Action and function of Faecalibacterium prausnitzii in health and disease

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Abstract

Faecalibacterium prausnitzii, anaerobic bacteria, is one of the main components of gut microbiota and the most important butyrate-producing bacteria in the human colon. So far, this commensal bacterium has 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 Faecalibacterium prausnitzii negatively correlates to the activity of inflammatory bowel disease and colorectal cancer. Therefore, counterbalancing dysbiosis using Faecalibacterium prausnitzii as a potential active component of probiotic formulations appears to be a promising therapeutic strategy for inflammatory 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 Faecalibacterium prausnitzii biology, anti-inflammatory metabolites, modulators of this bacterium population and its impact on human health.

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 displays 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 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 concentrations of Bacteroidetes and a higher concentration of Enterobacteriacee 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, supporting the idea that environmental factors such as sanitation, diet, hygiene, and ethnicity are important for defining the gut microbiota. 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 imbalance between beneficial and pathogenic bacteria, for instance, dominating species can become repressed and out-competed ones overgrow [8], [9], [10]. The list of diseases that have been connected to dysbiosis has been increasing year by year as it the case of inflammatory bowel disease, chronic fatigue syndrome, obesity, cancer, colitis, anorexia, and so on [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23]. In this review, we will focus our attention on Faecalibacterium prausnitzii and its impact on human health.

In general, the human microbiota works by symbiosis with host and provides nutrient and take part in xenobiotic and drug metabolism. 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 discoveries. It has been estimated by different techniques that Faecalibacterium 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 acetate, butyrate, d-lactate, and formate, its modest received attention 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 NAD+ 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 modulator 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 Faecalibacterium prausnitzii [35]. It was demonstrated that 10 μM 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 NFκB (Fig. 1). In addition, components of Faecalibacterium prausnitzii induce the production of IL-10 by peripheral blood mononuclear cells, dendritic 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 prausnitzii 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.

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-γ, and elevated secretion of the IL-10 anti-inflammatory cytokine [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 NFκB 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 patients 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 TNFα blocker, displayed an increased Faecalibacterium Prausnitzii population [40].

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. Importantly, Faecalibacterium Prausnitzii was highly discriminant for type 2 diabetes [41].

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 Faecalibacterium prausnitzii is reduced, and consequently, inflammatory process in the colon is favored with the risk of CRC [9]. In a study performed by Balamurugan et al. patients with CRC presented 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 Faecalibacterium prausnitzii was higher in survival CRC group, and importantly, it negatively correlates with the expression of β-catenin, MMP-9 and NFκB [45].

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 diagnosed 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].

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].

Section snippets

The host-pathogens interface – 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 important key regulators in inflammatory disorders beyond hemostasis and thrombosis. Inflammation wound repair, angiogenesis, atherosclerosis, and tumor metastasis are only some

Faecalibacterium prausnitzii modulators

Medicines and nutrition contribute to stimulating the maintenance of health-promoting flora population, including Faecalibacterium 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].

Concluding remarks

The list of the beneficial function of gut microbiota for the host has been increasing. Gut microbiota controls metabolism, immune response and protects the colon. For instance, in the case of dysbiosis, 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

Practice points

  • Faecalibacterium prausnitzii controls metabolism, immune response and protects the colon.

  • Butyrate and salicylic acid block NFκB 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 São Paulo Research Foundation (2015/20412-7 and 2016/14459-3).

References (61)

  • J. Chen et al.

    Interaction between microbes and host intestinal health: modulation by dietary nutrients and gutbrain-endocrine-immune axis

    Curr Protein Pept Sci

    (2015)
  • C. De Filippo et al.

    Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa

    Proc Natl Acad Sci U. S. A

    (2010)
  • A. Andoh et al.

    Multicenter analysis of fecal microbiota profiles in Japanese patients with Crohn's disease

    J Gastroenterol

    (2012)
  • A. Mika et al.

    Exercise is more effective at altering gut microbial composition and producing stable changes in lean mass in juvenile versus adult male F344 rats

    PLoS One

    (2015)
  • J. Tomas et al.

    Primocolonization is associated with colonic epithelial maturation during conventionalization

    FASEB J

    (2013)
  • C.P. Tamboli et al.

    Dysbiosis in inflammatory bowel disease

    Gut

    (2004)
  • S.R. Konstantinov et al.

    Functional genomic analyses of the gut microbiota for CRC screening

    Nat Rev Gastroenterol Hepatol

    (2013)
  • W.H. Moos et al.

    Microbiota and Neurological disorders: a gut Feeling

    Biores Open Access

    (2016)
  • P.J. Turnbaugh et al.

    An obesity- associated gut microbiome with increased capacity for energy harvest

    Nature

    (2006)
  • S.K. Mazmanian

    Capsular polysaccharides of symbiotic bacteria modulate immune responses during experimental colitis

    J Pediatr Gastroenterol Nutr

    (2008)
  • H. Sokol et al.

    Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients

    Proc Natl Acad Sci U. S. A

    (2008)
  • A. Swidsinski et al.

    Active Crohn's disease and ulcerative colitis can be specifically diagnosed and monitored based on the biostructure of the fecal flora

    Inflamm Bowel Dis

    (2008)
  • P. Marteau

    Bacterial flora in inflammatory bowel disease

    Dig Dis

    (2009)
  • P.J. Turnbaugh et al.

    A core gut microbiome in obese and lean twins

    Nature

    (2009)
  • S.E. Lakhan et al.

    Gut inflammation in chronic fatigue syndrome

    Nutr Metab (Lond)

    (2010)
  • I. Sobhani et al.

    Microbial dysbiosis in colorectal cancer (CRC) patients

    PLoS One

    (2011)
  • P. Lepage et al.

    A metagenomic insight into our gut's microbiome

    Gut

    (2013)
  • M. Castellarin et al.

    Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma

    Genome Res

    (2012)
  • A.D. Kostic et al.

    Genomic analysis identifies association of Fusobacterium with colorectal carcinoma

    Genome Res

    (2012)
  • S.M. Jandhyala et al.

    Role of the normal gut microbiota

    World J Gastroenterol

    (2015)
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