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Best Practice & Research Clinical Gastroenterology xxx (2017) 1e6

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Best Practice & Research Clinical Gastroenterology


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Action and function of Faecalibacterium prausnitzii in health and


disease
Carmen Veríssima Ferreira-Halder a, *, Alessandra Vale
ria de Sousa Faria a,
Sheila Siqueira Andrade b, **
a ~o Paulo, Brazil
Department of Biochemistry and Tissue Biology, University of Campinas, Sa
b ~o Paulo, Brazil
Plateinnove Biotechnology, Piracicaba, Sa

a r t i c l e i n f o a b s t r a c t

Article history: Faecalibacterium prausnitzii, anaerobic bacteria, is one of the main components of gut microbiota and the
Received 5 September 2017 most important butyrate-producing bacteria in the human colon. So far, this commensal bacterium has
Accepted 16 September 2017 been considered as a bioindicator of human health, once when its population is altered (decreased),
inflammatory processes are favored. Several reports in the literature highlighted that the amount of
Keywords: Faecalibacterium prausnitzii negatively correlates to the activity of inflammatory bowel disease and
Faecalibacterium prausnitzii
colorectal cancer. Therefore, counterbalancing dysbiosis using Faecalibacterium prausnitzii as a potential
Biology
active component of probiotic formulations appears to be a promising therapeutic strategy for inflam-
Anti-inflammatory
Platelets function
matory bowel diseases and colorectal cancer. However, once this microbial is very sensitive to oxygen,
the formulation development is a great challenge. In this review, we will focus our attention on Faeca-
libacterium prausnitzii biology, anti-inflammatory metabolites, modulators of this bacterium population
and its impact on human health.
© 2017 Elsevier Ltd. All rights reserved.

1. Introduction the host, such as pregnancy, age, and genetic background. For
instance, in a comparative study between gut microbiota of Italian
Human gut microbiota is a multi-complex system due to the children living in town with that one from African children living in
presence of viruses, fungi, protozoa, archaea and bacteria, which rural villages, De Filippo and collaborators detected lower con-
are the main components [1,2]. In general, the microbiota can be centrations of Bacteroidetes and a higher concentration of Enter-
divided into two main populations, one present in the lumen and obacteriacee in Italian children. These authors linked their findings
the other in the mucosa (adherent mucosa microbiota is located in to lower consumption of polysaccharide plants by Italian children
the mucus layer close to the tissue). Luminal gut microbiota dis- [4]. At the same direction, it was demonstrated by Andoh et al. a
plays a characteristic distribution along the intestine as its density difference in the gut microbiota of the Japanese population, sup-
raises from the proximal to the distal gut. In relation to adherent porting the idea that environmental factors such as sanitation, diet,
mucosa microbiota, it is composed by well-adapted and specialized hygiene, and ethnicity are important for defining the gut micro-
populations and is more stable over the time than the luminal biota. Mika and collaborators reported that physical exercise can
counterpart [3]. modulate gut microbiota composition as well as the abundance of
Gut microbiota is a very sensitivity system, for instance, it can be beneficial populations [5,6].
modified by diet, lifestyle, xenobiotics, physiological conditions of The close relationship between the host gut and the microbiota
plays crucial functional roles, such as mucosal physiology, vitamins
and short-chain fatty acids (SCFA) supply, protection against
* Corresponding author. Department of Biochemistry and Tissue Biology, Insitute
pathogenic organisms and maturation/modulation of the immune
of Biology, University of Campinas - UNICAMP, 255, Monteiro Lobato St., Cidade system [7]. Therefore, microbiota alteration can profoundly affect
ria Zeferino Vaz, Campinas, 13083-862, S~
Universita ao Paulo, Brazil. the host homeostasis. Dysbiosis refers to a deregulation or imbal-
** Corresponding author. Plateinnove Biotechnology, 1131, Limeira Ave., RM 10, ance between beneficial and pathogenic bacteria, for instance,
~o, Piracicaba, 13414-018, Sa
Areia ~o Paulo, Brazil.
dominating species can become repressed and out-competed ones
E-mail addresses: carmenv@unicamp.br (C.V. Ferreira-Halder), sheilasa@gmail.
com (S.S. Andrade).
overgrow [8e10]. The list of diseases that have been connected to

https://doi.org/10.1016/j.bpg.2017.09.011
1521-6918/© 2017 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Ferreira-Halder CV, et al., Action and function of Faecalibacterium prausnitzii in health and disease, Best
Practice & Research Clinical Gastroenterology (2017), https://doi.org/10.1016/j.bpg.2017.09.011
2 C.V. Ferreira-Halder et al. / Best Practice & Research Clinical Gastroenterology xxx (2017) 1e6

dysbiosis has been increasing year by year as it the case of in- 1.1.1. Ulcerative colitis and inflammatory bowel diseases
flammatory bowel disease, chronic fatigue syndrome, obesity, Faecalibacterium prausnitzii has recently gained increasing
cancer, colitis, anorexia, and so on [11e23]. In this review, we will attention due to its anti-inflammatory effects in certain forms of
focus our attention on Faecalibacterium prausnitzii and its impact on colitis. The in vitro stimulation of peripheral blood mononuclear
human health. cells by Faecalibacterium prausnitzii resulted in a significantly
reduced secretion of proinflammatory cytokines such as IL-12 and
1.1. Faecalibacterium prausnitzii supports the host health by IFN-g, and elevated secretion of the IL-10 anti-inflammatory cyto-
producing energy and anti-inflammatory metabolites kine [13]. Moreover, the presence of Faecalibacterium prausnitzii
cells, or their cell-free supernatant, markedly reduced the severity
In general, the human microbiota works by symbiosis with host of 2,4,6- trinitrobenzenesulfonic acid (TNBS)-induced colitis in
and provides nutrient and take part in xenobiotic and drug meta- mice. These anti-inflammatory effects were partly associated with
bolism. In this way, molecules and compounds that affect the flora secreted metabolites that are capable of blocking NFkB activation
can modify the nature of microbiota and consequently, display and IL-8 production [37].
beneficial or adverse health effects [24]. It has been reported that Along the last decades a plenty of data in human show that the
medicines and nutrition can stimulate the maintenance of health- microbiota (composition and diversity) is modified in patients with
promoting flora population, including Faecalibacterium prausnitzii inflammatory bowel diseases (IBD). Vermeire's group designed a
[25,26]. very nicely cohort study for not only comparing the microbiota
Faecalibacterium prausnitzii (formerly Fusobacterium prausnitzii) signature in Crohn's disease (CD) and ulcerative colitis (UC) but also
belongs to the Clostridium leptum cluster [27]. Until its complete microbial metabolites. It is important to highlight that the authors
characterization as a low-GC, gram-positive, non-spore- forming, excluded participants that were using or had used drugs (such as
strictly anaerobic, and non-motile firmicute, the understanding of antibiotics and sulfasalazine), probiotics or prebiotics in the last
the modulation of gut microbiota have undergone several discov- month before the beginning of the study. They observed the lower
eries. It has been estimated by different techniques that Faecali- abundance of Faecalibacterium prausnitzii in UC patients compared
bacterium prausnitzii represents for around 5% of the total bacteria to control ones, which also showed an inverse correlation with
detectable in stool samples from healthy adult human subjects [28]. disease activity (the lowest number of Faecalibacterium prausnitzii
Faecalibacterium prausnitzii displays a crucial role in producing was detected in patients with severe UC). In relation to the
energy to the colonocytes as well as anti-inflammatory metabolites metabolite, short-chain fatty acids were diminished in patients
that cooperate for the intestinal health [13]. The main contribution with UC, but the authors did not find a correlation between this
of Faecalibacterium prausnitzii metabolism is the prebiotic metabolite and Faecalibacterium Prausnitzii [38].
fermentation. Prebiotic is a nondigestible food component that Recently, based on the literature, Prosberg and collaborators
stimulates and defines the health microbiota population [29,30]. performed a systematic review of clinical studies, in which patients
Faecalibacterium prausnitzii strains show a limited ability to utilize with UC and CD were enrolled [39]. These authors found that pa-
polysaccharides that can be frequently encountered in the gut tients with active IBD had a lower amount of Faecalibacterium
lumen; these common polysaccharides include arabinogalactan, Prausnitzii compared to patients in remission.
xylan, and soluble starch [31]. Nevertheless, Faecalibacterium Interestingly, it was shown that patients treated with infliximab,
prausnitzii is well adapted to the gut environment where it is a TNFa blocker, displayed an increased Faecalibacterium Prausnitzii
possibly cross-fed by other members of the gut's microbiota. population [40].
Although Faecalibacterium prausnitzii can ferment glucose into ac-
etate, butyrate, D-lactate, and formate, its modest received atten- 1.1.2. Diabetes
tion is probably due to an extreme oxygen-sensitivity and Type 2 diabetes results from a combination of gene expression
difficulties encountered in its cultivation. This bacteria is the most patterns, environment and risk factors, such as age, family history,
important butyrate-producing in the human colon [13,28,32] - diet, lifestyle and obesity. Some reports have demonstrated that in
(Fig. 1). Butyrate represents the major pathway for electron disposal diabetics Faecalibacterium Prausnitzii is presented in very lower
in the butyrogenic faecalibaceria and the concomitant generation of amount in comparison to non-diabetics. Karlsson and collaborators
NADþ and reduced ferredoxin, facilitating immune response evaluated the composition of stool from 1645 European women
modulation and serving as a major energy source for colonocytes (70-years-old) that were divided into 3 groups: type 2 diabetes,
[13]. Under the immune response aspect, butyrate is a key modu- impaired glucose tolerance or normal glucose tolerance. Impor-
lator of colonic health, once it can protect the colon against tantly, Faecalibacterium Prausnitzii was highly discriminant for type
inflammation and colorectal cancer [29,33,34]. Salicylic acid is 2 diabetes [41].
another anti-inflammatory metabolite produced by Faecalibacte-
rium prausnitzii [35]. It was demonstrated that 10 mM salicylic acid, 1.1.3. Colorectal cancer
the similar concentration found in the colon, were able to decrease The relationship between chronic colitis and colorectal cancer
the level of in vitro IL-8 [35]. Both butyrate and salicylic acid are (CRC) has become evident for a long time. During the past 7 years,
strong modulators of the inflammatory process, once they inhibit bacteria that are indicators of dysbiosis and that can contribute for
the production of IL-8 by blocking the activation of NFkB (Fig. 1). In CRC have been described [42,43]. In this context, Faecalibacterium
addition, components of Faecalibacterium prausnitzii induce the prausnitzii has gained a lot of attention, once this organism is
production of IL-10 by peripheral blood mononuclear cells, den- beneficial by producing anti-inflammatory metabolites, such as
dritic cells and macrophages, consequently, the synthesis of pro- butyrate [30,33,34]. However, in CRC patients the amount of Fae-
inflammatory cytokines such as IL-6 and IL-12 is inhibited [13,36] calibacterium prausnitzii is reduced, and consequently, inflamma-
- (Fig. 1). Accordingly, along the last years several research groups tory process in the colon is favored with the risk of CRC [9]. In a
have demonstrated that the deficiency of Faecalibacterium praus- study performed by Balamurugan et al. patients with CRC pre-
nitzii might propitiate inflammation. Indeed, a significant inverse sented fourfold lesser Faecalibacterium prausnitzii compared to
correlation between pathological processes and the number of healthy individuals [44]. More recently, a study performed by Zhou
Faecalibacterium prausnitzii population has been reported. Some group evaluated the microbiota as well as molecular markers of the
examples are described below. inflammatory response in CRC patients. They found that the level of

Please cite this article in press as: Ferreira-Halder CV, et al., Action and function of Faecalibacterium prausnitzii in health and disease, Best
Practice & Research Clinical Gastroenterology (2017), https://doi.org/10.1016/j.bpg.2017.09.011
C.V. Ferreira-Halder et al. / Best Practice & Research Clinical Gastroenterology xxx (2017) 1e6 3

Fig. 1. Anti-inflammatory mechanism of Faecalibacterium prausnitzii. Butyrate and salicylic acid are strong modulators of inflammatory process by inhibiting NFkB and
consequently, the production of IL-8. Components of Faecalibacterium prausnitzii induce the production of IL-10 by peripheral blood mononuclear cells, dendritic cells and mac-
rophages, and in turn, inhibiting the synthesis of pro-inflammatory cytokines such as IL-6 and IL-12.

Faecalibacterium prausnitzii was higher in survival CRC group, and amount of Faecalibacterium prausnitzii in stool samples from
importantly, it negatively correlates with the expression of b-cat- healthy controls, patients with psoriasis or IBD and patients diag-
enin, MMP-9 and NFkB [45]. nosed with both IBD and psoriasis. Interestingly, these authors
observed that Faecalibacterium prausnitzii is dropped in the gut of
1.1.4. Psoriasis psoriasis patients with and without concomitant IBD [46].
A study conducted by Eppinga and collaborators, compared the

Please cite this article in press as: Ferreira-Halder CV, et al., Action and function of Faecalibacterium prausnitzii in health and disease, Best
Practice & Research Clinical Gastroenterology (2017), https://doi.org/10.1016/j.bpg.2017.09.011
4 C.V. Ferreira-Halder et al. / Best Practice & Research Clinical Gastroenterology xxx (2017) 1e6

1.1.5. Pregnancy the microbiota. The pathway of TLRs activation is linked to MyD88
The amount of Faecalibacterium prausnitzii increases along the (the myeloid differentiation primary response gene 88), which in-
first trimester of pregnancy [47]. Since this bacterium produces duces the production of pro-inflammatory cytokines [51]. Studies
butyrate as one of the main anti-inflammatory metabolite, the high have demonstrated that commensal organisms may target and
amount of Faecalibacterium prausnitzii might contribute for the inhibit NFkB activation to suppress inflammation. Sokol et al.
successful pregnancy [9]. identified Faecalibacterium prausnitzii when analyzing the compo-
sition of the intestinal microbiota in CD patients; that study also
1.2. The host-pathogens interface e the distinct behavior of demonstrated that Faecalibacterium prausnitzii counts are greatly
platelets in immune pathogens reduced as an anti-inflammatory commensal bacterium in the gut
of CD patients and that the supernatant of Faecalibacterium praus-
The elevation in platelets count (>450000  109/L), defined as nitzii inhibited NFkB activation in human cell lines and in a mouse
reactive thrombocytosis (RT), may frequently occur in certain colitis model [13,37].
conditions like hypoasplenism or asplenism, blood loss, acute or In this context and in a combined way, platelets CD40L
chronic inflammatory disorders, malignancies, and iron deficiency (þ)-derived vesicles seem to display an immune regulatory role by
[48]. activating peripheral blood B-cells in producing immunoglobulins
There are increasing data suggesting that platelets are impor- when in in vitro coculture conditions [54], and stimulating antigen
tant key regulators in inflammatory disorders beyond hemostasis specific IgG production through germinal center modulation in the
and thrombosis. Inflammation wound repair, angiogenesis, B-cell compartment [51].
atherosclerosis, and tumor metastasis are only some examples that CD40L is essential in activating the components of the immune
reveal the multifactorial role of platelets. In the pathogenesis of IBD, system in inflammatory bowel diseases. The infiltration of neu-
platelets activation could be the missing link between inflamma- trophils in the colonic mucosa of ulcerative colitis patients, and
tion and coagulation, which are two “independent” processes macrophage chemoattraction in granulomatous lesions in Crohn's
linked in such a way that activation and propagation are reciprocal disease, has been found to be mediated mainly by CD40/CD40L
[49]. interactions [54]. Immune fluorescence staining of CD40 (þ) was
Human intestines face limited exposure to microbial antigens in only observed at inflamed intestinal sites and not at intact mucosal
host microbial interactions in mucosal homeostasis/normal con- segments in intestinal endoscopic biopsies from IBD patients [48].
ditions. Viable pathogens are spatially separated from the gut Hence, increasing information about the balance between
epithelium via the mucosal lining, and the secretion of IL-10 and commensal bacteria and activated cells in the immune system, such
TGF-b regulates a tolerogenic state. Conversely, dysbiosis leads to as platelets, is the key to elucidate the process involved in the
microbial/pathogens invasion of epithelial cells in inflammatory regulation of homeostasis and inflammatory conditions.
bowel disease. The stimulation of Th1/Th2 cells by the persistent
secretion of IL-12, IL-23, IL-6, and TNF leads to a chronic tissue- and 1.3. Faecalibacterium prausnitzii modulators
epithelial damage [50].
In this scenario, neutrophils, dendritic cells (DCs), and platelets Medicines and nutrition contribute to stimulating the mainte-
are activated, which promotes their maturation and the presenta- nance of health-promoting flora population, including Faecali-
tion of pathogen antigens to T cells and B cells promoting immune bacterium prausnitzii [25]. Gut microbiota has an important
activation response through pattern recognition receptors, like contribution for the biological activities of polyphenols (found in
glycoprotein (GP) and Toll-like receptors (TLRs). For example, fruits, vegetables, cereals, tea, coffee and wine), once bacterial
platelets rapidly associate with the bacterial pathogen Listeria control the production and bioavailability of their metabolites. On
monocytogenes via GPIb when L. monocytogenes is decorated with the other hand, these metabolites will be important regulators of
C3 protein, which enhances the accumulation of pathogen in the microbiota composition [55,56]. Moreno-Indias and colleagues
splenic DCs. This process potentiates the processing and presen- described that the healthy subjects and metabolic syndrome pa-
tation of L. monocytogenes antigens to cognate T cells [51]. A similar tients presented an increase of beneficial microbiota, including
effect was also observed with Staphylococcus aureus, Enterococcus Faecalibacterium prausnitzii, after wine intake. This effect was
faecalis, and Bacillus subtilis. Moreover, the expansion of cytotoxic assigned to prebiotic-like of polyphenols present in wine [57].
CD8þ T cells is potentiated when platelets efficiently present. Patients with iron replacement therapy have a shift in bacterial
L. monocytogenes to DCs in this manner [52]. Interactions with population, comparing to oral and intravenous administration [58].
platelets also lead to increased cytokine production by DCs, Lee and colleagues reported in a preliminary study that the popu-
including increased production of interferon-g (IFNg), IL-12, IL-4, lation of Faecalibacterium prausnitzii increased in kidney-
and the co-stimulatory partners CD80eCD86 in monocyte-derived transplantation patients treated with tacrolimus. The study char-
DCs [51]. This series of events can efficiently polarize immune re- acterized the fecal microbiota in patients along the first month after
sponses to be optimally effective against a specific pathogen. transplantation. Therefore, the positive association with Faecali-
Therefore, platelet-mediated vectoring of microorganisms to bacterium prausnitzii and tacrolimus could be used to monitoring
antigen-presenting cells (APCs) and the shaping of APC responses the efficiency of this medicine [59]. Another interesting finding was
promote the coordination of innate and adaptive immune re- reported by Maccaferri et al., they evaluated the impact of Rifax-
sponses that are essential to antimicrobial host defense. This occurs imin, an antibiotic that has some important pharmacological
by the direct clearing of pathogens from the circulation via the characteristics: a broad spectrum of antimicrobial activity, a safety
reticuloendothelial system, processing and antigen presentation by profile and almost without drug interactions, on the faecal micro-
DCs to specify and optimize T cell- and/or B cell-mediated adaptive biota; Faecalibacterium prausnitzii amount was increased in pa-
immune responses, and refining the coordination of innate and tients treated with Rifaximin [60].
adaptive antimicrobial effectors for the most efficient defense re-
sponses [53]. 2. Concluding remarks
In addition, the modulation of intestinal inflammation by
commensal bacteria has identified a role for pattern-recognition The list of the beneficial function of gut microbiota for the host
receptors in mediating non-inflammatory immune responses to has been increasing. Gut microbiota controls metabolism, immune

Please cite this article in press as: Ferreira-Halder CV, et al., Action and function of Faecalibacterium prausnitzii in health and disease, Best
Practice & Research Clinical Gastroenterology (2017), https://doi.org/10.1016/j.bpg.2017.09.011
C.V. Ferreira-Halder et al. / Best Practice & Research Clinical Gastroenterology xxx (2017) 1e6 5

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Please cite this article in press as: Ferreira-Halder CV, et al., Action and function of Faecalibacterium prausnitzii in health and disease, Best
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