Objective Loss of the Crohn’s disease predisposing NOD2 gene results in an intestinal microenvironment conducive for colonisation by attaching-and-effacing enteropathogens. However, it remains elusive whether it relies on the intracellular recruitment of the serine-threonine kinase RIPK2 by NOD2, a step that is required for its activation of the transcription factor NF-κB.
Design Colonisation resistance was evaluated in wild type and mutant mice, as well as in ex-germ-free (ex-GF) mice which were colonised either with faeces from Ripk2-deficient mice or with bacteria with similar preferences for carbohydrates to those acquired by the pathogen. The severity of the mucosal pathology was quantified at several time points postinfection by using a previously established scoring. The community resilience in response to infection was evaluated by 16S ribosomal RNA gene sequence analysis. The control of pathogen virulence was evaluated by monitoring the secretion of Citrobacter-specific antibody response in the faeces.
Results Primary infection was similarly outcompeted in ex-GF Ripk2-deficient and control mice, demonstrating that the susceptibility to infection resulting from RIPK2 deficiency cannot be solely attributed to specific microbiota community structures. In contrast, delayed clearance of Citrobacter rodentium and exacerbated histopathology were preceded by a weakened propensity of intestinal macrophages to afford innate lymphoid cell activation. This tissue protection unexpectedly required the regenerating family member 3β by instigating interleukin (IL) 17A-mediated neutrophil recruitment to the intestine and subsequent phosphorylation of signal transducer and activator of transcription 3.
Conclusions These results unveil a previously unrecognised mechanism that efficiently protects from colonisation by diarrhoeagenic bacteria early in infection.
- Barrier Function
- Colonic Microflora
- Antibacterial Peptide
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.
SK and TS contributed equally.
Contributors NW and MC performed study design, acquisition of data, analysis and interpretation of data and statistical analysis. NW, SK, TS, VZ, OB and LFP acquired, analysed and interpreted data with the help of EF, OB, MD and BL. H-PP, AS, MLR, PL and HS contributed to interpretation of microarray data, pyrosequencing data and statistical analysis. J-MC, J-CD, GE, BR, NK and JLI provided critical materials. NW and MC wrote the manuscript and all authors discussed the results and commented on the manuscript.
Funding This work was supported by the Fondation pour la Recherche Médicale grant (grant number DEQ20130326475) to MC and by the Agence Nationale de la Recherche grant (grant number ANR-13-BSV3-0014) to MC, AS and HS. NW is a recipient of a postdoctoral fellowship from the Agence Nationale de la Recherche (grant number ANR-13-BSV3-0014) and VZ is a recipient of a postdoctoral fellowship from the Agence Nationale de la Recherche (grant number ANR-13-PRTS-0006).
Competing interests None declared.
Patient consent Experimental studies using mice only.
Ethics approval The local investigational review board approved all animal studies (CEEA – “75 Comité d’Ethique en Expérimentation Animale Nord - Pas de Calais” (CEEA232009R). Animal experiments were performed in an accredited establishment (N° B59–108) according to FELASA and governmental guidelines N°86/609/CEE.
Provenance and peer review Not commissioned; externally peer reviewed.