. breve NCIMB 8807 L. salivarius Ls33

cells cell (heat-killed), conditioned medium

unknown unknown

no yes

yes no

Jones and Versalovic, 2009 Pena and Versalovic, 2003; Roselli et al., 2006 Villena et al., 2012 Habil et al., 2011

cell wall

yes

yes

Fernandez et al., 2011

L. salivarius UCC118 L. salivarius, LDR0723, BNL1059, RGS1746 and CRL1528 L. salivarius CECT5713, Lactobacillus fermentum CECT5716 Leuconostoc mesenteroides KCTC3100 Ruminococcus gnavus FRE1 Salmonella pollurum Staphylococcus aureus Streptococcus Streptococcus thermophilus

cells cells

peptidoglycan and derivates unknown unknown

yes yes

no no

O’Hara et al., 2006 Drago et al., 2010

cells

unknown

yes

no

Perez-Cano et al., 2010

cell (heat killed) conditioned medium cellular cell wall conditioned medium conditioned medium

unknown unknown unknown lipoteichoic acid unknown unknown

yes yes yes yes yes yes

no no no no no no

Kim et al., 2011 Menard et al., 2004 Neish et al., 2000 Kim et al., 2008a,b Menard et al., 2004 Menard et al., 2004

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interferon-γ production showing an anti-inflammatory profile (Saemann et al., 2000). In fact, long-term incubations (~24 h) show a pro-inflammatory role of butyrate in HT29 cells with a stable NFκB-secreted embryonic alkaline phosphatase (SEAP) reporter system stimulated by TNF-α (Lakhdari et al., 2011), while it has been demonstrated that butyrate inhibits TNF-α-induced nuclear translocation of the pro-inflammatory transcription factor NFκB within 30 min of TNF-α stimulation by suppressing Iκβ-α degradation and proteasome activity (Yin et al., 2001).

Additionally, the lack of additional virulence factors or other molecules on the bacterial surface as well as slight structural modifications can lead to a different host response for beneficial versus pathogenic bacteria. When different polysaccharides, which vary in their sugar composition, ring forms, linkage positions, anomeric-centre configurations, isomer forms and conformations, interact with the immune system, a different epitope is generated. The presentation of the different epitopes will thus elicit a different immune response (Mazmanian and Kasper, 2006).

Recently, another interesting method of analysis has been achieved with the use of genome sequences and predicted proteomes that allows the in silico determination of putative microorganism-associated molecular patterns (MAMPs), such as the bacteriocin plantaricin from L. plantarum found to have inmmunomodulatory activity (Bron et al., 2012; Molenaar et al., 2005; Siezen et al., 2013; van Hemert et al., 2010).

5. Concluding remarks

Differential immune activation: beneficial bacteria versus pathogenic ones It is clear that host cells, including the immune system, react in a different way to beneficial bacteria (e.g. probiotics) than to pathogenic microorganisms, but how can the human host cells distinguish between beneficial and pathogenic microorganisms? Bacterial surface macromolecules are key factors interacting with host receptors in gastrointestinal mucosa. The subtle differences in MAMPs existing between probiotic and commensal bacteria and also with pathogenic bacteria have been reviewed recently by Lebeer et al. (2010). Briefly, the authors conclude that the final response of the host cell depends on the combination of the different MAMPs that are recognised by specific pattern recognition receptors (PRRs) and co-receptors (Chu and Mazmanian, 2013; Fischer et al., 2006). The accessibility, subcellular distribution, compartmentalisation and expression levels of the co-receptors direct the final responsiveness of the cell to the bacteria. These PRRs are comprised of TLRs, NLRs (nucleotide-binding oligomerisation domains), adhesion molecules and lectins (Gomez-Llorente et al., 2010). To trigger transient pro-inflammatory responses, pathogens need specific virulence factors to active specific TLR co-receptors and adaptator molecules (Rumbo et al., 2006). For instance, the flagellins of the probiotic bacteria E. coli Nissle 1917 and the pathogen S. typhimurium are both recognised by TLR-5 but, while the first one does not have a known co-receptor, the second one needs the presence of gangliosides (asialo-GM1) to develop response (Hayashi et al., 2001; Ogushi et al., 2004; Schlee et al., 2007). Furthermore, investigations have shown that the interactions of commensal bacteria with TLRs are critical for intestinal homeostasis (Rakoff-Nahoum et al., 2004).


The crosstalk between the host and endogenous microbiota favours mutual growth, survival and wellbeing. Although the knowledge of human microbiota has dramatically increased during the last years, the complete comprehension of all the interactions is still a challenge for the future. New in vivo options, such as customised or humanised mice (Hansen et al., 2013; Kashyap et al., 2013), and in vitro test (McDonald et al., 2013) joint to ‘omics’ technology tools (metagenomic, metabolomic, metatranscriptomics, proteomics and glycomics) (Lamendella et al., 2012) open the field to new interesting approaches to study all the gut microbiota as a whole complex and dynamic ecosystem.

Acknowledgements R. Martín and S. Miquel receive a salary from FPARIS collaborative project selected and supported by the Vitagora Competitive Cluster and funded by the French FUI (Fond Unique Interministériel; FUI: n°F1010012D), the FEDER (Fonds Européen de Développement Régional; Bourgogne: 34606), the Burgundy Region, the Conseil Général 21 and the Grand Dijon.

Conflict of interest The authors declare that they have no conflict of interest.

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Collective unconscious: how gut microbes shape human behavior.

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How brain waves help us make sense of speech.

First Foods and Gut Microbes.

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Gut microbiota: Please pass the microbes.

Help us find the cures.

Insights from the Den: How Hibernating Bears May Help Us Understand and Treat Human Disease.

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How Can Genetic Studies Help Us to Understand Links Between Birth Weight and Type 2 Diabetes?

Hypnosis as a "state of consciousness": how quantifying the mind can help us better understand hypnosis.

Inner Workings: How do mosquitoes smell us? The answers could help eradicate disease.

Quantifying uncertainty in partially specified biological models: how can optimal control theory help us?

Microbes without Borders: Decompartmentalization of the Aging Gut.

Can anxiety help us tolerate pain?

Gut microbes may facilitate insect herbivory of chemically defended plants.

For lack of gut microbes, the blood-brain barrier 'leaks'.

Unraveling the influence of gut microbes on the mind.

Interactions between gut microbes and host cells control gut barrier and metabolism.

Evolution of host specialization in gut microbes: the bee gut as a model.

Gut-associated lymphoid tissue, gut microbes and susceptibility to experimental autoimmune encephalomyelitis.

Your microbes at work: fiber fermenters keep us healthy.

How pharmacists can help their dementia patients.