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Z. Alnabhani, *. Phd, ?. , N. Montcuquet, §. Phd et al.,

M. Roy, *. , ?. , E. Ogier-denis, *. Phd et al., Ileal Crohn's disease is related to NOD2 mutations and to a gut barrier dysfunction. Pseudomonas fluorescens has also been associated with ileal Crohn's disease. The aim of this study was to determine the impact of P

, Methods: To explore this question, in vivo and ex vivo experiments were performed in wild-type, Nod2 2/2 , Nod2 2939iC , and IL-1R 2/2 mice together with in vitro analyses using the Caco-2 (epithelial) and the THP-1 (monocyte) human cell lines

, Results: Pseudomonas fluorescens increased the paracellular permeability of the intestinal mucosa through the secretion of IL-1b by the immune cell populations and the activation of myosin light chain kinase in the epithelial cells. Induction of the IL-1b pathway required the expression of Nod2 in the hematopoietic compartment

, and IL-1b levels were measured by enzyme-linked immunosorbent assay (BD Biosciences, Heidelberg, Germany). In vitro, cytokine concentrations were determined in the supernatant 2, 6, and 24 hours after infection of macrophages, Cytokines In vivo, 7 days after infection, PP and ileal mucosa from WT

. Macherey-nagel and F. ). Hoerdt, total RNA was converted to complementary DNA using random hexonucleotides. Polymerase chain reaction was performed using QuantiTect SYBR Green PCR Kit (Applied Biosystems, Saint Aubin, France), sense and antisense primers specific for Claudin-2, Claudin-5, Claudin-8, Occludin, and G3PDH and for the long isoform of MLCK. Sequences are shown in Table, Real-Time PCR After extraction by the NucleoSpin RNA II Kit, vol.1, p.2

, THP-1 cells were transfected according to manufacturer's instructions (Invitrogen, Cergy Pontoise, France). P. aeruginosa PAO1, IL-1b and TNF-a levels increased (Fig. 2C, D). Similarly, 2 hours after infection (MOI ¼ 10) of the human monocyte-derived THP-1 cell line, P. fluorescens MFN1032 and P. aeruginosa PAO1 induced the secretion of IL-1b and TNF-a (Fig. 2E, F), Small Interfering RNAs The ON-TARGET plus SMARTpool small interfering RNAs targetting NOD2, Rick

, IL-1b Expression Induced by P. fluorescens MFN1032 Disrupts Intestinal Barrier Function Because IL-1b is known to increase the gut ParaP, vol.43

, A and B, Biopsies of PP or ileal mucosa were removed and (A) IL-1b and (B) TNF-a levels were measured by enzymelinked immunosorbent assay. C and D, Bone marrow stem cells from WT mice were differentiated into MF cells and infected (MOI ¼ 10) with P. fluorescens MFN1032, P. fluorescens MF37, or P. aeruginosa PAO1 for 2, 6, or 24 hours. Then (C) IL-1b or (D) TNF-a levels into the supernatant were assessed by enzyme-linked immunosorbent assay. E and F, THP-1 cells were exposed (MOI ¼ 10) to P. fluorescens MFN1032, P. fluorescens MF37, or P. aeruginosa for 2, 6, or 24 hours. After centrifugation, the levels of (E) IL-1b or (F) TNF-a were measured in the supernatants by enzyme-linked immunosorbent assay, FIGURE 2. Pseudomonas triggers IL-1b and TNF-a synthesis. A and B, WT mice were ig inoculated with 10 8 CFU of P. fluorescens MFN1032 or P. aeruginosa PAO1 and killed 7 days after infection

, A, ParaP was investigated by measuring the quantity of FD4 in the serum. B, After mice were killed, biopsies of PP or ileal mucosa were mounted in UC, and the ParaP was measured for 1 hour. C, Biopsies of PP or ileum from uninfected WT mice were mounted in UC and incubated with P. fluorescens MFN1032. Where indicated, WT mice were intraperitoneally treated with Anakinra (an IL-1 receptor antagonist; 300 mg/mice) or with Z-YVAD-FMK (a caspase-1 inhibitor, 100 mg/mice) 2 days before experimentation. During experimentation, Anakinra (50 mg/mL) or Z-YVAD-FMK (20 mg/mL) was added into UC. Then, ParaP was measured for 1 hour. D, IL-1b and (E) TNF-a levels were measured by enzyme-linked immunosorbent assay in PP or in ileal mucosa. F, Caco-2 cells were cultivated on TSs. THP-1 cells infected by P. fluorescens MFN1032 for 6 hours were then added into the basolateral compartment, and ParaP was monitored. To investigate the involvement of IL-1b receptor or TNF-a in the increase of ParaP, FIGURE 3. IL-1b expression induced by P. fluorescens MFN1032 disrupts intestinal barrier function. A-D, WT or IL-1R 2/2 mice were ig inoculated with 10 8 CFU of P. fluorescens MFN1032 for 7 days

, After mice were killed, biopsies from PP or ileum were mounted in UC, and (B) the ParaP was measured together with (C) IL-1b and TNF-a levels (enzyme-linked immunosorbent assay). D, Bone marrow stem cells from WT and Nod2 2/2 mice were differentiated into MF and infected with P. fluorescens MFN1032 for 2, 6, or 24 hours. Then, IL-1b and TNF-a levels were analyzed by enzyme-linked immunosorbent assay in the supernatant. E and F, THP-1 cells were transfected with siRNA against NOD2, TLR-2, TLR-4, or not targeting siRNA (NT) and infected by P. fluorescens MFN1032, FIGURE 5. Nod2 is required to alter the epithelial barrier function. A-C, WT, Nod2 2/2 , and Nod2 2939iC mice were ig inoculated with 10 8 CFU of P. fluorescens MFN1032 for 7 days

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, Dans ce contexte, nous avons recherché si Pseudomonas fluorescens était capable ou non de percevoir certains facteurs entéroendocriniens tels que la sérotonine, l'épinéphrine, la substance P, l'alpha-melanocytestimulating-hormone ou le peptide YY, et si ceux-ci pouvaient avoir un impact sur la croissance et la virulence de cette bactérie. Les résultats ont montré que la croissance de P. fluorescens est faiblement affectée par ces molécules, qui sont capables au contraire d'entrainer une modulation de la virulence bactérienne, dépendante du facteur entéroendocrinien considéré et de l'origine de la souche testée (clinique ou environnementale). la virulence d'E. faecalis V583. Il favorise l'agglutination de la bactérie, augmente son hydrophobicité, son pouvoir cytotoxique, Résumé La lumière intestinale héberge 10 14 bactéries qui sont en contact permanent avec le système entéro-endocrinien et les médiateurs qu'il délivre. L'impact de ces facteurs eucaryotes sur les bactéries de l'intestin n'est pas bien connu

, Dans le but d'apprécier ensuite l'effet global de perturbations hormonales sur la composition du microbiote intestinal, les contenus caecaux de souris modèle d'anorexie (ABA) ont été comparés à des souris contrôle

, Cette étude a montré une augmentation de la proportion des Firmicutes, et une diminution du phylum des Proteobacteries chez les souris ABA, mais aussi chez les souris RA, ce qui laisse supposer une modification surtout liée à la diminution de leur alimentation. En revanche, chez les souris ABA, nous avons également pu mettre en évidence l'apparition ou la disparition de certains genres bactériens

, L'ensemble de ce travail de thèse montre que certaines bactéries intestinales sont capables de percevoir des facteurs entéro-endocriniens, et que ceux-ci sont capables de moduler la virulence bactérienne, alors que dans le cas de pathologies variées telles que la maladie de Crohn