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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 24 January 2017, Vol.114(4), pp.E506-E513
    Description: The intestinal epithelium is continuously renewed by intestinal epithelial stem cells (IESCs) positioned at the base of each crypt. Mesenchymal-derived factors are essential to maintain IESCs; however, the cellular composition and development of such mesenchymal niche remains unclear. Here, we identify pericryptal CD34 Gp38 αSMA mesenchymal cells closely associated with Lgr5 IESCs. We demonstrate that CD34 Gp38 cells are the major intestinal producers of the niche factors Wnt2b, Gremlin1, and R-spondin1, and are sufficient to promote maintenance of Lgr5 IESCs in intestinal organoids, an effect mainly mediated by Gremlin1. CD34 Gp38 cells develop after birth in the intestinal submucosa and expand around the crypts during the third week of life in mice, independently of the microbiota. We further show that pericryptal CD34gp38 cells are rapidly activated by intestinal injury, up-regulating niche factors Gremlin1 and R-spondin1 as well as chemokines, proinflammatory cytokines, and growth factors with key roles in gut immunity and tissue repair, including IL-7, Ccl2, Ptgs2, and Amphiregulin. Our results indicate that CD34 Gp38 mesenchymal cells are programmed to develop in the intestine after birth to constitute a specialized microenvironment that maintains IESCs at homeostasis and contribute to intestinal inflammation and repair after injury.
    Keywords: Cd34 ; Inflammation ; Intestinal Stem Cells ; Mesenchymal Niche ; Stem Cell Niche ; Antigens, Cd34 -- Metabolism ; Mesenchymal Stem Cells -- Cytology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    In: Nature, 2015
    Description: The gut microbiota plays a crucial role in the maturation of the intestinal mucosal immune system of its host (1,2). Within the thousand bacterial species present in the intestine, the symbiont segmented filamentous bacterium (SFB) is unique in its ability to potently stimulate the post-natal maturation of the B- and T-cell compartments and induce a striking increase in the small-intestinal Th17 responses (3-5). Unlike other commensals, SFB intimately attaches to absorptive epithelial cells in the ileum and cells overlying Peyer's patches (6,7). This colonization does not result in pathology; rather, it protects the host from pathogens (4). Yet, little is known about the SFB-host interaction that underlies the important immunostimulatory properties of SFB, because SFB have resisted in vitro culturing for more than 50 years. Here we grow mouse SFB outside their host in an SFB-host cell co-culturing system. Single-celled SFB isolated from monocolonized mice undergo filamentation, segmentation, and differentiation to release viable infectious particles, the intracellular offspring, which can colonize mice to induce signature immune responses. In vitro, intracellular offspring can attach to mouse and human host cells and recruit actin. In addition, SFB can potently stimulate the upregulation of host innate defence genes, inflammatory cytokines, and chemokines. In vitro culturing thereby mimics the in vivo niche, provides new insights into SFB growth requirements and their immunostimulatory potential, and makes possible the investigation of the complex developmental stages of SFB and the detailed dissection of the unique SFB-host interaction at the cellular and molecular levels.
    Keywords: Host-Bacteria Relationships -- Identification And Classification ; Host-Bacteria Relationships -- Growth ; Anaerobic Bacteria -- Health Aspects ; Anaerobic Bacteria -- Growth;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 3
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 24 May 2016, Vol.113(21), pp.E2993-3001
    Description: Antimicrobial peptides (AMP) are defense effectors of the innate immunity playing a crucial role in the intestinal homeostasis with commensals and protection against pathogens. Herein we aimed to investigate AMP gene regulation by deciphering specific characteristics allowing their enhanced expression among innate immune genes, particularly those encoding proinflammatory mediators. Our emphasis was on epigenetic regulation of the gene encoding the AMP β-defensin 2 (HBD2), taken as a model of possibly specific induction, upon challenge with a commensal bacterium, compared with the proinflammatory cytokine IL-8. Using an in vitro model of colonic epithelial cells challenged with Escherichia coli K12, we showed that inhibition of histone deacetylases (HDAC) by trichostatin A dramatically enhanced induction of HBD2 expression, without affecting expression of IL-8. This mechanism was supported by an increased phosphorylation of histone H3 on serine S10, preferentially at the HBD2 promoter. This process occurred through activation of the IκB kinase complex, which also led to activation of NF-κB. Moreover, we demonstrated that NF-κB was modified by acetylation upon HDAC inhibition, partly by the histone acetyltransferase p300, and that both NF-κB and p300 supported enhanced induction of HBD2 expression. Furthermore, we identified additional genes belonging to antimicrobial defense and epithelial restitution pathways that showed a similar pattern of epigenetic control. Finally, we confirmed our finding in human colonic primary cells using an ex vivo organoid model. This work opens the way to use epigenetic pharmacology to achieve induction of epithelial antimicrobial defenses, while limiting the deleterious risk of an inflammatory response.
    Keywords: Acetylation ; Antimicrobial Peptides ; Colonic Mucosa ; Epigenetic ; Epithelial Cells ; E1a-Associated P300 Protein -- Antagonists & Inhibitors ; Epigenesis, Genetic -- Drug Effects ; Escherichia Coli K12 -- Immunology ; Histone Deacetylase Inhibitors -- Pharmacology ; Interleukin-8 -- Immunology ; Beta-Defensins -- Immunology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 4
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States, Jan 24, 2017, Vol.114(4), p.637(1)
    Keywords: Stem Cells – Health Aspects ; T Cells – Health Aspects ; Homeostasis – Health Aspects
    ISSN: 0027-8424
    E-ISSN: 10916490
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  • 5
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 23 June 2015, Vol.112(25), pp.E3282-90
    Description: Few studies within the pathogenic field have used advanced imaging and analytical tools to quantitatively measure pathogenicity in vivo. In this work, we present a novel approach for the investigation of host-pathogen processes based on medium-throughput 3D fluorescence imaging. The guinea pig model for Shigella flexneri invasion of the colonic mucosa was used to monitor the infectious process over time with GFP-expressing S. flexneri. A precise quantitative imaging protocol was devised to follow individual S. flexneri in a large tissue volume. An extensive dataset of confocal images was obtained and processed to extract specific quantitative information regarding the progression of S. flexneri infection in an unbiased and exhaustive manner. Specific parameters included the analysis of S. flexneri positions relative to the epithelial surface, S. flexneri density within the tissue, and volume of tissue destruction. In particular, at early time points, there was a clear association of S. flexneri with crypts, key morphological features of the colonic mucosa. Numerical simulations based on random bacterial entry confirmed the bias of experimentally measured S. flexneri for early crypt targeting. The application of a correlative light and electron microscopy technique adapted for thick tissue samples further confirmed the location of S. flexneri within colonocytes at the mouth of crypts. This quantitative imaging approach is a novel means to examine host-pathogen systems in a tailored and robust manner, inclusive of the infectious agent.
    Keywords: Shigella Flexneri ; Bioimage Analysis ; Host–Pathogen Interactions ; Intestinal Crypts ; Tissue Microbiology ; Colon -- Microbiology ; Dysentery, Bacillary -- Pathology ; Shigella Flexneri -- Pathogenicity
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 6
    Language: English
    In: Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 05 November 2016, Vol.371(1707)
    Description: Metagenomic analysis of the human intestinal microbiome has provided a wealth of information that allowed an exceptionally detailed description of its microbial content and physiological potential. It also set the basis for studies allowing correlation of alterations in the balance of this microbiota and the occurrence of a certain number of emerging diseases, such as inflammatory bowel diseases, obesity and diabetes, and possibly colorectal cancer. The time has come to give the intestinal microbiota in symbiosis with its host an experimental dimension. This brief review summarizes our attempt at developing a cellular microbiology of the mutualistic symbiosis established between the gut microbiota and the host intestinal surface. Particular attention is paid to the intestinal crypt, due to its role in epithelial regeneration.This article is part of the themed issue 'The new bacteriology'.
    Keywords: Gut Microbiota ; Intestinal Crypts ; Pathobiont ; Symbiosis ; Gastrointestinal Microbiome -- Physiology ; Intestines -- Microbiology
    ISSN: 09628436
    E-ISSN: 1471-2970
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  • 7
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 09 January 2018, Vol.115(2), pp.E283-E291
    Description: Colonization by subsp. (SGG) is strongly associated with the occurrence of colorectal cancer (CRC). However, the factors leading to its successful colonization are unknown, and whether SGG influences the oncogenic process or benefits from the tumor-prone environment to prevail remains an open question. Here, we elucidate crucial steps that explain how CRC favors SGG colonization. By using mice genetically prone to CRC, we show that SGG colonization is 1,000-fold higher in tumor-bearing mice than in normal mice. This selective advantage occurs at the expense of resident intestinal enterococci. An SGG-specific locus encoding a bacteriocin ("gallocin") is shown to kill enterococci in vitro. Importantly, bile acids strongly enhance this bacteriocin activity in vivo, leading to greater SGG colonization. Constitutive activation of the Wnt pathway, one of the earliest signaling alterations in CRC, and the decreased expression of the bile acid apical transporter gene , as an effect of the founding mutation, may thereby sustain intestinal colonization by SGG. We conclude that CRC-specific conditions promote SGG colonization of the gut by replacing commensal enterococci in their niche.
    Keywords: APC/Notch ; S. Bovis ; S. Gallolyticus ; Bacteriocin ; Colorectal Cancer ; Colorectal Neoplasms -- Metabolism ; Gastrointestinal Tract -- Microbiology ; Streptococcus Gallolyticus -- Physiology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 8
    Language: English
    In: Cell Host & Microbe, 11 June 2014, Vol.15(6), pp.792-798
    Description: The intestinal crypt is a site of potential interactions between microbiota products, stem cells, and other cell types found in this niche, including Paneth cells, and thus offers a potential for commensal microbes to influence the host epithelium. However, the complexity of this microenvironment has been a challenge to deciphering the underlying mechanisms. We used in vitro cultured organoids of intestinal crypts from mice, reinforced with in vivo experiments, to examine the crypt-microbiota interface. We find that within the intestinal crypt, Lgr5 stem cells constitutively express the cytosolic innate immune sensor Nod2 at levels much higher than in Paneth cells. Nod2 stimulation by its bona fide agonist, muramyl-dipeptide (MDP), a peptidoglycan motif common to all bacteria, triggers stem cell survival, which leads to a strong cytoprotection against oxidative stress-mediated cell death. Thus, gut epithelial restitution is Nod2 dependent and triggered by the presence of microbiota-derived molecules. The intestinal crypt is the site of epithelial regeneration and of potential interactions between microbiota products and stem cells. Nigro et al. show that intestinal Lgr5+ stem cells express the cytosolic innate immune sensor Nod2, whose stimulation by the bacterial ligand muramyl-dipeptide affords potent cytoprotection to the stem cells.
    Keywords: Biology
    ISSN: 1931-3128
    E-ISSN: 1934-6069
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  • 9
    Language: English
    In: Current Stem Cell Reports, 2015, Vol.1(1), pp.48-52
    Description: The relationship between gut microbiota and the host is symbiotic and mutualistic. Gut microbiota has been shown to influence many aspects of host biology, including metabolism, development, and immunity. Due to the close proximity of the microbes to epithelial surfaces, this barrier represents the primary gateway for potential interactions. Alterations in the balance between gut microbiota and host are now clearly recognized as an influencing factor in the cause of a wide range of intestinal diseases. It is therefore important to gain a better understanding of the mechanisms regulating signals that gut microbiota provides to intestinal epithelial cells. In this context, it is expected that an important role is to be played by intestinal stem cells in their role in epithelial regeneration, homeostasis post-damage repair.
    Keywords: Intestinal stem cells ; Microbiota ; Intestinal crypts ; Intestinal homeostasis ; Germ-free ; NODs ; TLRs
    E-ISSN: 2198-7866
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  • 10
    In: EMBO Journal, 03 December 2018, Vol.37(23), pp.n/a-n/a
    Description: While mucosal inflammation is a major source of stress during enteropathogen infection, it remains to be fully elucidated how the host benefits from this environment to clear the pathogen. Here, we show that host stress induced by different stimuli mimicking inflammatory conditions strongly reduces the binding of to epithelial cells. Mechanistically, stress activates acid sphingomyelinase leading to host membrane remodeling. Consequently, knockdown or pharmacological inhibition of the acid sphingomyelinase blunts the stress‐dependent inhibition of binding to host cells. Interestingly, stress caused by intracellular replication also results in remodeling of the host cell membrane, and , which precludes re‐infection by this and other non‐motile pathogens. In contrast, Typhimurium overcomes the shortage of permissive entry sites by gathering effectively at the remaining platforms through its flagellar motility. Overall, our findings reveal host membrane remodeling as a novel stress‐responsive cell‐autonomous defense mechanism that protects epithelial cells from infection by non‐motile bacterial pathogens. Stress‐induced host membrane remodeling constitutes a novel cell‐autonomous defensive mechanism that protects epithelial cells from infection by and other non‐motile bacterial pathogens. Host oxidative stress strongly reduces S. flexneri binding to epithelial cells. Stress leads to host membrane remodeling, via activation of the acid sphingomyelinase by the MAPK p38 pathway, resulting in the formation of ceramide domains. Intracellular Shigella replication induces remodeling of the host cell membrane, in vitro and in vivo. Stress‐induced host membrane remodeling precludes re‐infection by non‐motile pathogens; motile pathogens are able to overcome this barrier through flagellar motility. Host membrane remodeling is a cell‐autonomous defense mechanism that protects epithelial cells from infection by .
    Keywords: Acid Sphingomyelinase ; Host Stress Response ; Membrane Remodeling ; Salmonella ; Shigella
    ISSN: 0261-4189
    E-ISSN: 1460-2075
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