Nowadays, humans can be considered as “meta-organisms” composed of 10-fold more microorganisms than human cells (Neish, 2009), which means 150-fold more genes than the human genome itself (Qin et al., 2010; Bruls and Weissenbach, 2011). These microorganisms, named microbiota (and by extension all their genes as a whole, named microbiome) are different depending on the tissue considered. The human gastrointestinal tract (GIT) is one of the most complex ecosystems. The advances of molecular techniques have shown that the collective adult human GIT microbiota is composed of up to 1000–1150 bacterial species (Frank et al., 2007; Qin et al., 2010). The predominant species (46–58%) are those with low GC-content being the clostridium group the most abundant (Zoetendal et al., 2002; Qin et al., 2010). As a consequence of the mutualism established between the host and its microbiota, the GIT micro-ecosystem is key to maintain the homeostasis of a healthy individual (Leser and Molbak, 2009). Indeed, gut microbiota supplies essential nutrients, metabolize indigestible compounds and protects the host against colonization by opportunistic pathogens (Leser and Molbak, 2009; Martín et al., 2013). It also contributes to the development of the intestinal architecture as well as several immuno-modulatory functions (Mazmanian et al., 2005). In some abnormal conditions, an imbalance in the microbial ecosystem may happen leading to a microbial imbalance known as dysbiosis. This dysbiosis is characterized by the growth of different non-predominant bacteria and/or the depletion of commensal ones that can lead to a situation of illness. As a result, this imbalance can also lead to the lack of some beneficial effects of these commensal bacteria, and thus unchain pathogenic conditions not only due to pathogen overgrowth (Martín et al., 2013).

As gut microbiota is now considered as a major actor underlying health, the idea of using some well-known microbiota components as next generation probiotics (NGPs) is very promising. Probiotics are “live microorganisms which when administered in adequate amounts confer a health benefit on the host” (FAO/WHO, 2001). Recently, this definition has been clarified by an expert panel of the International Scientific Association for Probiotics and Prebiotics (ISAPP) and re-defined as: “live microorganisms that, when administrated in adequate amounts, confer a health benefit on the host” (Hill et al., 2014). Most of the traditional probiotics belong to both lactic acid bacteria (LAB) and Bifidobacteria groups. These novel probiotics are thus considered as NGPs in contrast to traditional ones, which were not selected on the basis of human microbiota analysis. To consider a strain as probiotic, it should be: (i) well-characterized, (ii) achieve safety requirements, and (iii) confer beneficial effects on the host. However, a careful selection should be made in each case as probiotic properties are usually strain specific and cannot be extrapolated to another strain even belonging to the same species (Pineiro and Stanton, 2007; Gareau et al., 2010).

Similarly, as probiotic therapy is mainly based on restoring the normal balance of the intestinal ecosystem, we consider that the use of commensal bacteria as NGPs is a natural way to restore the dysbiotic situation within the GIT (Miquel et al., 2015a). Nevertheless, in contrast to most of probiotic lactobacilli or bifidobacteria strains, these NGPs are not listed neither on QPS (for Qualified Presumption of Safety), nor on GRAS (for Generally Recognized As Safe organisms) lists. Furthermore, as they have not a long record of safe consumption (precisely no documented safe use in Europe prior to 1997), these NGPs can only be used either as novel foods or drugs and the requirements to allow their market in Europe are more severe than for conventional probiotic strains (Miquel et al., 2015a). Nowadays, the inclusion of Faecalibacterium on the QPS list might be difficult due to its lack of a history of safe use. In addition, full toxicology assays and characterization of the strain are still needed for regulatory approval (Brodmann et al., 2017). We have reviewed this problematic in detail elsewhere (Miquel et al., 2015a).

As Faecalibacterium prausnitzii is an extremely oxygen sensitive (EOS) bacterium and difficult to grow (Duncan et al., 2002), most of the data about its physiology are based on metagenomic studies (Miquel et al., 2013), with some exceptions (Duncan et al., 2002; Ramirez-Farias et al., 2009; Lopez-Siles et al., 2012; Foditsch et al., 2014; Martín et al., 2017). F. prausnitzii is a member of the Clostridium group (phylum Firmicutes, class Clostridia, family Ruminococcaceae), specifically of the C. leptum group (Benevides et al., 2017), and represents around 5% of the total fecal microbiota in healthy adults being one of the most abundant bacterium in the human intestinal microbiota in healthy conditions (Hold et al., 2003). The first isolates were classified as Fusobacterium praustnizzi, but latter on its close relation with members of the C. leptum group was established thorough analysis of 16S rRNA gene (Miquel et al., 2014). The establishment of F. prausnitzii along the GIT may result from a combination of environmental factors such as other commensal species, redox mediators, oxygen concentration, mucus layer as well as bile salt concentrations and pH (Duncan et al., 2009; Lopez-Siles et al., 2012). In early infancy, F. prausnitzii abundance is very low and increases after the establishment of primo-colonizing bacteria (Hopkins et al., 2005). In the last years, this bacterium has been suggested as a biosensor and a major actor of the human intestinal health (Miquel et al., 2013). Indeed, F. prausnitzii levels have been found to be reduced in patients suffering from several syndromes and diseases such as inflammatory bowel diseases (IBDs), irritable bowel syndrome (IBS), colorectal cancer (CRC), obesity, and celiac disease (Balamurugan et al., 2008; Sokol et al., 2008; Neish, 2009; De Palma et al., 2010; Furet et al., 2010; Rajilic-Stojanovic et al., 2011) as well as in frail elderly (van Tongeren et al., 2005). We have more deeply review F. prausnitzii physiology and beneficial effect elsewhere (Miquel et al., 2013, 2014). Nevertheless, its EOS condition, make viable intestinal delivery one of the current challenges, due to their stringent survival conditions (El Hage et al., 2017).

Because of its important role in GIT homeostasis, F. prausnitzii is considered today as a potential NGPs. Its potential utilization has been already proposed for livestock animals, for instance the isolation and characterization of F. prausnitzii strains from stool of calves and piglets have been already performed (Foditsch et al., 2014). Also a specific formulation keeping this EOS bacterium alive at ambient air conditions has been also proposed for patients with intestinal dysbiosis-associated diseases (Khan et al., 2014). In order to evaluate its potential beneficial effects as a NGP, we have successfully used this bacterium in several murine models of IBD and IBS (Sokol et al., 2008; Martín et al., 2014a; Laval et al., 2015; Miquel et al., 2016) and other groups have also clearly demonstrated its beneficial effects in vivo (Carlsson et al., 2013; Rossi et al., 2015, 2016). Briefly, we have found that mice treated with either F. prausnitzii A2-165 or its supernatant (SN) present lower symptoms of inflammation in both acute and chronic chemically-induced colitis models as well as improved gut permeability and function in a model of gut impairment induced by dinitrobenzene sulfonic acid (DNBS) (Sokol et al., 2008; Martín et al., 2014a, 2015; Laval et al., 2015). We have also observed that A2-165 strain was able to reduce pain sensibility in partial restraint stress (PRS) and neo-maternal separation (NMS) murine models (Miquel et al., 2016). Furthermore, Carlsson et al. (2013) and Rossi et al. (2015, 2016) have found similar anti-inflammatory results as well as restoration of increased intestinal permeability in dextran sulfate sodium (DSS) induced colitis.

Staring the host pathways involved in the beneficial effects displayed by F. prausnitzii, in vitro tests have shown that: (i) although F. prausnitzii itself had no effect on IL-1β-induced NF-κB activity, its SN abolished it in Caco-2 cells transfected with a reporter gene for NF-κB activity and (ii) peripheral blood mononuclear cell (PBMC) stimulation by F. prausnitzii led to significantly lower IL-12 and IFN-γ production levels and higher secretion of IL-10 (Sokol et al., 2008). In this sense, human dendritic cells (DCs) stimulation with A2-165 and HTF-F strains also induced the production of IL-10 (Rossi et al., 2015). IL-10 has been established to be an important immune-regulatory cytokine that successfully suppresses the exacerbated mucosal immune response associated with colonic inflammation (Schreiber et al., 2000). This increasing in IL-10 induced by F. praustnizii has also been observed in vivo (Sokol et al., 2008). Furthermore, Rossi et al. (2016) found that the strain of F. prausnitzii A2-165 has a strong capacity to induce IL-10 in human and murine DCs and influence the T-cell differentiation in vitro and in vivo. In this sense, F. prausnitzii is also able to increase lymphocyte T regulatory (Treg) population in vivo after a colonic chemical challenge (Martín et al., 2014a) and has been identified as the major inducer of a specific IL-10 secreting Treg subset named CD4CD8α lymphocytes present in the human colonic lamina propria and blood which is deficient in IBD patients (Sarrabayrouse et al., 2014).

Since the first study about F. prausnitzii performed in our laboratory almost 10 years ago (Sokol et al., 2008), we have sought to identify the bacterial effectors underlying its beneficial effects. We have been focused on its SN which showed anti-inflammatory properties in both in vivo and in vitro experiments (Sokol et al., 2008; Martín et al., 2013). Our main hypothesis was that F. prausnitzii can produce an anti-inflammatory soluble molecule. First, we tried to identify the chemical nature of the molecule by submitting the SN to several enzymatic and physical methods and as shown in Figures 1A–C, none of them were able to suppress the anti-inflammatory “properties” from the SN pointing out the possible presence of more than one effector on F. praustnizii SN. Of course, this result can also support an important role of butyrate in F. prausnitzii effects, although in vivo and in vitro experiments point out for a more complex situation (see below). Nevertheless, we need to consider that the beneficial effects of F. prausnitzii might not be present only in its SN. For instance, we have found that some beneficial effects, such as the anti-nociceptive one, are observed only when the animals where treated with the bacterium but not with its SN (Miquel et al., 2016).

Some of the putative bacterial effectors identified until now are presented in the Figure 2 and are described in the next paragraphs.

The lack of clearness about F. prausnitzii effectors is linked to the lack of knowledge in its biology and phylogeny. Furthermore, as we mentioned above, probiotic characteristics are strain-specific, and therefore individual studies should be performed in order to determine the individual beneficial effects as well as the individual effectors linked to these effects. If we compare to a classic probiotic group, lactobacilli, we can find that although all lactobacilli are able to produce lactic acid (proved to have beneficial effects in some ecosystems such as the vaginal), not all of them are equipped with the same arsenal of bacterial effectors (bacteriocins, biosulfactants, H₂O₂, etc…) that are strain specific. In the case of Faecalibacterium, the framework should be similar, as even if all the strains are able to produce butyrate, other possible molecules could be responsible of additional strain-specific beneficial effects.

Recently, we have isolated a collection of novel F. prausnitzii strains form healthy volunteers that we have characterized (Miquel et al., 2015a) and analyzed for anti-inflammatory properties with the aim of selecting new NGPs candidates (Martín et al., 2017). The deeper phylogenic analysis of the complete genome of this bacterial collection joint to the genomes already present in the public data bases has revealed that there are at least three separate clusters, spanning the classical Phylogroups I and II already found in F. praustnizii (Lopez-Siles et al., 2012, 2016; Martín et al., 2017) and that some strains appear to represent a deeper, more divergent branch of the “Faecalibacterium prausnitzii” taxon (Benevides et al., 2017). This new truth about F. prausnitzii provides evidence that the phylogeny of F. praustnizii should be reconsidered. In line with these results, in the future we should take into account the presence of at least three different genospecies inside Faecalibacterium group to better characterize their beneficial effects, their crosstalk with the host and the possible effectors underlying these effects. Furthermore, the pangenome analysis have been performed to get a global view of the genome of this genus. A total of 10,366 core-genome codifying DNA sequences have been found (3.33-fold the average total number of genes of the 17 analyzed strains) (Benevides et al., 2017). Nevertheless, up today no extensive genomic description of this taxon has been finished, being an ongoing task with a key role in the future perspectives of the analysis of this genus.

In this perspective article, we have tended to highlight the importance and problematic of asserting the probiotic characterization of a NGP, a field on the focus of the research of Frontiers in Microbiology audience. Nowadays, the research community recognizes the importance of F. prausnitzii in the human health. A decrease of this bacterium in the GIT has been linked to several diseases and syndromes but it is still not clear if this is a cause or a consequence of them. As mentioned above, this special condition, make this species a unique bacterial sensor and actor in the human health, mainly related with intestinal issues, but not only. Taking advantage of this, its use as NGP is being explored for both human and animal use. However, more research in its phylogeny, physiology, safety, and beneficial effects should be performed to fill the lack that currently exists between the knowledge of the biology of the bacterium and the medical interest that it produces. As an example, the analysis of the possible bacterial effectors taking into account the phylogeny and the biological effects related should be performed in more detail to find the best probiotic candidate and refine its use as biomarker in several human disorders.

RM, LB-H, and PL designed the perspective and the experiments. RM wrote the manuscript and performed the experiments. LB-H and PL corrected the manuscript. All the authors approved the last version of the manuscript.

PL is one of the co-founders of NextBiotiX, a start-up aimed to produce an anti-inflammatory drug based on Faecalibacterium prausnitzii. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.