Mathias Chamaillard

Publications of Mathias Chamaillard

• Nod-like receptor pyrin domain-containing protein 6 (NLRP6) controls epithelial self-renewal and colorectal carcinogenesis upon injury.

  Authors: Sylvain Normand, Anne Delanoye-Crespin, Aude Bressenot, Ludovic Huot, Teddy Grandjean, Laurent Peyrin-Biroulet, Yves Lemoine, David Hot, Mathias Chamaillard

  Proceedings of the National Academy of Sciences of the United States of America. 06/2011; 108(23):9601-6.

  The colonic epithelium self-renews every 3 to 5 d, but our understanding of the underlying processes preserving wound healing from carcinogenesis remains incomplete. Here, we demonstrate thatThe colonic epithelium self-renews every 3 to 5 d, but our understanding of the underlying processes preserving wound healing from carcinogenesis remains incomplete. Here, we demonstrate that Nod-like receptor pyrin domain-containing protein 6 (NLRP6) suppresses inflammation and carcinogenesis by regulating tissue repair. NLRP6 was primarily produced by myofibroblasts within the stem-cell niche in the colon. Although NLRP6 expression was lowered in diseased colon, NLRP6-deficient mice were highly susceptible to experimental colitis. Upon injury, NLRP6 deficiency deregulated regeneration of the colonic mucosa and processes of epithelial proliferation and migration. Consistently, absence of NLRP6 accelerated colitis-associated tumor growth in mice. A gene-ontology analysis on a whole-genome expression profiling revealed a link between NLRP6 and self-renewal of the epithelium. Collectively, the integrity of the epithelial barrier is preserved by NLRP6 that may be manipulated to develop drugs capable of preventing adenoma formation in inflammatory bowel diseases.

• Defensins couple dysbiosis to primary immunodeficiency in Crohn's disease.

  Authors: Mathias Chamaillard, Rodrigue Dessein

  World journal of gastroenterology : WJG. 02/2011; 17(5):567-71.

  Antimicrobial peptides, including defensins, are essential effectors in host defence and in the maintenance of immune homeostasis. Clinical studies have linked the defective expression of both α- andAntimicrobial peptides, including defensins, are essential effectors in host defence and in the maintenance of immune homeostasis. Clinical studies have linked the defective expression of both α- and β-defensin to the reduced killing of certain microorganisms by the intestinal mucosa of patients suffering from ileal and colonic Crohn's disease (CD), respectively. Only recently have the events leading to defective expression of defensins in CD been further elucidated, and are discussed herein. These events may account for CD-associated alterations in the microbiome and may subsequently precipitate the development of granulomatous inflammatory lesions in genetically-predisposed patients. We also address how these discoveries may pave the way for the development of a molecular medicine aimed at restoring gut barrier function in CD.

• Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47.

  Authors: Carl A Anderson, Gabrielle Boucher, Charlie W Lees, Andre Franke, Mauro D'Amato, Kent D Taylor, James C Lee, Philippe Goyette, Marcin Imielinski, Anna Latiano [......] Mark J Daly, Jeffrey C Barrett, Miles Parkes, Vito Annese, Hakon Hakonarson, Graham Radford-Smith, Richard H Duerr, Séverine Vermeire, Rinse K Weersma, John D Rioux

  Nature genetics. 02/2011; 43(3):246-52.

  Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide associationGenome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.

• Corrigendum: Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47.

  Authors: Carl A Anderson, Gabrielle Boucher, Charlie W Lees, Andre Franke, Mauro D'Amato, Kent D Taylor, James C Lee, Philippe Goyette, Marcin Imielinski, Anna Latiano [......] Mark J Daly, Jeffrey C Barrett, Miles Parkes, Vito Annese, Hakon Hakonarson, Graham Radford-Smith, Richard H Duerr, Séverine Vermeire, Rinse K Weersma, John D Rioux

  Nature genetics. 01/2011; 43(9):919.

• Peroxisome proliferator-activated receptor gamma activation is required for maintenance of innate antimicrobial immunity in the colon.

  Authors: Laurent Peyrin-Biroulet, Julia Beisner, Guoxing Wang, Sabine Nuding, Sajit Thottathil Oommen, Denise Kelly, Erika Parmentier-Decrucq, Rodrigue Dessein, Emilie Merour, Philipe Chavatte, Teddy Grandjean, Aude Bressenot, Pierre Desreumaux, Jean-Frédéric Colombel, Béatrice Desvergne, Eduard F Stange, Jan Wehkamp, Mathias Chamaillard

  Proceedings of the National Academy of Sciences of the United States of America. 05/2010; 107(19):8772-7.

  Crohn's disease (CD), a major form of human inflammatory bowel disease, is characterized by primary immunodeficiencies. The nuclear receptor peroxisome proliferator-activated receptor gammaCrohn's disease (CD), a major form of human inflammatory bowel disease, is characterized by primary immunodeficiencies. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is essential for intestinal homeostasis in response to both dietary- and microbiota-derived signals. Its role in host defense remains unknown, however. We show that PPARgamma functions as an antimicrobial factor by maintaining constitutive epithelial expression of a subset of beta-defensin in the colon, which includes mDefB10 in mice and DEFB1 in humans. Colonic mucosa of Ppargamma mutant animals shows defective killing of several major components of the intestinal microbiota, including Candida albicans, Bacteroides fragilis, Enterococcus faecalis, and Escherichia coli. Neutralization of the colicidal activity using an anti-mDefB10 blocking antibody was effective in a PPARgamma-dependent manner. A functional promoter variant that is required for DEFB1 expression confers strong protection against Crohn's colitis and ileocolitis (odds ratio, 0.559; P = 0.018). Consistently, colonic involvement in CD is specifically linked to reduced expression of DEFB1 independent of inflammation. These findings support the development of PPARgamma-targeting therapeutic and/or nutritional approaches to prevent colonic inflammation by restoring antimicrobial immunity in CD.

• Remote control of intestinal tumorigenesis by innate immunity.

  Authors: Thomas Secher, Olivier Gaillot, Bernhard Ryffel, Mathias Chamaillard

  Cancer research. 02/2010; 70(5):1749-52.

  Chronic intestinal inflammation has been linked to the development of colorectal cancer. Recent studies suggest that during chronic inflammation, the innate immune system may facilitate colonChronic intestinal inflammation has been linked to the development of colorectal cancer. Recent studies suggest that during chronic inflammation, the innate immune system may facilitate colon tumorigenesis in genetically predisposed individuals in response to certain indigenous microorganisms and/or cell remnants. In these individuals, therapeutic approaches that reroute the innate immune system's inflammatory and antimicrobial activities might help prevent colon tumorigenesis and metastasis.

• Lessons from the inflammasome: a molecular sentry linking Candida and Crohn's disease.

  Authors: Linda M Rehaume, Thierry Jouault, Mathias Chamaillard

  Trends in immunology. 02/2010; 31(5):171-5.

  Candida albicans is a diploid fungus that colonizes the gastrointestinal tract asymptomatically in a large proportion of the human population, but can cause life-threatening conditions inCandida albicans is a diploid fungus that colonizes the gastrointestinal tract asymptomatically in a large proportion of the human population, but can cause life-threatening conditions in immunocompromised patients. Recent immunological investigations have revealed the Nod-like receptor pyrin domain-containing protein 3 (NLRP3) to be a cytosolic surveillance mechanism against germinating Candida. These observations point to the idea of a molecular link between Candida and a spectrum of auto-inflammatory diseases. When excessive activation of NLRP3 occurs, it can confer resistance against disseminating Candida infection but might also cause NLRP3-associated periodic syndromes. Alternatively, we propose a pathophysiological model whereby a defective NLRP3-coupled inflammasome can result in enhanced mucosal colonization of granuloma-provoking microorganisms, including C. albicans, precipitating the formation of Crohn's disease-associated inflammatory lesions.

• Intestinal Microbiota Gives a Nod to the Hygiene Hypothesis in Type 1 Diabetes.

  Authors: Rodrigue Dessein, Laurent Peyrin-Biroulet, Mathias Chamaillard

  Gastroenterology. 06/2009;

• Candida albicans Colonization and ASCA in Familial Crohn's Disease.

  Authors: Annie Standaert-Vitse, Boualem Sendid, Marie Joossens, Nadine François, Peggy Vandewalle-El Khoury, Julien Branche, Herbert Van Kruiningen, Thierry Jouault, Paul Rutgeerts, Corinne Gower-Rousseau, Christian Libersa, Christel Neut, Franck Broly, Mathias Chamaillard, Séverine Vermeire, Daniel Poulain, Jean-Frédéric Colombel

  The American journal of gastroenterology. 06/2009;

  OBJECTIVES:Anti-Saccharomyces cerevisiae antibodies (ASCAs) are present in 50-60% of patients with Crohn's disease (CD) and in 20-25% of their healthy relatives (HRs). The yeast, Candida albicans,OBJECTIVES:Anti-Saccharomyces cerevisiae antibodies (ASCAs) are present in 50-60% of patients with Crohn's disease (CD) and in 20-25% of their healthy relatives (HRs). The yeast, Candida albicans, has been shown to generate ASCAs, but the presence of C. albicans in the digestive tract of CD patients and their HRs has never been investigated. Therefore, we studied C. albicans carriage in familial CD and its correlation with ASCAs.METHODS:Study groups consisted of 41 CD families composed of 129 patients and 113 HRs, and 14 control families composed of 76 individuals. Mouth swabs and stool specimens were collected for isolation, identification, and quantification of yeasts. Serum samples were collected for detection of ASCAs and anti-C. albicans mannan antibodies (ACMAs).RESULTS:C. albicans was isolated significantly more frequently from stool samples from CD patients (44%) and their HRs (38%) than from controls (22%) (P<0.05). The prevalence of ACMAs was similar between CD patients, their HRs, and controls (22, 19, and 21%, respectively, P=0.845), whereas the prevalence of ASCAs was significantly increased in CD families (72 and 34% in CD and HRs, respectively, in contrast to 4% in controls, P<0.0001). AMCA levels correlated with C. albicans colonization in all populations. ASCA levels correlated with C. albicans colonization in HRs but not in CD patients.CONCLUSIONS:CD patients and their first-degree HRs are more frequently and more heavily colonized by C. albicans than are controls. ASCAs correlate with C. albicans colonization in HRs but not in CD. In HRs, ASCAs could result from an altered immune response to C. albicans. In CD, a subsequent alteration in sensing C. albicans colonization could occur with disease onset.Am J Gastroenterol advance online publication, 26 May 2009; doi:10.1038/ajg.2009.225.

• Familial aggregation and antimicrobial response dose-dependently affect the risk for Crohn's disease.

  Authors: Marie Joossens, Kristel Van Steen, Julien Branche, Boualem Sendid, Paul Rutgeerts, Francis Vasseur, Daniel Poulain, Franck Broly, Jean-Frédéric Colombel, Séverine Vermeire, Mathias Chamaillard

  Inflammatory bowel diseases. 06/2009;

  BACKGROUND:: An increased risk of Crohn's disease (CD) has been reported consistently in first-degree relatives of patients. Our aim was to test whether a combination of CD-associated genes involvedBACKGROUND:: An increased risk of Crohn's disease (CD) has been reported consistently in first-degree relatives of patients. Our aim was to test whether a combination of CD-associated genes involved in innate immunity and/or antibody responses to microbial antigens may be valuable in identifying healthy relatives at risk. METHODS:: We investigated 86 families from Belgium and northern France, 45 with at least 3 first-degree relatives with CD, 24 with a single case, and 17 control families without inflammatory bowel disease (IBD). The cohort consisted of 186 CD patients, 290 healthy relatives, and 142 controls (total 618). Genetic (NOD2, NOD1, TLR4, CARD8) and serologic markers (ASCA, ACMA, ALCA, ACCA, ASigmaMA, OmpC, CBir1, I2) were determined in all subjects. All Belgian families were prospectively followed up for 54 months. RESULTS:: In multiple-affected families, an increment of affected first-degree relatives and of positive antibodies were additive risks factors for CD (P < 0.0001), independent of NOD2 mutations. When comparing subjects from multiple-affected families, having 3 additional first-degree relatives with CD and 1 additional positive antibody increased the odds for CD to 9.19 (95% confidence interval [CI]: 4.07-20.80). After a follow-up of 54 months among all Belgian families, a total of 4 new diagnoses of IBD were confirmed in the multiple-affected families only, resulting in a 57-fold increase in incidence within multiple-affected families compared to the known incidence of IBD in our region. CONCLUSIONS:: We found an additive risk increment for CD in subjects from multicase families per additional affected relative and per additional positive antibody, independent of NOD2. Furthermore, a very high disease incidence was observed in these multiple-affected families. Inflamm Bowel Dis 2009.

• TLR2 is critical for induction of REG3{beta} expression and intestinal clearance of Yersinia pseudotuberculosis.

  Authors: Rodrigue Dessein, Meritxell Gironella, Cécile Vignal, Laurent Peyrin-Biroulet, Harry Sokol, Thomas Secher, Sandra Lacas-Gervais, Jean-Jacques Gratadoux, Frank Lafont, Jean-Charles Dagorn, Bernhard Ryffel, Shizuo Akira, Philippe Langella, Gabriel Nùñez, Jean-Claude Sirard, Juan Iovanna, Michel Simonet, Mathias Chamaillard

  Gut. 02/2009;

  OBJECTIVE: Yersinia pseudotuberculosis causes ileitis and mesenteric lymphadenitis by mainly invading the Peyer's patches (PPs) that are positioned in the terminal ileum. Whereas Toll-like-receptor 2OBJECTIVE: Yersinia pseudotuberculosis causes ileitis and mesenteric lymphadenitis by mainly invading the Peyer's patches (PPs) that are positioned in the terminal ileum. Whereas Toll-like-receptor 2 (TLR2) controls mucosal inflammation by detecting certain microbiota-derived signals, its exact role in protecting PPs against bacterial invasion has not been defined. DESIGN: Wild-type, Tlr2-, Nod2- and MyD88-deficient animals were challenged by Y. pseudotuberculosis via oral or systemic route. The role of microbiota in conditioning PPs against Yersinia through TLR2 was assessed by delivering ad libitum exogenous TLR2 agonists in drinking water to Germ-Free and streptomycin-treated animals. Bacterial eradication from PPs was measured by using a colony-forming unit assay. Expression of cryptdins and the c-type lectin Reg3beta were quantified by quantitative RT-PCR. RESULTS: Our data demonstrated that Tlr2-deficient mice failed to limit Yersinia dissemination from the PPs and succumbed to sepsis independently of NOD2. Recognition of both microbiota-derived and MyD88-mediated elicitors was found to be critically involved in gut protection against Yersinia-induced lethality, while TLR2 was dispensable to systemic Yersinia infection. Gene expression analyses revealed that optimal epithelial transcript level of the anti-infective Reg3beta requires TLR2 activation. Consistently, Yersinia infection triggered TLR2-dependent Reg3beta expression in PPs. Importantly, oral treatment with exogenous TLR2 agonists in Germ-Free animals was able to further enhance Yersinia-induced expression of Reg3beta and to restore intestinal resistance to Yersinia. Lastly, genetic ablation of Reg3beta resulted in impaired clearance of the bacterial load in PPs. CONCLUSIONS: TLR2/REG3beta is thus an essential component in conditioning epithelial defense signaling pathways against bacterial invasion.

• Genetic variants of Wnt transcription factor TCF-4 (TCF7L2) putative promoter region are associated with small intestinal Crohn's disease.

  Authors: Maureen J Koslowski, Irmgard Kübler, Mathias Chamaillard, Elke Schaeffeler, Walter Reinisch, Guoxing Wang, Julia Beisner, Alexander Teml, Laurent Peyrin-Biroulet, Stefan Winter, Klaus R Herrlinger, Paul Rutgeerts, Séverine Vermeire, Rachel Cooney, Klaus Fellermann, Derek Jewell, Charles L Bevins, Matthias Schwab, Eduard F Stange, Jan Wehkamp

  PLoS ONE. 02/2009; 4(2):e4496.

  Reduced expression of Paneth cell antimicrobial alpha-defensins, human defensin (HD)-5 and -6, characterizes Crohn's disease (CD) of the ileum. TCF-4 (also named TCF7L2), a Wnt signalling pathwayReduced expression of Paneth cell antimicrobial alpha-defensins, human defensin (HD)-5 and -6, characterizes Crohn's disease (CD) of the ileum. TCF-4 (also named TCF7L2), a Wnt signalling pathway transcription factor, orchestrates Paneth cell differentiation, directly regulates the expression of HD-5 and -6, and was previously associated with the decrease of these antimicrobial peptides in a subset of ileal CD. To investigate a potential genetic association of TCF-4 with ileal CD, we sequenced 2.1 kb of the 5' flanking region of TCF-4 in a small group of ileal CD patients and controls (n = 10 each). We identified eight single nucleotide polymorphisms (SNPs), of which three (rs3814570, rs10885394, rs10885395) were in linkage disequilibrium and found more frequently in patients; one (rs3814570) was thereby located in a predicted regulatory region. We carried out high-throughput analysis of this SNP in three cohorts of inflammatory bowel disease (IBD) patients and controls. Overall 1399 healthy individuals, 785 ulcerative colitis (UC) patients, 225 CD patients with colonic disease only and 784 CD patients with ileal involvement were used to determine frequency distributions. We found an association of rs3814570 with ileal CD but neither with colonic CD or UC, in a combined analysis (allele positivity: OR 1.27, 95% CI 1.07 to 1.52, p = 0.00737), which was the strongest in ileal CD patients with stricturing behaviour (allele frequency: OR 1.32, 95% CI 1.08 to1.62, p = 0.00686) or an additional involvement of the upper GIT (allele frequency: OR 1.38, 95% CI 1.03 to1.84, p = 0.02882). The newly identified genetic association of TCF-4 with ileal CD provides evidence that the decrease in Paneth cell alpha-defensins is a primary factor in disease pathogenesis.

• Innate immunity in Crohn's disease: the reverse side of the medal.

  Authors: Rodrigue Dessein, Mathias Chamaillard, Silvio Danese

  Journal of clinical gastroenterology. 09/2008; 42 Suppl 3 Pt 1:S144-7.

  The etiology of Crohn's disease (CD) remains poorly understood. Both mice and human studies suspected a perverse link between the microbiota and the lining of the gut mucosa. There is now emergingThe etiology of Crohn's disease (CD) remains poorly understood. Both mice and human studies suspected a perverse link between the microbiota and the lining of the gut mucosa. There is now emerging evidence that suggests that such a pathologic condition might result from an overly aggressive immune response to microbial antigens in genetically predisposed individuals. However, the multiple pathophysiologic processing steps linking environmental exposure to the clinical expression of CD are, for the most part, unknown. Herein, we review evidences reflecting a general causing defect of the innate immune function of the intestinal mucosa of CD patients, which might lead to a sustained microbial-induced inflammatory response. Changing the paradigms of CD pathophysiology might lead to entirely new therapeutic approaches aiming to boost the innate immune response.

• Detection of antisynthetic mannoside antibodies (ASigmaMA) reveals heterogeneity in the ASCA response of Crohn's disease patients and contributes to differential diagnosis, stratification, and prediction.

  Authors: Peggy Vandewalle-El Khoury, Jean-Frederic Colombel, Sofie Joossens, Annie Standaert-Vitse, Mayeul Collot, Jonas Halfvarson, Ali Ayadi, Carol J Landers, Severine Vermeire, Paul Rutgeerts, Stephan R Targan, Mathias Chamaillard, Jean-Maurice Mallet, Boualem Sendid, Daniel Poulain

  The American journal of gastroenterology. 05/2008; 103(4):949-57.

  OBJECTIVES: Anti-S. cerevisiae mannan antibodies (ASCA) are human antibodies associated with Crohn's disease (CD) reacting with Saccharomyces cerevisiae (S. cerevisiae) mannan polymer. As mannan is aOBJECTIVES: Anti-S. cerevisiae mannan antibodies (ASCA) are human antibodies associated with Crohn's disease (CD) reacting with Saccharomyces cerevisiae (S. cerevisiae) mannan polymer. As mannan is a complex and variable repertoire of oligomannoses acting as epitopes, we chemically synthesized (Sigma) two major oligomannose epitopes, Man alpha-1,3 Man alpha-1,2 Man (SigmaMan3) and Man alpha-1,3 Man alpha-1,2 Man alpha-1,2 Man (SigmaMan4), and then explored how antisynthetic mannoside antibodies (ASigmaMA) compare with ASCA as markers of CD. METHODS: The study involved different cohorts of CD and ulcerative colitis (UC) patients and healthy controls who had been studied previously in several medical centers in Europe, the United States, and North Africa to determine the clinical value of ASCA in terms of differential diagnosis, evolution of indeterminate colitis (IC), and serotype-phenotype correlations. The comparison of ASigmaMA and ASCA included a total of 1,365 subjects: 772 CD, 261 UC, 43 IC, and 289 controls. RESULTS: The specificity of ASigmaMA was similar to that of ASCA (89% vs 93%), although the sensitivity was lower (38% vs 55%). Unexpectedly, 24% of the CD patients who were negative for ASCA and/or other CD-associated serologic markers were positive for ASigmaMA. ASigmaMA were associated with colonic involvement in CD (odds ratio [OR] 1.609, 95% confidence interval [CI] 1.033-2.506, P = 0.03) and were 100% predictive of CD in patients with IC. CONCLUSIONS: ASigmaMA reveal the heterogeneity of the antioligomannose antibody response in CD patients and increase the sensitivity of CD diagnosis when combined with ASCA. The subset of ASCA-negative CD patients diagnosed by ASigmaMA had preferentially a colonic involvement, which confirms the high predictive value of ASigmaMA for determining IC evolution toward CD.

• NOD2: a potential target for regulating liver injury.

  Authors: Mathilde Body-Malapel, Sébastien Dharancy, Dominique Berrebi, Alexandre Louvet, Jean-Pierre Hugot, Dana J Philpott, Marco Giovannini, Fabrice Chareyre, Gilles Pages, Emilie Gantier, Stephen E Girardin, Irène Garcia, Sylvie Hudault, Filoména Conti, Philippe J Sansonetti, Mathias Chamaillard, Pierre Desreumaux, Laurent Dubuquoy, Philippe Mathurin

  Laboratory investigation; a journal of technical methods and pathology. 04/2008; 88(3):318-27.

  The recent discovery of bacterial receptors such as NOD2 that contribute to crosstalk between innate and adaptive immune systems in the digestive tract constitutes an important challenge in ourThe recent discovery of bacterial receptors such as NOD2 that contribute to crosstalk between innate and adaptive immune systems in the digestive tract constitutes an important challenge in our understanding of liver injury mechanisms. The present study focuses on NOD2 functions during liver injury. NOD2, TNF-alpha and IFN-gamma mRNA were quantified using real-time PCR in liver samples from patients and mice with liver injury. We evaluated the susceptibility of concanavalin A (ConA) challenge in NOD2-deficient mice (Nod2-/-) compared to wild-type littermates. We tested the effect of muramyl dipeptide (MDP), the specific activator of NOD2, on ConA-induced liver injury in C57BL/6 mice. We studied the cellular distribution and the role of NOD2 in immune cells and hepatocytes. We demonstrated that NOD2, TNF-alpha and IFN-gamma were upregulated during liver injury in mice and humans. Nod2-/- mice were resistant to ConA-induced hepatitis compared to their wild-type littermates, through reduced IFN-gamma production by immune cells. Conversely, administration of MDP exacerbated ConA-induced liver injury. MDP was a strong inducer of IFN-gamma in freshly isolated human PBMC, splenocytes and hepatocytes. Our study supports the hypothesis that NOD2 contributes to liver injury via a regulatory mechanism affecting immune cells infiltrating the liver and hepatocytes. Taken together, our results indicate that NOD2 may represent a new therapeutic target in liver diseases.

• IBD serological panels: facts and perspectives.

  Authors: Laurent Peyrin-Biroulet, Annie Standaert-Vitse, Julien Branche, Mathias Chamaillard

  Inflammatory bowel diseases. 01/2008; 13(12):1561-6.

  Beyond a defective innate immune response in inflammatory bowel disease (IBD), an increased immunological response toward microbial and self antigens has been intrinsically linked to the pathogenesisBeyond a defective innate immune response in inflammatory bowel disease (IBD), an increased immunological response toward microbial and self antigens has been intrinsically linked to the pathogenesis of such common immunopathologies of the gut. Mounting evidence indicates that increased seroreactivity toward certain antigens are a predictive and quantitative heritable trait, including the anti-Saccharomyces cerevisiae antibody (ASCA). Consistently, Candida albicans and Crohn's disease-associated NOD2 mutations have been recently identified as immunogen and genetic determinants for ASCA, respectively. In clinical practice, current panels of serological markers are not recommended for diagnosis, stratifying, and monitoring IBD. Therefore, prospective studies and highly sensitive serological panels of markers are eagerly awaited before guiding clinical decisions. Better understanding of the serological response in IBD might also provide new insights into their epidemiology and pathophysiology.

• Nod-like receptors: cytosolic watchdogs for immunity against pathogens.

  Authors: Jean-Claude Sirard, Cécile Vignal, Rodrigue Dessein, Mathias Chamaillard

  PLoS pathogens. 01/2008; 3(12):e152.

  In mammals, tissue-specific sets of pattern-recognition molecules, including Nod-like receptors (NLR), enable concomitant and sequential detection of microbial-associated molecular patterns from bothIn mammals, tissue-specific sets of pattern-recognition molecules, including Nod-like receptors (NLR), enable concomitant and sequential detection of microbial-associated molecular patterns from both the extracellular and intracellular microenvironment. Repressing and de-repressing the cytosolic surveillance machinery contributes to vital immune homeostasis and protective responses within specific tissues. Conversely, defective biology of NLR drives the development of recurrent infectious, autoimmune and/or inflammatory diseases by failing to mount barrier functions against pathogens, to tolerate commensals, and/or to instruct the adaptive immune response against microbes. Better decoding microbial strategies that are evolved to circumvent NLR sensing will provide clues for the development of rational therapies aimed at curing and/or preventing common and emerging immunopathologies.

• Prevention and treatment of colitis with Lactococcus lactis secreting the immunomodulatory Yersinia LcrV protein.

  Authors: Benoit Foligne, Rodrigue Dessein, Michael Marceau, Sabine Poiret, Mathias Chamaillard, Bruno Pot, Michel Simonet, Catherine Daniel

  Gastroenterology. 09/2007; 133(3):862-74.

  BACKGROUND & AIMS: The low calcium response V (LcrV) protein synthesized by gram-negative, pathogenic yersiniae participates in bacterial evasion of the host's innate immune response by stimulatingBACKGROUND & AIMS: The low calcium response V (LcrV) protein synthesized by gram-negative, pathogenic yersiniae participates in bacterial evasion of the host's innate immune response by stimulating synthesis of the anti-inflammatory interleukin (IL)-10 and preventing the activation of proinflammatory cytokines. METHODS: We genetically engineered the food-grade bacterium Lactococcus lactis to secrete the LcrV protein from the enteropathogenic species Yersinia pseudotuberculosis. The protective and therapeutic potential of orally administered LcrV-secreting L lactis was evaluated in 2 models of acute experimental colitis (induced by trinitrobenzene sulfonic acid [TNBS] and dextran sodium sulfate [DSS], respectively) in wild-type and knockout mice. RESULTS: Oral administration of LcrV-secreting L lactis led to active delivery of LcrV and induction of IL-10 (via a Toll-like receptor 2-dependent pathway) in the colon and prevented TNBS-induced colitis, in contrast to the L lactis control not producing LcrV. Down-regulation of tissue inflammatory markers correlated well with the reduction in damage to the colonic mucosa. In contrast, TNBS-induced colitis was not prevented in IL-10(-/-) mice pretreated with LcrV-secreting L lactis, thus showing that IL-10 is required for LcrV protection. Administration of LcrV-secreting L lactis also proved to be very effective in preventing and treating acute DSS-induced colitis. CONCLUSIONS: LcrV-secreting L lactis decreased experimentally induced intestinal inflammation in 2 murine models of colitis. This novel approach highlights the potential of using pathogen-derived immunomodulating molecules in vivo as novel therapeutics for inflammatory bowel diseases.

• micro-Opioid receptor activation prevents acute hepatic inflammation and cell death.

  Authors: Dania Chakass, David Philippe, Edmone Erdual, Sébastien Dharancy, Mathilde Malapel, Caroline Dubuquoy, Xavier Thuru, Jerome Gay, Claire Gaveriaux-Ruff, Pierre Dubus, Philippe Mathurin, Brigitte L Kieffer, Pierre Desreumaux, Mathias Chamaillard

  Gut. 08/2007; 56(7):974-81.

  BACKGROUND AND AIMS: The detrimental impact of opioid agonist on the clinical management of inflammatory diseases remains elusive. Given the anti-inflammatory properties of the mu-opioid receptorBACKGROUND AND AIMS: The detrimental impact of opioid agonist on the clinical management of inflammatory diseases remains elusive. Given the anti-inflammatory properties of the mu-opioid receptor (MOR) agonists at the intestinal barrier, we hypothesised that MOR activation might also dampen acute hepatic inflammation and cell death-major determinants in the pathogenesis of liver diseases. PATIENTS AND METHODS: The expression of MOR in liver biopsy specimens and peripheral blood mononuclear cells of untreated patients with chronic hepatitis C virus infection and controls, primary hepatocytes and cell lines was determined by quantitative PCR, immunoblotting and/or immunohistochemistry. The effects of peripheral MOR agonist (d-Ala2,NMe-Phe4,Gly5-ol (DAMGO)) and/or antagonist (naloxone methiodide) were explored in two models of acute hepatitis in mice. MOR-deficient mice were used to evaluate the essential regulatory role of MOR during carbon tetrachloride (CCl(4))-induced hepatitis. The role of DAMGO in cell death was investigated using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) analysis and quantification of lactate dehydrogenase release. RESULTS: The key role of MOR in the prevention of acute hepatic inflammation and cell death in vivo and in vitro is reported. Whereas MOR gene expression increased transiently in the model of acute liver injury and TNFalpha-treated HepG2 cells, an impaired expression of MOR mRNA in human chronic hepatitis C samples was found. Furthermore, preventive administration of the selective MOR agonist DAMGO enhanced hepatoprotective-signalling pathways in vivo that were blocked by using naloxone methiodide. Consistently, genetic and pharmacological inhibition of MOR enhanced the severity associated with experimental hepatotoxin-induced hepatitis. Finally, treatment with DAMGO was shown to prevent cell death in vitro in HepG2 cells in a MOR-dependent manner and to prevent concanavalin A- and CCl(4)-induced cell death in vivo, providing a possible explanation for the anti-inflammatory role of MOR activation in the liver. CONCLUSIONS: The results indicate that MOR agonists may prevent acute hepatitis and hold promising therapeutic use to maintain remission in both chronic inflammatory bowel and liver diseases.

• Vascular and cellular stress in inflammatory bowel disease: revisiting the role of homocysteine.

  Authors: Laurent Peyrin-Biroulet, Rosa-Maria Rodriguez-Guéant, Mathias Chamaillard, Pierre Desreumaux, Bing Xia, Jean-Pierre Bronowicki, Marc-André Bigard, Jean-Louis Guéant

  The American journal of gastroenterology. 06/2007; 102(5):1108-15.

  Moderate hyperhomocysteinemia is a complex trait commonly associated with inflammatory bowel disease (IBD). Nutritional deficiencies and genetic determinants have been identified as risk factors forModerate hyperhomocysteinemia is a complex trait commonly associated with inflammatory bowel disease (IBD). Nutritional deficiencies and genetic determinants have been identified as risk factors for moderate hyperhomocysteinemia, such as folate and vitamin B(12) deprivation and polymorphisms in the 5,10 methylenetetrahydrofolate reductase (MTHFR) encoding gene, respectively. Homocysteine has a crucial role in cellular stress, epigenetic events, inflammatory processes, and host-microbial interactions. Hyperhomocysteinemia might therefore influence the clinical history of IBD, including disease severity, susceptibility to particular enteric infections, and the risk for the development of colorectal cancer. In contrast, homocysteine metabolism does not seem to contribute to the greater risk of thrombosis in IBD subjects. Herein, we review the evidence linking homocysteine metabolism to the pathophysiology of IBD. Furthermore, we discuss the relevance of screening and treating folate and vitamin B(12) deficiencies in IBD subjects. Given the peculiar frequency of such deficiencies in IBD, normalizing vitamin levels should be an integral part of the management of these patients, especially those with active disease, history of intestinal resection, and/or treated with methotrexate.