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Inflammatory Bowel Disease
Anti-inflammatory capacity of selected lactobacilli in experimental colitis is driven by NOD2-mediated recognition of a specific peptidoglycan-derived muropeptide
  1. Elise Macho Fernandez1,
  2. Véronique Valenti1,
  3. Christoph Rockel2,
  4. Corinna Hermann2,
  5. Bruno Pot1,
  6. Ivo Gomperts Boneca3,4,
  7. Corinne Grangette1
  1. 1Bactéries Lactiques et Immunité des Muqueuses, Centre d'Infection et d'Immunité de Lille (CIIL), INSERM U1019-CNRS UMR 8204, Institut Pasteur de Lille (IPL), Université Lille Nord de France, Lille, France
  2. 2Department of Biochemical Pharmacology, Konstanz University, Konstanz, Germany
  3. 3Departement de Microbiologie, Institut Pasteur, Groupe Biologie et Génétique de la Paroi Bactérienne, Paris, France
  4. 4INSERM, Groupe Avenir, Paris, France
  1. Correspondence to Corinne Grangette, Bactéries Lactiques et Immunité des Muqueuses, Centre d'Infection et d'Immunité de Lille, Institut Pasteur de Lille, 1 rue du Pr Calmette, 59019 Lille Cedex, France; corinne.grangette{at}ibl.fr

Abstract

Background and aims Inflammatory bowel disease (IBD) has been linked to a loss of tolerance towards the resident microflora. Therapeutic use of probiotics is known to be strain specific, but precise mechanisms remain unclear. The role of NOD2 signalling and the protective effect of Lactobacillus peptidoglycan (PGN) and derived muropeptides in experimental colitis were evaluated.

Methods The anti-inflammatory capacity of lactobacilli and derived bacterial compounds was evaluated using the 2,4,6-trinitrobenzene sulfonic acid (TNBS) colitis model. The role of NOD2, MyD88 and interleukin 10 (IL-10) in this protection was studied using Nod2−/−, MyD88−/− and Il10-deficient mice, while induction of regulatory dendritic cells (DCs) was monitored through the expansion of CD103+ DCs in mesenteric lymph nodes or after adoptive transfer of bone marrow-derived DCs. The development of regulatory T cells was investigated by following the expansion of CD4+FoxP3+ cells. High-performance liquid chromatography and mass spectrometry were used to analyse the PGN structural differences.

Results The protective capacity of strain Lactobacillus salivarius Ls33 was correlated with a local IL-10 production and was abolished in Nod2-deficient mice. PGN purified from Ls33 rescued mice from colitis in an IL-10-dependent manner and favoured the development of CD103+ DCs and CD4+Foxp3+ regulatory T cells. In vitro Ls33 PGN induced IL-10-producing DCs able to achieve in vivo protection after adoptive transfer in a NOD2-dependent way. This protection was also correlated with an upregulation of the indoleamine 2,3-dioxygenase immunosuppressive pathway. The protective capacity was not obtained with PGN purified from a non-anti-inflammatory strain. Structural analysis of PGNs highlighted in Ls33 the presence of an additional muropeptide, M-tri-Lys. The synthesised ligand protected mice from colitis in a NOD2-dependent but MyD88-independent manner.

Conclusions The results indicated that PGN and derived muropeptides are active compounds in probiotic functionality and might represent a useful therapeutic strategy in IBD.

  • Probiotics
  • peptidoglycan
  • IBD
  • NOD2
  • dendritic cells
  • inflammatory bowel disease
  • mucosal immunity
  • 2,4,6-trinitrobenzene sulfonic acid

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Footnotes

  • Funding This work was financially supported by l'Institut Pasteur de Lille, l'Association François Aupetit, by INSERM and by a European Research Council starting grant (202283-PGNfromSHAPEtoVIR) to IGB. EMF was supported by a doctoral fellowship from the Ministère de l'Enseignement Supérieur et de la Recherche.

  • Competing interests None.

  • Ethics approval Animal experiments were performed in compliance with European guidelines in accredited establishments (no. A59107; Institut Pasteur de Lille and no. B 75 15-01 Institut Pasteur, Paris). All animal protocols were approved by the locally appointed investigational review board (number 86/609/EEC).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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