Distinct Bifidobacterium strains drive different immune responses in vitro
Introduction
Bifidobacterium sp. are one of the most relevant probiotic microorganisms since they colonize the intestinal tract soon after birth and are present at high population levels in both infants and adults (Guarner and Malagelada, 2003). These bacteria have a long history of being safely consumed (Salminen et al., 1998). Although there is a lot of information about the healthy properties of probiotics (Kopp-Hoolihan, 2001, Marteau et al., 2001), it is not always based on proven evidence and little is known about the precise mechanisms of action by which such bacteria may exert their beneficial effects. The events underlying these healthy effects are now beginning to be understood mainly from in vitro studies of host intestinal epithelial cell or immune cell responses to probiotic strains. Thus, probiotics are known to beneficially modulate several host cell functions, the most prevalent of which are immune responses and intestinal barrier integrity.
Host defense against foreign challenge is elicited by the innate and the acquired immune systems, that induce both the systemic and the mucosal immune responses. At the gut mucosal level, the innate immune response provides the first line of defense against pathogenic microorganisms but also provides the signals that instruct the adaptive immnune response (Macpherson et al., 2005). In this respect, dendritic cells (DCs) are considered as the link between innate and adaptive immunity. They are the most powerful antigen-presenting cells, promoting specific adaptive immune responses, but they also play a central role in the innate defense (Steinman and Hemmi, 2006). It has been shown that these antigen-presenting cells open the tight junctions between intestinal epithelial cells, send dendrites outside the epithelium and directly sample bacteria from the intestinal lumen (Rescigno et al., 2001). Contact with antigens or inflammatory stimuli can induce the maturation of DCs, accompanied by functional and phenotypic changes like the upregulation of costimulatory molecules and cytokine production (Joffre et al., 2009, Reis E Sousa, 2006), thus acquiring the ability to induce naive T cell proliferation and polarization towards Th1, Th2 or Th17 effector cells or, alternatively, to regulatory T cells (Zhu and Paul, 2008).
A number of works indicated that commensal intestinal bacteria administered orally, such as probiotics, have the potential to modulate and regulate the immune response, at least in part, through their effects on intestinal mucosa DCs. In this respect, it has been described that different lactic acid bacteria and bifidobacteria induced very different maturation and cytokine production patterns on DCs, even generating opposite T cell responses. Certain probiotics were demonstrated to induce IL-12 production by macrophages and DCs, thus promoting IFNγ secretion and inflammatory Th1 responses (Fujiwara et al., 2004, Mohamadzadeh et al., 2005, Pochard et al., 2005), whereas other reports have shown that probiotic-induced IL-10 levels play a main role limiting Th1-mediated proinflammatory responses (Hart et al., 2004, Zeuthen et al., 2006). Furthermore, recent studies showed that Th17 cells are essential for the first-line defense against intestinal infection, although little is known about the effects of probiotic bacteria on human Th17 polarization, a not well-known phenomenon in which IL-1β and IL-23 seem to play an important role (Annunziato et al., 2008, Boniface et al., 2008, Mills, 2008). Finally, DCs exposed to probiotic bacteria may acquire tolerogenic properties and then T cell activation could be biased towards the generation of regulatory T cells (Smits et al., 2005).
Like other probiotic bacteria, it has been described that Bifidobacterium sp. may present distinct immunomodulatory effects both in vitro (Baba et al., 2008, Hart et al., 2004, Latvala et al., 2008, Medina et al., 2007, Niers et al., 2007, Young et al., 2004, Zeuthen et al., 2006) and in vivo (Fujiwara et al., 2004, Isolauri et al., 2000, Marteau et al., 2001, Myllyluoma et al., 2005, Schiffrin et al., 1995). However, comparative studies on the immunological traits of different strains of bifidobacteria that could support a rationale selection of probiotic strains for specific immunomodulatory benefits are very limited. For this reason, the aim of this study was to determine and compare the specific immune activation properties of different Bifidobacterium strains in order to establish useful criteria for their evaluation and selection which could be applied for further possible biotechnological or clinical applications. To this end, we determined maturation and cytokine production of human monocyte-derived DCs after exposure to different bifidobacterial strains. In addition, since most Bifidobacterium species are commensal microorganisms usually present in the gut of adult individuals, and thus interacting with immune cells, we analyzed the pattern of cytokine production by PBMCs after bifidobacterial stimulation to estimate the type of Th profile that could be induced in healthy individuals by each bacterial strain.
Section snippets
Bacterial strains and culture conditions
The different bacterial strains used in this study are shown in Table 1. Bifidobacterial strains were grown in MRS medium (Difco, Becton, Dickinson and Company, Le Pont de Claix, France) supplemented with a 0.25% l-cysteine (Sigma Chemical Co, St. Louis, MO) (MRSc) and incubated at 37 °C in anaerobic conditions (10% H2, 10% CO2 and 80% N2) in a Mac 500 chamber (Don Whitley Scientific, West Yorkshire, UK). Escherichia coli was grown in LB medium at 37 °C under aerobic conditions. For Lactococcus
Differential activation of dendritic cells by Bifidobacterium sp
The effect of bifidobacteria on in vitro DC function was evaluated by analyzing maturation and cytokine production of immature monocyte-derived DCs exposed during 48 h to twelve different Bifidobacterium strains, Escherichia coli LMG 2092T or Lactococcus lactis IL594, a widely used food microorganism isolated from a cheese starter. Results were compared with that of immature DCs cultured in medium alone or with LPS, habitually used to induce in vitro DC maturation. To determine the possible
Discussion
It is widely accepted that intestinal microbiota possesses immunomodulatory capacity and plays an important role for the health of the host. Elucidation of the mechanisms by which intestinal microorganisms, including potential probiotics, modulate the immune system may facilitate implementation of probiotic supplements that are individually tailored for their immunoregulatory properties. In this regard, DC activation after bacterial stimulation is a pivotal factor for the generation of immune
Acknowledgments
This work was financed by European Union FEDER funds, the Spanish Plan Nacional de I+D (project AGL2007-61805) and by the Consejo Superior de Investigaciones Científicas (CSIC PIE 200870I049).
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