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
Human gut microbiota is a multi-complex system due to the
presence of viruses, fungi, protozoa, archaea and bacteria, which
are the main components [1,2]. In general, the microbiota can be
divided into two main populations, one present in the lumen and
the other in the mucosa (adherent mucosa microbiota is located in
the mucus layer close to the tissue). Luminal gut microbiota dis-
plays a characteristic distribution along the intestine as its density
raises from the proximal to the distal gut. In relation to adherent
mucosa microbiota, it is composed by well-adapted and specialized
populations and is more stable over the time than the luminal
counterpart [3].
Gut microbiota is a very sensitivity system, for instance, it can be
modified by diet, lifestyle, xenobiotics, physiological conditions of
* Corresponding author. Department of Biochemistry and Tissue Biology, Insitute
of Biology, University of Campinas - UNICAMP, 255, Monteiro Lobato St., Cidade

ria Zeferino Vaz, Campinas, 13083-862, S~
Universita ao Paulo, Brazil.
** Corresponding author. Plateinnove Biotechnology, 1131, Limeira Ave., RM 10,
~o, Piracicaba, 13414-018, Sa
Areia ~o Paulo, Brazil.
E-mail addresses: carmenv@unicamp.br (C.V. Ferreira-Halder), sheilasa@gmail.
com (S.S. Andrade).
the host, such as pregnancy, age, and genetic background. For
instance, in a comparative study between gut microbiota of Italian
children living in town with that one from African children living in
rural villages, De Filippo and collaborators detected lower con-
centrations of Bacteroidetes and a higher concentration of Enter-
obacteriacee in Italian children. These authors linked their findings
to lower consumption of polysaccharide plants by Italian children
[4]. At the same direction, it was demonstrated by Andoh et al. a
difference in the gut microbiota of the Japanese population, sup-
porting the idea that environmental factors such as sanitation, diet,
hygiene, and ethnicity are important for defining the gut micro-
biota. Mika and collaborators reported that physical exercise can
modulate gut microbiota composition as well as the abundance of
beneficial populations [5,6].
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
pathogenic organisms and maturation/modulation of the immune
system [7]. Therefore, microbiota alteration can profoundly affect
the host homeostasis. Dysbiosis refers to a deregulation or imbal-
ance between beneficial and pathogenic bacteria, for instance,
dominating species can become repressed and out-competed ones
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-
flammatory bowel disease, chronic fatigue syndrome, obesity,
cancer, colitis, anorexia, and so on [11e23]. In this review, we will
focus our attention on Faecalibacterium prausnitzii and its impact on
human health.
1.1. Faecalibacterium prausnitzii supports the host health by
producing energy and anti-inflammatory metabolites
In general, the human microbiota works by symbiosis with host
and provides nutrient and take part in xenobiotic and drug meta-
bolism. In this way, molecules and compounds that affect the flora
can modify the nature of microbiota and consequently, display
beneficial or adverse health effects [24]. It has been reported that
medicines and nutrition can stimulate the maintenance of health-
promoting flora population, including Faecalibacterium prausnitzii
[25,26].
Faecalibacterium prausnitzii (formerly Fusobacterium prausnitzii)
belongs to the Clostridium leptum cluster [27]. Until its complete
characterization as a low-GC, gram-positive, non-spore- forming,
strictly anaerobic, and non-motile firmicute, the understanding of
the modulation of gut microbiota have undergone several discov-
eries. It has been estimated by different techniques that Faecali-
bacterium prausnitzii represents for around 5% of the total bacteria
detectable in stool samples from healthy adult human subjects [28].
Faecalibacterium prausnitzii displays a crucial role in producing
energy to the colonocytes as well as anti-inflammatory metabolites
that cooperate for the intestinal health [13]. The main contribution
of Faecalibacterium prausnitzii metabolism is the prebiotic
fermentation. Prebiotic is a nondigestible food component that
stimulates and defines the health microbiota population [29,30].
Faecalibacterium prausnitzii strains show a limited ability to utilize
polysaccharides that can be frequently encountered in the gut
lumen; these common polysaccharides include arabinogalactan,
xylan, and soluble starch [31]. Nevertheless, Faecalibacterium
prausnitzii is well adapted to the gut environment where it is
possibly cross-fed by other members of the gut's microbiota.
Although Faecalibacterium prausnitzii can ferment glucose into ac-
etate, butyrate, D-lactate, and formate, its modest received atten-
tion is probably due to an extreme oxygen-sensitivity and
difficulties encountered in its cultivation. This bacteria is the most
important butyrate-producing in the human colon [13,28,32] -
(Fig. 1). Butyrate represents the major pathway for electron disposal
in the butyrogenic faecalibaceria and the concomitant generation of
NADþ and reduced ferredoxin, facilitating immune response
modulation and serving as a major energy source for colonocytes
[13]. Under the immune response aspect, butyrate is a key modu-
lator of colonic health, once it can protect the colon against
inflammation and colorectal cancer [29,33,34]. Salicylic acid is
another anti-inflammatory metabolite produced by Faecalibacte-
rium prausnitzii [35]. It was demonstrated that 10 mM salicylic acid,
the similar concentration found in the colon, were able to decrease
the level of in vitro IL-8 [35]. Both butyrate and salicylic acid are
strong modulators of the inflammatory process, once they inhibit
the production of IL-8 by blocking the activation of NFkB (Fig. 1). In
addition, components of Faecalibacterium prausnitzii induce the
production of IL-10 by peripheral blood mononuclear cells, den-
dritic cells and macrophages, consequently, the synthesis of pro-
inflammatory cytokines such as IL-6 and IL-12 is inhibited [13,36]
- (Fig. 1). Accordingly, along the last years several research groups
have demonstrated that the deficiency of Faecalibacterium praus-
nitzii might propitiate inflammation. Indeed, a significant inverse
correlation between pathological processes and the number of
Faecalibacterium prausnitzii population has been reported. Some
examples are described below.
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
1.1.1. Ulcerative colitis and inflammatory bowel diseases
Faecalibacterium prausnitzii has recently gained increasing
attention due to its anti-inflammatory effects in certain forms of
colitis. The in vitro stimulation of peripheral blood mononuclear
cells by Faecalibacterium prausnitzii resulted in a significantly
reduced secretion of proinflammatory cytokines such as IL-12 and
IFN-g, and elevated secretion of the IL-10 anti-inflammatory cyto-
kine [13]. Moreover, the presence of Faecalibacterium prausnitzii
cells, or their cell-free supernatant, markedly reduced the severity
of 2,4,6- trinitrobenzenesulfonic acid (TNBS)-induced colitis in
mice. These anti-inflammatory effects were partly associated with
secreted metabolites that are capable of blocking NFkB activation
and IL-8 production [37].
Along the last decades a plenty of data in human show that the
microbiota (composition and diversity) is modified in patients with
inflammatory bowel diseases (IBD). Vermeire's group designed a
very nicely cohort study for not only comparing the microbiota
signature in Crohn's disease (CD) and ulcerative colitis (UC) but also
microbial metabolites. It is important to highlight that the authors
excluded participants that were using or had used drugs (such as
antibiotics and sulfasalazine), probiotics or prebiotics in the last
month before the beginning of the study. They observed the lower
abundance of Faecalibacterium prausnitzii in UC patients compared
to control ones, which also showed an inverse correlation with
disease activity (the lowest number of Faecalibacterium prausnitzii
was detected in patients with severe UC). In relation to the
metabolite, short-chain fatty acids were diminished in patients
with UC, but the authors did not find a correlation between this
metabolite and Faecalibacterium Prausnitzii [38].
Recently, based on the literature, Prosberg and collaborators
performed a systematic review of clinical studies, in which patients
with UC and CD were enrolled [39]. These authors found that pa-
tients with active IBD had a lower amount of Faecalibacterium
Prausnitzii compared to patients in remission.
Interestingly, it was shown that patients treated with infliximab,
a TNFa blocker, displayed an increased Faecalibacterium Prausnitzii
population [40].
1.1.2. Diabetes
Type 2 diabetes results from a combination of gene expression
patterns, environment and risk factors, such as age, family history,
diet, lifestyle and obesity. Some reports have demonstrated that in
diabetics Faecalibacterium Prausnitzii is presented in very lower
amount in comparison to non-diabetics. Karlsson and collaborators
evaluated the composition of stool from 1645 European women
(70-years-old) that were divided into 3 groups: type 2 diabetes,
impaired glucose tolerance or normal glucose tolerance. Impor-
tantly, Faecalibacterium Prausnitzii was highly discriminant for type
2 diabetes [41].
1.1.3. Colorectal cancer
The relationship between chronic colitis and colorectal cancer
(CRC) has become evident for a long time. During the past 7 years,
bacteria that are indicators of dysbiosis and that can contribute for
CRC have been described [42,43]. In this context, Faecalibacterium
prausnitzii has gained a lot of attention, once this organism is
beneficial by producing anti-inflammatory metabolites, such as
butyrate [30,33,34]. However, in CRC patients the amount of Fae-
calibacterium prausnitzii is reduced, and consequently, inflamma-
tory process in the colon is favored with the risk of CRC [9]. In a
study performed by Balamurugan et al. patients with CRC pre-
sented fourfold lesser Faecalibacterium prausnitzii compared to
healthy individuals [44]. More recently, a study performed by Zhou
group evaluated the microbiota as well as molecular markers of the
inflammatory response in CRC patients. They found that the level of
 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
importantly, it negatively correlates with the expression of b-cat-
enin, MMP-9 and NFkB [45].
1.1.4. Psoriasis
A study conducted by Eppinga and collaborators, compared the
amount of Faecalibacterium prausnitzii in stool samples from
healthy controls, patients with psoriasis or IBD and patients diag-
nosed with both IBD and psoriasis. Interestingly, these authors
observed that Faecalibacterium prausnitzii is dropped in the gut of
psoriasis patients with and without concomitant IBD [46].

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 amount of Faecalibacterium prausnitzii increases along the
first trimester of pregnancy [47]. Since this bacterium produces
butyrate as one of the main anti-inflammatory metabolite, the high
amount of Faecalibacterium prausnitzii might contribute for the
successful pregnancy [9].
1.2. The host-pathogens interface e the distinct behavior of
platelets in immune pathogens
The elevation in platelets count (>450000  109/L), defined as
reactive thrombocytosis (RT), may frequently occur in certain
conditions like hypoasplenism or asplenism, blood loss, acute or
chronic inflammatory disorders, malignancies, and iron deficiency
[48].
There are increasing data suggesting that platelets are impor-
tant key regulators in inflammatory disorders beyond hemostasis
and thrombosis. Inflammation wound repair, angiogenesis,
atherosclerosis, and tumor metastasis are only some examples that
reveal the multifactorial role of platelets. In the pathogenesis of IBD,
platelets activation could be the missing link between inflamma-
tion and coagulation, which are two “independent” processes
linked in such a way that activation and propagation are reciprocal
[49].
Human intestines face limited exposure to microbial antigens in
host microbial interactions in mucosal homeostasis/normal con-
ditions. Viable pathogens are spatially separated from the gut
epithelium via the mucosal lining, and the secretion of IL-10 and
TGF-b regulates a tolerogenic state. Conversely, dysbiosis leads to
microbial/pathogens invasion of epithelial cells in inflammatory
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
epithelial damage [50].
In this scenario, neutrophils, dendritic cells (DCs), and platelets
are activated, which promotes their maturation and the presenta-
tion of pathogen antigens to T cells and B cells promoting immune
activation response through pattern recognition receptors, like
glycoprotein (GP) and Toll-like receptors (TLRs). For example,
platelets rapidly associate with the bacterial pathogen Listeria
monocytogenes via GPIb when L. monocytogenes is decorated with
C3 protein, which enhances the accumulation of pathogen in
splenic DCs. This process potentiates the processing and presen-
tation of L. monocytogenes antigens to cognate T cells [51]. A similar
effect was also observed with Staphylococcus aureus, Enterococcus
faecalis, and Bacillus subtilis. Moreover, the expansion of cytotoxic
CD8þ T cells is potentiated when platelets efficiently present.
L. monocytogenes to DCs in this manner [52]. Interactions with
platelets also lead to increased cytokine production by DCs,
including increased production of interferon-g (IFNg), IL-12, IL-4,
and the co-stimulatory partners CD80eCD86 in monocyte-derived
DCs [51]. This series of events can efficiently polarize immune re-
sponses to be optimally effective against a specific pathogen.
Therefore, platelet-mediated vectoring of microorganisms to
antigen-presenting cells (APCs) and the shaping of APC responses
promote the coordination of innate and adaptive immune re-
sponses that are essential to antimicrobial host defense. This occurs
by the direct clearing of pathogens from the circulation via the
reticuloendothelial system, processing and antigen presentation by
DCs to specify and optimize T cell- and/or B cell-mediated adaptive
immune responses, and refining the coordination of innate and
adaptive antimicrobial effectors for the most efficient defense re-
sponses [53].
In addition, the modulation of intestinal inflammation by
commensal bacteria has identified a role for pattern-recognition
receptors in mediating non-inflammatory immune responses to
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
the microbiota. The pathway of TLRs activation is linked to MyD88
(the myeloid differentiation primary response gene 88), which in-
duces the production of pro-inflammatory cytokines [51]. Studies
have demonstrated that commensal organisms may target and
inhibit NFkB activation to suppress inflammation. Sokol et al.
identified Faecalibacterium prausnitzii when analyzing the compo-
sition of the intestinal microbiota in CD patients; that study also
demonstrated that Faecalibacterium prausnitzii counts are greatly
reduced as an anti-inflammatory commensal bacterium in the gut
of CD patients and that the supernatant of Faecalibacterium praus-
nitzii inhibited NFkB activation in human cell lines and in a mouse
colitis model [13,37].
In this context and in a combined way, platelets CD40L
(þ)-derived vesicles seem to display an immune regulatory role by
activating peripheral blood B-cells in producing immunoglobulins
when in in vitro coculture conditions [54], and stimulating antigen
specific IgG production through germinal center modulation in the
B-cell compartment [51].
CD40L is essential in activating the components of the immune
system in inflammatory bowel diseases. The infiltration of neu-
trophils in the colonic mucosa of ulcerative colitis patients, and
macrophage chemoattraction in granulomatous lesions in Crohn's
disease, has been found to be mediated mainly by CD40/CD40L
interactions [54]. Immune fluorescence staining of CD40 (þ) was
only observed at inflamed intestinal sites and not at intact mucosal
segments in intestinal endoscopic biopsies from IBD patients [48].
Hence, increasing information about the balance between
commensal bacteria and activated cells in the immune system, such
as platelets, is the key to elucidate the process involved in the
regulation of homeostasis and inflammatory conditions.
1.3. Faecalibacterium prausnitzii modulators
Medicines and nutrition contribute to stimulating the mainte-
nance of health-promoting flora population, including Faecali-
bacterium prausnitzii [25]. Gut microbiota has an important
contribution for the biological activities of polyphenols (found in
fruits, vegetables, cereals, tea, coffee and wine), once bacterial
control the production and bioavailability of their metabolites. On
the other hand, these metabolites will be important regulators of
the microbiota composition [55,56]. Moreno-Indias and colleagues
described that the healthy subjects and metabolic syndrome pa-
tients presented an increase of beneficial microbiota, including
Faecalibacterium prausnitzii, after wine intake. This effect was
assigned to prebiotic-like of polyphenols present in wine [57].
Patients with iron replacement therapy have a shift in bacterial
population, comparing to oral and intravenous administration [58].
Lee and colleagues reported in a preliminary study that the popu-
lation of Faecalibacterium prausnitzii increased in kidney-
transplantation patients treated with tacrolimus. The study char-
acterized the fecal microbiota in patients along the first month after
transplantation. Therefore, the positive association with Faecali-
bacterium prausnitzii and tacrolimus could be used to monitoring
the efficiency of this medicine [59]. Another interesting finding was
reported by Maccaferri et al., they evaluated the impact of Rifax-
imin, an antibiotic that has some important pharmacological
characteristics: a broad spectrum of antimicrobial activity, a safety
profile and almost without drug interactions, on the faecal micro-
biota; Faecalibacterium prausnitzii amount was increased in pa-
tients treated with Rifaximin [60].
2. Concluding remarks
The list of the beneficial function of gut microbiota for the host
has been increasing. Gut microbiota controls metabolism, immune
 C.V. Ferreira-Halder et al. / Best Practice & Research Clinical Gastroenterology xxx (2017) 1e6
response and protects the colon. For instance, in the case of dys-
biosis, the dominance of Faecalibacterium prausnitzii in the colon is
affected, and consequently, it contributes to the etiology of diseases
of the large intestine, such as IBD and CRC [13,14,18,19,22,61]. These
observations indicate that Faecalibacterium prausnitzii contributes
substantially to gut health, that's why it is considered as a
biomarker not only of human health but either for diagnosis or
treatment follows up. In addition, Faecalibacterium prausnitzii has
gained a lot of attention as a potential active component of pro-
biotic formulations. However, once this microbial is very sensitive
to oxygen, the formulation development is a great challenge.
Practice points
 Faecalibacterium prausnitzii controls metabolism, immune
response and protects the colon.
 Butyrate and salicylic acid block NFkB signaling.
 Faecalibacterium prausnitzii population is a biomarker of human
health, for diagnosis and therapy efficiency.
 Faecalibacterium prausnitzii is a potential active component of
probiotic formulations.
Research agenda
 Identification of Faecalibacterium prausnitzii metabolites, in vivo,
is needed.
 In vitro scalable culture of Faecalibacterium prausnitzii is a
challenge due to its oxygen sensitivity.
Conflict of interest
No conflict of interest has been declared by the authors.
Acknowledgment
Research conducted by the authors in the colorectal cancer
signal transduction and platelet function fields is financed by S~
ao
Paulo Research Foundation (2015/20412-7 and 2016/14459-3).
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