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Understand how bacterial stress can shape and permanently disrupt the stability of the genome and epigenome

from basic science:
to the translational research:
Laurence Arbibe
Genome plasticity and infections

Laurence Arbibe is an INSERM director and a team leader at the INEM since 2014. After a residency in Intensive Care and Anesthesiology, a PhD on the biochemistry of phospholipase A2 (Institut Pasteur, L. Touqui team) and a postdoc in immunology at the Scripps Research Institute (R. Ulevitch lab), she obtained an academic position at the INSERM in P. Sansonetti Lab (Institut Pasteur). She dedicated her career to research and focused on signal transduction pathways driving the innate immune response (Arbibe et al, Nature Immunol, 2000). LA has provided pioneering data showing that a bacterial effector can target epigenetic information carried by host promoter chromatin and thereby takes over the control of a small number of immune genes (Arbibe et al, Nature Immunol 2007). Using bacterial proteins as probes to identify new mechanisms controlling the immune epigenome, the group has accumulated expertise in the field of chromatin regulation of innate immune gene expression. The research is now focused on the mechanisms by which bacterial stress imposed by commensal or pathogenic bacteria can shape chromatin information and eventually destabilize the epigenome and genome in the gut.


  • Unraveling epigenetic regulators sustaining tolerance in the gut and exploring their therapeutic potential in Inflammatory Bowel Diseases (IBD).
  • Identifying bacterial mechanisms promoting genomic instability in the gut, with a focus on genotoxins released by enterobacteria.
  • Identifying the role of Escherichia coli in the inflammatory state found in IBD patients
  • Developing new immunotherapeutic approaches to prevent or treat bacterial infection, including those caused by multi-drug and pan resistant strains by identifying bacterial factors interacting with the host inflammatory and immune systems.


Tolerance is a host defense strategy by which a tissue can protect against immune–inflammatory stressors. With the constant assault of antigens and resident microbes, the gut is by essence submitted to environmental stresses. Control of inflammation and tissue repair capacity are equally central for gut tolerance. Epigenetics captures environmental stresses and translate them into specific gene expression patterns. However, little is known on the mechanisms by which gut tolerance is epigenetically regulated and how those mechanisms nurture inflammatory states seen in Inflammatory Bowel Diseases (IBD). Thus, identifying epigenetic regulators sustaining tolerance is mandatory for understanding IBD pathogenesis and should lead to novel therapeutic strategies.

Inflammation and genomic instability can be prevented under gnotobiotic conditions revealing a link between the commensal flora and intestinal diseases. Genotoxins are a family of microbial effectors in pathogenic and commensal bacteria. So far only three types of bacterial genotoxins are identified. To what extend these effectors act as virulence factors during in vivo infections is unclear. Moreover, whether the carcinogenic effect shown in vitro is relevant in vivo during chronic intoxication remains uncertain. Thus, there is a need for identification of new genotoxins and for development of models exploring their implication in infectious diseases and tumorigenesis.

IBD involve the inappropriate activation of the gastro-intestinal (GI) immune system in genetically susceptible hosts. The gut microbiota is now clearly identified as a major driving force in the disease. An imbalance in the gut microbiota composition (dysbiosis) in IBD patients has been repeatedly reported. One of the major and most common features of this dysbiosis is an increase of Proteobacteria and particularly of Enterobacteriaceae in IBD patients compared to healthy subjects. These changes in the microbiota composition likely have functional consequences as Enterobacteriaceae have proinflammatory effects whereas some Firmicutes have anti-inflammatory properties. Escherichia coli is a prototypic member of the Enterobacteriaceae family. There are two hypotheses to be explored regarding the increased levels of E. coli in IBD: it could be either a primary event triggering inflammation or a secondary event induced by the inflammatory cascade and further promoting destructive pathology. In any case, understanding and exploring E. coli virulence factors associated with the inflammation found in IBD would fill in gaps in our knowledge about the pathophysiology of the disease and may also uncover new therapeutic targets.

Inflammation caused by bacteria Is present in IBD but is also a major characteristic of bacterial infections. Studying both bacterial and host sides during an infectious process should provide important information to understand bacterial pathogenesis in both sepsis and IBD and may reveal new putative therapeutic targets for an immunotherapeutic approach either passive (monoclonal antibodies), or active (Vaccine development) against to prevent and/or treat these pathologies.

Research objectives

  1. Explore the implication of the chromatin reader HP1 in anti-inflammation and tissue regeneration in the gut:

    Our studies spotlighted the epigenetic regulator HP1γ as a sensor of acute inflammation in the colon. HP1 is a chromatin-associated transcriptional silencer enriched in heterochromatin, while also silencing inducible genes. We showed that HP1 acts as a repressor of inflammatory chemokines while its function in gut physiology unexplored. Through the development of various mice models conditionally inactivating HP1 in the gut epithelium, our research aims at:

    • Decrypting the functions of HP1 in the regulation of gene expression programs involved in intestinal stem cell renewal and commitment
    • Unraveling its functions in anti-inflammation and intestinal regeneration
    • Developing innovative approaches reinforcing HP1 bioactivity in the intestine

  2. Identify genotoxins and explore their implication in infectious diseases and genomic instability:

    We have shown that some enteropathogens such as Shigella flexneri can inactivate the tumor suppressor gene p53 in the context of genotoxic stress to preserve the life of its own epithelial niche. This example illustrates a mechanism by which bacteria can potentially induce genomic instability. In this context, the identification of bacterial traits that can directly alter the host genome is crucial to understanding how some bacterial species promote cancer. Thus, our second line of research aims at:

    • Identifying new bacterial genotoxins released by both commensal and pathogenic enterobacteria E. coli species, including Adherent-Invasive E. coli.
    • Modelizing the long-term impact of this genotoxic stress on the stability of the host genome and epigenome.

  3. Identify and explore E. coli virulence factors associated with IBD inflammatory state:

    Adherent-Invasive E. coli (AIEC) are particularly implicated in Crohn’s disease as they are found in the mucosa of more than one third of IBD patients. One of these AIEC strains, LF82, is able to adhere and invade intestinal epithelial cells, replicate within macrophages and promote TNF-alpha production by infected macrophages. Using two E. coli strains: the commensal E. coli MG1655 and E. coli LF82, we intend to conduct a systematic analysis of the role of E. coli genes in an inflammatory gastro-intestinal (GI) tract environment by identifying and studying the genes required to colonize murine GI tracts in steady state and inflammatory conditions, in both conventional and germ-free mice and in different parts of the GI tract: Ileum, Jejunum, Colon, and Cecum.

  4. Genomic approaches to microbial pathogenesis and vaccine development: a translational approach to bring new vaccine from bench to bed:

    We use TnSeq to (i) better understand bacterial pathogenesis by identifying and studying the genes and regulatory genetic elements contributing to optimal fitness of bacterial pathogens within its host (E. coli K1 and P. aeruginosa), (ii), identify and develop new vaccine candidates via a process we have called TnSeq vaccinology. This approach exploits the TnSeq tool to test the effect of host immunity, induced by vaccination with a broadly-protective immunogen such as antibiotic-killed cells, on selection of strains with Tn-interrupted genes. This approach should impact all types of vaccine antigens, not just proteins, a limitation of current antigen identification systems such as reverse vaccinology. Thus, our lab is invested in advancing vaccine development from target discovery to efficacy studies in relevant animal models.

5 main publications

  • Mata-Garrido, J., Chang-Marchand, Y., Cherbuy, C., Batsche, E., Muchardt, C. & Arbibe, L.
    HP1γ sets the biological age of the intestinal epithelium.
    bioRxiv 11, 61-22 (2020).
  • Zhang, Y., Devocelle, A., Souza, L., Foudi, A., Tenreira Bento, S., Desterke, C., Sherrard, R., Ballesta, A., Adam, R., Giron-Michel, J., Chang, Y.
    BMAL1 knockdown triggers different colon carcinoma cell fates by altering the delicate equilibrium between AKT/mTOR and P53/P21 pathways.
    Aging (Albany NY) 12, 8067-8083 (2020).
  • Meijer, B. M., Jang, S. M., Guerrera, I. C., Chhuon, C., Lipecka, J., Reisacher, C., Baleux, F., Sansonetti, P. J., Muchardt, C., Arbibe, L.
    Threonine eliminylation by bacterial phosphothreonine lyases rapidly causes cross-linking of mitogen-activated protein kinase (MAPK) in live cells.
    J. Biol. Chem. 292, 7784-7794 (2017).
  • Roux, D., Danilchanka, O., Guillard, T., Cattoir, V., Aschard, H., Fu, Y., Angoulvant, F., Messika, J., Ricard, J.-D., Mekalanos, J. J., Lory, S., Pier, G. B., Skurnik, D.
    Fitness cost of antibiotic susceptibility during bacterial infection.
    Sci Transl Med 7, 297ra114-297ra114 (2015)
  • Harouz, H., Rachez, C., Meijer, B. M., Marteyn, B., Donnadieu, F., Cammas, F., Muchardt, C., Sansonetti, P., Arbibe, L.
    Shigella flexneri targets the HP1γ subcode through the phosphothreonine lyase OspF.
    EMBO J. 33, 2606-2622 (2014).
Last 30 publications


  • Harouz H, Rachez C, Meijer BM, Marteyn B, Donnadieu F, Cammas F, Muchardt C, Sansonetti P, Arbibe L.Shigella flexneri targets the HP1γ subcode through the phosphothreonine lyase OspF. EMBO J. 2014 Nov 18;33(22):2606-22.
  • 2012

  • Bergounioux J, Arbibe L. [Calpain activation by Shigella flexneri regulates key steps in the life and death of bacterium's epithelial niche]. Med Sci (Paris). 2012 Dec;28(12):1029-31.
  • Bergounioux J, Elisee R, Prunier AL, Donnadieu F, Sperandio B, Sansonetti P, Arbibe L. Calpain activation by the Shigella flexneri effector VirA regulates key steps in the formation and life of the bacterium's epithelial niche. Cell Host Microbe. 2012 Mar 15;11(3):240-52.
  • ≤ 2010

  • Tran Van Nhieu G, Arbibe L. Genetic reprogramming of host cells by bacterial pathogens. F1000 Biol Rep. 2009 Oct 29;1:80.
  • Arbibe L. Immune subversion by chromatin manipulation: a 'new face' of host-bacterial pathogen interaction. Cell Microbiol. 2008 Aug;10(8):1582-90.
  • Mazurkiewicz P, Thomas J, Thompson JA, Liu M, Arbibe L, Sansonetti P, Holden DW. SpvC is a Salmonella effector with phosphothreonine lyase activity on host mitogen-activated protein kinases. Mol Microbiol. 2008 Mar;67(6):1371-83.
  • Arbibe L, Sansonetti PJ. Epigenetic regulation of host response to LPS: causing tolerance while avoiding Toll errancy. Cell Host Microbe. 2007 Jun 14;1(4):244-6.
  • Arbibe L, Sansonetti P. [Shigella flexneri modulates host cell epigenetic information as a strategy to shape the transcriptional response]. Med Sci (Paris). 2007 Mar;23(3):238-40.
  • Arbibe L, Kim DW, Batsche E, Pedron T, Mateescu B, Muchardt C, Parsot C, Sansonetti PJ. An injected bacterial effector targets chromatin access for transcription factor NF-kappaB to alter transcription of host genes involved in immune responses. Nat Immunol. 2007 Jan;8(1):47-56.
  • Kaltschmidt B, Ndiaye D, Korte M, Pothion S, Arbibe L, Prüllage M, Pfeiffer J, Lindecke A, Staiger V, Israël A, Kaltschmidt C, Mémet S. NF-kappaB regulates spatial memory formation and synaptic plasticity through protein kinase A/CREB signaling. Mol Cell Biol. 2006 Apr;26(8):2936-46.
  • Pendaries C, Tronchère H, Arbibe L, Mounier J, Gozani O, Cantley L, Fry MJ, Gaits-Iacovoni F, Sansonetti PJ, Payrastre B. PtdIns5P activates the host cell PI3-kinase/Akt pathway during Shigella flexneri infection. EMBO J. 2006 Mar 8;25(5):1024-34.
  • Arbibe L, Mira JP, Teusch N, Kline L, Guha M, Mackman N, Godowski PJ, Ulevitch RJ, Knaus UG. Toll-like receptor 2-mediated NF-kappa B activation requires a Rac1-dependent pathway. Nat Immunol. 2000 Dec;1(6):533-40.
  • Mira JP, Cariou A, Grall F, Delclaux C, Losser MR, Heshmati F, Cheval C, Monchi M, Teboul JL, Riché F, Leleu G, Arbibe L, Mignon A, Delpech M, Dhainaut JF. Association of TNF2, a TNF-alpha promoter polymorphism, with septic shock susceptibility and mortality: a multicenter study. JAMA. 1999 Aug 11;282(6):561-8.
  • Touqui L, Arbibe L. A role for phospholipase A2 in ARDS pathogenesis. Mol Med Today. 1999 Jun;5(6):244-9.
  • Berger A, Havet N, Vial D, Arbibe L, Dumarey C, Watson ML, Touqui L. Dioleylphosphatidylglycerol inhibits the expression of type II phospholipase A2 in macrophages. Am J Respir Crit Care Med. 1999 Feb;159(2):613-8.
  • Arbibe L, Koumanov K, Vial D, Rougeot C, Faure G, Havet N, Longacre S, Vargaftig BB, Béréziat G, Voelker DR, Wolf C, Touqui L. Generation of lyso-phospholipids from surfactant in acute lung injury is mediated by type-II phospholipase A2 and inhibited by a direct surfactant protein A-phospholipase A2 protein interaction. J Clin Invest. 1998 Sep 15;102(6):1152-60.
  • Vial D, Arbibe L, Havet N, Dumarey C, Vargaftig B, Touqui L. Down-regulation by prostaglandins of type-II phospholipase A2 expression in guinea-pig alveolar macrophages: a possible involvement of cAMP. Biochem J. 1998 Feb 15;330 ( Pt 1):89-94.
  • Arbibe L, Vial D, Rosinski-Chupin I, Havet N, Huerre M, Vargaftig BB, Touqui L. Endotoxin induces expression of type II phospholipase A2 in macrophages during acute lung injury in guinea pigs: involvement of TNF-alpha in lipopolysaccharide-induced type II phospholipase A2 synthesis. J Immunol. 1997 Jul 1;159(1):391-400.
  • Permanent researcher
    Laurence Arbibe
    +33 (0)1 40 61 54 30
    Yunhua Chang Marchand
    +33 (0)1 40 61 54 99
    Hedi Mammeri
    Damien Roux
    Professor Researcher
    +33 (0)1 40 61 54 84
    David Skurnik
    Professor Researcher
    Fabrice Uhel
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    Permanent engineer
    Elisabeth Ageron-Ardila
    Assistant in Biological Techniques
    +33 (0)1 40 61 54 31
    Eric Frapy
    +33 (0)1 40 61 54 84
    Non permanent engineer
    Caroline Reisacher
    +33 (0)1 40 61 54 31
    Post-doctoral degree
    Youssouf Sereme
    Post-Doctoral Researcher
    +33 (0)1 40 61 54 31
    Estelle Saifi
    PhD Student
    +33 (0)1 40 61 54 31
    Yao Xiang
    PhD Student
    +33 (0)1 40 61 54 99

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