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Real friends: Faecalibacterium prausnitzii supports mucosal immune homeostasis
  1. Mathias W Hornef1,
  2. Oliver Pabst2
  1. 1Institute of Medical Microbiology, RWTH University Hospital, Aachen, Germany
  2. 2Institute of Molecular Medicine, RWTH University Hospital, Aachen, Germany
  1. Correspondence to Professor Mathias W Hornef, Institute of Medical Microbiology, RWTH University Hospital, Pauwelsstr. 30, Aachen 52074, Germany; mhornef{at}ukaachen.de

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IBD is commonly considered as an exaggerated immune response to the microbiota in a genetically susceptible host. This statement recognises the central role of the enteric microbiota in the pathogenesis of IBD. Consistently, in animal models of IBD, inflammation is not observed in the absence of live bacteria and distinct members of the microbiota differ in their potential to trigger disease. Patients with IBD present substantial changes of their microbiota commonly described as dysbiosis.1–4 However, intestinal bacteria not only drive disease but quite the contrary, individual commensal members also dampen inflammatory responses and might thereby contribute to maintain host–microbial homeostasis (figure 1). This aspect seems of particular interest since it may provide the opportunity to develop therapeutic anti-inflammatory strategies.

Figure 1

Immunomodulatory effects of the microbiota and specific commensal bacteria. Tryptophan metabolites via the aryl hydrocarbon receptor (AhR) modulate intraepithelial lymphocytes (IELs) and stimulate RAR-related orphan receptor ((ROR)γt+) type 3 innate lymphocytes (ILCs) to promote cryptopatch and isolated lymphoid follicles (ILFs) as well as interleukin 22 (IL-22) secretion. IL-22 in turn stimulates the expression of the antibacterial c-type lectin Reg3γ. Also, short-chain fatty acids (SCFAs) resulting from bacterial degradation of dietary fibres induce the expression of an antimicrobial peptide, the cathelicidin LL37. SCFAs additionally activate the G-coupled protein receptors 43 and 109a inducing K+ release and stimulation of the inflammasome leading to barrier reinforcement. SCFAs also induce differentiation and proliferation of T regulatory (TREG) cells. Examples of specific effects are the microbial anti-inflammatory molecules (MAM) secreted from Faecalibacterium prausnitzii that inhibit cellular NF-κB signalling and inflammation. Polysaccharide A (PSA) produced by Bacteroides fragilis stimulates via Toll-like receptor (TLR)2 interleukin 10 (IL-10) secretion and the differentiation of TREG cells. Lactocepin released from Lactobacillus paracasei degrades interferon γ (IFN-γ)-induced protein (IP)10, a potent chemoattractant and thereby reduces mucosal inflammation.

Already some years ago, the enteric commensal bacterium Faecalibacterium prausnitzii, a member of the Clostridium leptum group, was proposed to provide such beneficial immunomodulatory capacity. F. prausnitzii was under-represented in faecal samples of patients with IBD compared with healthy controls.5 ,6 Moreover, oral administration of live bacteria or cell culture supernatant inhibited the production of inflammatory mediators and protected in a murine model of overt chronic colitis and low-grade inflammation.7 ,8 The anti-inflammatory effect exerted by F. prausnitzii was associated with various metabolic changes but the precise molecular mechanisms remained undefined.9

Quévrain and colleagues in this issue of GUT report the identification of the immunomodulatory mechanism provided by F. prausnitzii.10 They obtained extracts of bacterial supernatants that contained inhibitory activity and identified several peptides derived from a single so far uncharacterised F. prausnitzii protein named microbial anti-inflammatory molecule (MAM). Cloning and overexpression of MAM in human epithelial cells revealed an inhibitory effect on nuclear factor-κB (NF-κB) activity. Recombinant expression of MAM by orally administered commensal bacterium Lactococcus lactis resulted in detectable MAM levels in intestinal enterocytes. Importantly, administration of MAM-expressing L. lactis but not the isogenic L. lactis wild-type strain reduced disease activity in 2,4-dinitrobenzene sulfonic acid (DNBS)-induced colitis. Animals that received MAM-expressing L. lactis showed improved histopathology, less severe weight loss and reduced interferon γ (IFN-γ) and interleukin 17 (IL-17) expression compared with controls. These experiments establish a causative role of MAM in the control of mucosal inflammation in vivo.

Thus, Quévrain and colleagues attribute an individual bacterial species and a particular bacterial product to a specific aspect of host–microbiota interaction. Further examples of such specific immunomodulatory activities are still rare. Polysaccharide A (PSA) produced by Bacteroides fragilis was shown to promote immune homeostasis. PSA acts via direct interaction with Toll-like receptor (TLR)2 on CD4+ T lymphocytes inducing Foxp3+ T regulatory cells.11 Another type of activity has been reported for lactocepin produced by Lactobacillus paracasei that degrades IFN-γ-induced protein (IP)10, a potent lymphocyte-recruiting chemokine.12 Consistently, administration of wild-type L. paracasei but not a lactocepin-negative (ΔprtP) L. paracasei mutant was able to reduce inflammation in a T cell transfer model of colitis.

These MAM, PSA and lactocepin-mediated-specific effects of individual commensal bacteria might synergise with other emerging immunomodulatory activities of the microbiota that seem less strain specific. Common to various members of the Clostridium genus is their capacity to produce short-chain fatty acids (SCFAs) from fibres. SCFAs exert various effects. SCFAs via binding to metabolite G-protein-coupled receptor (GRP)43 and GRP109A activate the NLRP3 inflammasome in somatic cells and promote gut epithelial integrity.13 SCFAs via epigenetic regulation also support antimicrobial peptide production14 as well as the expansion and differentiation of regulatory T lymphocytes.15–18 Interestingly, F. prausnitzii was suggested to induce a similar interleukin 10 (IL-10)-producing regulatory T cell population in humans.19 Similarly, microbiota-derived tryptophan metabolites via the aryl hydrocarbon receptor (AhR) can modulate intraepithelial lymphocytes and induce type 3 innate lymphocytes and the formation of intestinal follicles to protect the epithelial barrier integrity from infection.20 ,21 Even though some members of the microbiota are particularly active producers of SCFAs and/or tryptophan metabolites, these examples illustrate that general microbial metabolites can exert potent immunomodulatory functions.

In order to define what has been termed dysbiosis, we will need a detailed understanding of how individual bacteria, their immunomodulatory products and metabolites affect gut physiology and immunity. Such information may ultimately allow to interpret the results from microbiota analyses. In addition, administration of MAM-like immunomodulatory molecules or their respective producing bacteria as well as the expansion of beneficial commensal bacteria by nutritional stimuli represent possible strategies to manipulate the inflammatory tone at the intestinal mucosa. The study by Quévrain and colleagues provides a proof of principle of the therapeutic value of such strategy. Administration of F. prausnitzii or MAM may represent a new therapeutic way to reduce mucosal inflammation in patients with established disease. More insight into the regulation, bacterial secretion and cellular internalisation of MAM will be required to reach this goal. An interesting avenue might also be to explore potential synergistic effects of different immunomodulatory molecules produced by additional commensal species. Quévrain suggests that MAM acts at the levels of the central signalling molecule IκB kinase α (IKKα). Additional manipulation of signal transduction molecules upstream or downstream of IKKα might significantly potentiate the effect. Additionally, MAM might reach systemic body sites and help to control inflammatory diseases at anatomical locations other than the intestine. In fact, microbiota-derived constituents such as flagellin and the peptidoglycan fragment muramyl dipeptide were found at systemic body sites and shown to stimulate cell differentiation and immune activation.22 ,23 In order to obtain a lasting effect by administration of live bacteria, however, we need to establish methods to permanently colonise an adult host. This obstacle has hindered previous therapeutic attempts with probiotic bacteria.

From a more basic point of view, one might ask why bacterial immunomodulatory effector molecules evolved in the first place. Recent studies have shown that pathogenic bacteria such as Salmonella enterica profit from inducing mucosal inflammation because inflammation increases the local concentration of host metabolites such as tetrathionate, nitrate or ethanolamine used by S. enterica but not most common commensal microbiota.24 ,25 Conversely, other bacterial species such as F. prausnitzii might benefit from the metabolic environment typically associated with low levels of inflammation and thus developed active inflammation-suppressing properties. However, if MAM significantly impairs epithelial cell signal transduction, could F. prausnitzii potentially impair the antimicrobial host response and render individuals that carry high numbers of MAM-producing F. prausnitzii more susceptible to infection? Similar to the mode of action of MAM, the internalin (Inl)C protein from the enteropathogen Listeria monocytogenes was shown to inhibit IKKα impairing the innate immune response.26 Similar to the regulatory circuits of the immune system itself, a trade-off might thus exist for the selection of commensal bacteria with immunomodulatory capacity.

Although at its infancy, we start to realise the immense complexity of how the microbiota interacts with its host and vice versa. Further characterisation of this interplay will require enormous efforts. In the end, however, it may provide the means to decipher the risks and benefits of a particular microbiota composition and offer molecular tools to re-establish host–microbial homeostasis in patients with inflammatory diseases.

References

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Footnotes

  • Contributors MWH and OP contributed equally to write the manuscript.

  • Funding Deutsche Forschungsgemeinschaft. MWH is supported by the German Research Foundation (DFG Ho2236/8-1), the DFG Priority Programs SPP1580 and SSP1565, the Collaborative Research Center SFB900, as well as the Niedersachsen-Research Network on Neuroinfectiology (N-RENNT) and the German Israel Collaborative Initiative (11-76251-99-10/12).

  • Competing interests None declared.

  • Provenance and peer review Commissioned; internally peer reviewed.

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