Papers by Jean-pierre Hugot
Journal of Crohn's and Colitis
Background Like in other chronic pathologies, evidence has shown disruption of host immune-microb... more Background Like in other chronic pathologies, evidence has shown disruption of host immune-microbial interactions and intestinal dysbiosis in the pathogenesis of Inflammatory Bowel Diseases (IBD), also characterized by chronic inflammation and increased intestinal permeability. Faecal microRNAs (miRNAs) have recently emerged as potential inter-kingdom mediators between the host and its microbiota, but the influence of its interaction on chronic intestinal disorders remains unclear. Here, we aimed to study the impact of colitis-associated miRNAs on intestinal inflammation, permeability and microbiota. Methods A panel of faecal miRNAs was profiled in IL10-/- mice, known as a model of spontaneous colitis. Faecal miRNAs and microbiota composition were compared between IBD and healthy controls. Identified colitis-associated miRNAs were then administered with/out antibiotics ad libitum to C57BL6 mice. Parameters of inflammation, intestinal epithelial barrier function, as well as microbiot...
ObjectiveWhile appendectomy may reduce colorectal inflammation in patients with ulcerative coliti... more ObjectiveWhile appendectomy may reduce colorectal inflammation in patients with ulcerative colitis (UC), appendectomy has been suggested to be associated with an increased risk of colitis-associated cancer (CAC). The aim of this study was to explore the mechanism underlying the appendectomy-associated increased risk of CAC.DesignFive-week-old male BALB/c mice underwent appendectomy, appendicitis induction or sham laparotomy. They were then exposed to azoxymethane/dextran sodium sulfate (AOM/DSS) to induce CAC. Mice were sacrificed 12 weeks later, and colons were taken for pathological analysis and immunohistochemistry (CD3 and CD8 staining). Human colonic tumors from 21 UC patients who underwent surgical resection for CAC were immunophenotyped and stratified according to the appendectomy status.ResultsWhile appendectomy significantly reduced colitis severity and increased CAC number, appendicitis induction without appendectomy led to opposite results. Intra-tumor CD3+ and CD8+ T-cel...
Journal of Crohn's and Colitis, 2020
Crohn’s disease [CD] is an inflammatory bowel disease of unknown aetiology. During recent decades... more Crohn’s disease [CD] is an inflammatory bowel disease of unknown aetiology. During recent decades, significant technological advances led to development of -omic datasets allowing a detailed description of the disease. Unfortunately these have not, to date, resolved the question of the aetiology of CD. Thus, it may be necessary to [re]consider hypothesis-driven approaches to resolve the aetiology of CD. According to the cold chain hypothesis, the development of industrial and domestic refrigeration has led to frequent exposure of human populations to bacteria capable of growing in the cold. These bacteria, at low levels of exposure, particularly those of the genus Yersinia, are believed to be capable of inducing exacerbated inflammation of the intestine in genetically predisposed subjects. We discuss the consistency of this working hypothesis in light of recent data from epidemiological, clinical, pathological, microbiological, and molecular studies.
Medical Technologies Journal, 2020
Background: Chronic Inflammatory Bowel Diseases (IBD) including Crohn's disease (CD) and ulcerati... more Background: Chronic Inflammatory Bowel Diseases (IBD) including Crohn's disease (CD) and ulcerative colitis (UC) are gastrointestinal disorders under the influence of a complex genetic basis. One hundred sixty-three predisposition loci were identified by genome-wide association (GWAS) studies, refocusing the pathogenesis of IBD on immunity genes. Autophagy is a fundamental mechanism in the maintenance of intestinal homeostasis. Failures of this mechanism appear to be a major risk factor in the setting up of chronic intestinal inflammation. Two single nucleotide polymorphisms (SNPs) within two genes, were selected namely (rs2241880 A G) for ATG16L1 and (rs10065172 C T) for IRGM.These two genes are both involved in the autophagy mechanism. We investigated these two SNP in an Algerian cohort for the first time since no previous association studies between IBD and the two studied genes were available for the Algerian population. Methods: A case-control study was performed on a cohort including 95 Algerian patients with Crohn's disease and ulcerative colitis versus 116 Controls. Genotyping of the cohort involved allelic discrimination by TaqMan SNP Genotyping Assay. Results: A statistically significant association of the rs2241880 A Gmutation of the ATG16L1 gene was demonstrated in IBD (p = 0.04) and, more particularly in Crohn's disease (p = 0.03).The presence of this mutation would increase the risk of Crohn's disease by a factor of 2 in its GG homozygous mutated form (OR = 2.11 95% CI (1.
Journal of Crohn's and Colitis, 2019
Background and Aims Nucleotide oligomerization domain 2 [NOD2] mutations are key risk factors for... more Background and Aims Nucleotide oligomerization domain 2 [NOD2] mutations are key risk factors for Crohn’s disease [CD]. NOD2 contributes to intestinal homeostasis by regulating innate and adaptive immunity together with intestinal epithelial function. However, the exact roles of NOD2 in CD and other NOD2-associated disorders remain poorly known. Methods We initially observed that NOD2 expression was increased in epithelial cells away from inflamed areas in CD patients. To explore this finding, Nod2 mRNA expression, inflammation, and cytokines expression were examined in the small bowel of wild-type [WT], Nod2 knockout and Nod2 mutant mice after rectal instillation of 2,4,6-trinitrobenzene sulphonic acid [TNBS]. Results In WT mice, Nod2 upregulation upstream to rectal injury was associated with pro-inflammatory cytokine expression but no overt histological inflammatory lesions. Conversely, in Nod2-deficient mice the inflammation spread from colitis to ileum and duodenum. Conclusions ...
Cells, 2019
The macrophages from Crohn’s Disease (CD) patients are defective to control the replication of CD... more The macrophages from Crohn’s Disease (CD) patients are defective to control the replication of CD-associated adherent-invasive E. coli (AIEC). We aimed to identify the host factors associated with AIEC replication focusing on polymorphisms related to autophagy. Peripheral blood monocyte-derived macrophages (MDM), obtained from 95 CD patient, 30 ulcerative colitis (UC) patients and 15 healthy subjects, were genotyped for several CD-associated polymorphisms. AIEC bacteria survival increased within MDM from CD patients compared to UC (p = 0.0019). AIEC bacteria survival increased in patients with CD-associated polymorphism IRGM (p = 0.05) and reduced in those with CD-associated polymorphisms XBP-1 (p = 0.026) and ULK-1 (p = 0.033). AIEC infection led to an increase of pro-inflammatory cytokines IL-1β (p < 0.0001) and TNF-α (p < 0.0001) in CD macrophages. ULK-1 expression increased in AIEC-infected MDM from CD patients compared to MDM from UC patients or healthy subjects (p = 0.00...
Frontiers in Cellular and Infection Microbiology, 2018
Journal of Crohn's and Colitis, 2019
Background and Aims Nucleotide Oligomerisation Domain 2 [NOD2] is a key gene of innate immunity w... more Background and Aims Nucleotide Oligomerisation Domain 2 [NOD2] is a key gene of innate immunity which participates in the host defence against pathogens. Several loss-of-function NOD2 mutations are associated with Crohn’s disease [CD]. Their high frequencies in populations of European ancestry suggest a model of balancing selection. Because NOD2 deficiency has been associated with a resistance to Yersinia pseudotuberculosis in mice, we hypothesised that NOD2 mutations have been selected during past plague outbreaks due to the closely related bacterium Yersinia pestis. Methods Contemporary frequencies of the main CD-associated NOD2 mutations [R702W, G908R, and 1007fs], measured in healthy people from European and Mediterranean countries, were collected from 60 studies via a PubMed search. Plague exposure was calculated from a dataset providing outbreaks from 1346 to 1860 in Europe and the Mediterranean Bassin. A plague index was built to capture the intensity of plague exposure in th...
NOD2 mutations are key risk factors for Crohn's disease (CD). NOD2 contributes to intestinal ... more NOD2 mutations are key risk factors for Crohn's disease (CD). NOD2 contributes to intestinal homeostasis by regulating innate and adaptive immunity together with intestinal epithelial function. However, the roles of NOD2 during gut inflammation is not known. We initially observed that NOD2 expression was increased in epithelial cells remote from inflamed areas in CD patients. To explore this finding, Nod2 mRNA expression, inflammation and gut permeability were examined in the small bowel of wild-type (WT), Nod2 knockout and Nod2 mutant mice after rectal instillation of 2,4,6-trinitrobenzene sulfonic acid (TNBS). In WT mice, Nod2 upregulation remote to rectal injury was associated with pro-inflammatory cytokine expression, recirculating CD4+ T-cells, increased paracellular permeability and myosin like chain kinase activity. Nod2 knockout or mutation led to duodenitis and ileitis demonstrating the remote protective role of Nod2. Bone morrow stem cell (BMSC) transplantations indica...
Journal of clinical medicine research, 2018
Inflammatory bowel disease (IBD) is a multisystemic disease, and pancreatic manifestations of IBD... more Inflammatory bowel disease (IBD) is a multisystemic disease, and pancreatic manifestations of IBD are not uncommon. The incidence of several pancreatic diseases in Crohn's disease and ulcerative colitis is more frequent compared to the general population. Pancreatic manifestations in IBD include a wide heterogenic group of disorders and abnormalities of the pancreas and range from mild self-limited diseases to severe disorders. Acute pancreatitis, chronic pancreatitis, autoimmune pancreatitis, pancreatic autoantibodies, exocrine pancreatic insufficiency and asymptomatic imaging and laboratory abnormalities are included in related-IBD pancreatic manifestations. Involvement of the pancreas in IBD may be the result of IBD itself or of medications used.
Cellular and Molecular Gastroenterology and Hepatology, 2018
Stem cell Paneth cell Enterocytes Goblet cell Nod2 Mutations Hematopoietic cells Microbiota Colit... more Stem cell Paneth cell Enterocytes Goblet cell Nod2 Mutations Hematopoietic cells Microbiota Colitis and colorectal cancer SUMMARY Although the association between Crohn's disease susceptibility and nucleotide-binding oligomerization domain 2 polymorphisms was shown in 2001, the mechanisms involved remain largely unknown. In this review, we report the role of nucleotide-binding oligomerization domain 2 in epithelial cells in the development of colitis and associated carcinogenesis. Nucleotide-binding oligomerization domain 2 (NOD2) is an intracellular pattern recognition receptor that senses bacterial peptidoglycan-conserved motifs in cytosol and stimulates host immune response including epithelial and immune cells. The association of NOD2 mutations with a number of inflammatory pathologies including Crohn's disease (CD), graft-versus-host diseases, or Blau syndrome, highlights its pivotal role in inflammatory response and the associated-carcinogenesis development. Since its identification in 2001 and its association with CD, the role of NOD2 in epithelial cells and immune cells has been investigated extensively but the precise mechanism by which NOD2 mutations lead to CD and the associated carcinogenesis development is largely unknown. In this review, we present and discuss recent developments about the role of NOD2 inside epithelial cells on the control of the inflammatory process and its linked carcinogenesis development.
Journal of Crohn's and Colitis, 2016
PLOS ONE, 2016
Inflammation contributes to growth failure associated with inflammatory bowel diseases. Anti-TNFα... more Inflammation contributes to growth failure associated with inflammatory bowel diseases. Anti-TNFα therapy induces sustained remission and short-term improvements in height velocity and/or height standard deviation score (H-SDS) patients with Crohn's disease. The purpose of this study was to evaluate growth and adult height in patients with Crohn's disease taking maintenance infliximab or adalimumab therapy.This university-hospital based retrospective study included 61 patients, with a median follow-up of 2.6 years (2.0; 3.3). 38 patients (62%) reached their adult height. H-SDS was collected at diagnosis and together with disease activity markers (Harvey-Bradshaw Index, albumin, and C-reactive protein) at treatment initiation (baseline), and follow-up completion. Wilcoxon's signed-rank test was chosen for comparisons. Median H-SDS decreased from diagnosis to baseline (-0.08 [-0.73; +0.77] to-0.94 [-1.44; +0.11], p<0.0001) and then increased to follow-up completion (-0.63 [-1.08; 0.49], p = 0.003 versus baseline), concomitantly with an improvement in disease activity. Median adult H-SDS was within the normal range (-0.72 [-1.25; +0.42]) but did not differ from baseline H-SDS and was significantly lower than the target H-SDS (-0.09 [-0.67; +0.42], p = 0.01). Only 2 (6%) males had adult heights significantly below their target heights (10.5 and-13.5 cm [-1.75 and-2.25 SD]). In conclusion, anti-tumor necrosis factor α (TNF) therapy prevented loss of height without fully restoring the genetic growth potential in this group of patients with CD. Earlier treatment initiation might improve growth outcomes in these patients.
PLOS ONE, 2016
Background Numerous genetic and environmental risk factors play a role in human complex genetic d... more Background Numerous genetic and environmental risk factors play a role in human complex genetic disorders (CGD). However, their complex interplay remains to be modelled and explained in terms of disease mechanisms. Methods and findings Crohn's Disease (CD) was modeled as a modular network of patho-physiological functions, each summarizing multiple gene-gene and gene-environment interactions. The disease resulted from one or few specific combinations of module functional states. Network aging dynamics was able to reproduce age-specific CD incidence curves as well as their variations over the past century in Western countries. Within the model, we translated the odds ratios (OR) associated to at-risk alleles in terms of disease propensities of the functional modules. Finally, the model was successfully applied to other CGD including ulcerative colitis, ankylosing spondylitis, multiple sclerosis and schizophrenia. Conclusion Modeling disease incidence may help to understand disease causative chains, to delineate the potential of personalized medicine, and to monitor epidemiological changes in CGD.
Journal of Crohn's and Colitis, 2016
Background and Aims: Crohn's disease [CD] is a complex disorder characterised by an inappropriate... more Background and Aims: Crohn's disease [CD] is a complex disorder characterised by an inappropriate immune response, impaired barrier function and microbial dysbiosis. Mutations in nucleotide oligomeriation domain 2 [NOD2] are CD risk factors. Increase of intestinal permeability, CD4 + T cell infiltration, and bacterial dysbiosis are also seen in Nod2-knockout [Nod2 KO ] mice. However, the specificity and relationship between these Nod2-associated abnormalities remain largely unexplored. Methods: Wild-type [WT], Nod1-knockout [Nod1 KO ] and Nod2 KO mice were analysed in parallel. Microbial composition was defined by 454-pyrosequencing of bacterial 16S rRNA genes. Mucin and antimicrobial peptide expression was assessed by RT-PCR. Cell populations from Peyer's patches were determined by flow cytometry. Ussing chambers were used to measure intestinal permeability and bacterial translocation. Finally, to explore the impact of colonisation with mother's microbiota at birth, analyses were also performed in Nod2 KO and WT mice born from WT surrogate mothers after embryo transfer. Results: Nod2 KO mice exhibited colonic bacterial dysbiosis different from WT and Nod1 KO mice. Altered expression of antimicrobial peptides and mucins in ileum and colon was associated with the microbial composition. Bacterial composition of Nod2 KO and WT mice obtained by embryo transfer was similar to that observed in Nod2 KO mice, arguing for a dominant effect of Nod2 KOassociated dysbiosis. In contrast, increased levels of CD4 + T cells and gut barrier defects across Peyer's patches were specific to Nod2 deficiency and independent of Microbial dysbiosis.
World journal of gastroenterology : WJG, Jan 7, 2015
To analyse allelic frequency of NOD2 gene variants and to assess their correlation with inflammat... more To analyse allelic frequency of NOD2 gene variants and to assess their correlation with inflammatory bowel disease (IBD) in Algeria. We studied 132 unrelated patients diagnosed with IBD, 86 with Crohn's disease (CD) and 46 with ulcerative colitis (UC). Data was prospectively collected between January 2011 and December 2013. The demographic and clinical characteristics were recorded for all the patients. A group of 114 healthy unrelated individuals were selected as controls. All groups studied originated from different regions of North Algeria and confirmed the Algerian origin of their parents and grandparents. Informed and written consent was obtained from each of the participants. All individuals were genotyped for the three CD-associated NOD2 variants (p.Arg(702)Trp, p.Gly908Arg and p.Leu(1007)fsinsC mutations) using the polymerase chain reaction-restriction fragment length polymorphism method. Allele and genotype frequencies in patients and control subjects were compared by χ...
Journal of Crohn's & colitis, Jan 24, 2015
Ileal lesions of Crohn's disease (CD) patients are colonized by adherent-invasive Escherichia... more Ileal lesions of Crohn's disease (CD) patients are colonized by adherent-invasive Escherichia coli (AIEC) able to survive in macrophage cell lines. We analyzed the ability of monocyte-derived macrophages (MDM) from CD patients to control AIEC intracellular replication and the pro-inflammatory cytokine response of the infected-MDM. Peripheral blood MDM were obtained from 24 CD genotyped for NOD2 and ATG16L1 mutations, 5 ulcerative colitis (UC) patients and 12 healthy controls (HC). The numbers of intracellular bacteria were determined using gentamicin assay. Cytokine secretion was quantified by ELISA. We observed that higher levels of bacteria were internalized within MDM from CD patients than MDM from HC or UC patients. MDM from CD patients were unable to restrict AIEC intracellular replication. Infection of MDM from CD patients with AIEC resulted in significantly increased secretion of IL-6 and TNF-alpha than infection with non-pathogenic E. coli. AIEC-infected MDM from CD pati...
Journal of Crohn's & colitis, 2014
Children and adolescents with Crohn's disease (CD) present often with a more complicated dise... more Children and adolescents with Crohn's disease (CD) present often with a more complicated disease course compared to adult patients. In addition, the potential impact of CD on growth, pubertal and emotional development of patients underlines the need for a specific management strategy of pediatric-onset CD. To develop the first evidenced based and consensus driven guidelines for pediatric-onset CD an expert panel of 33 IBD specialists was formed after an open call within the European Crohn's and Colitis Organisation and the European Society of Pediatric Gastroenterolog, Hepatology and Nutrition. The aim was to base on a thorough review of existing evidence a state of the art guidance on the medical treatment and long term management of children and adolescents with CD, with individualized treatment algorithms based on a benefit-risk analysis according to different clinical scenarios. In children and adolescents who did not have finished their growth, exclusive enteral nutriti...
Surgery (Oxford), 2005
Abstract Ulcerative colitis and Crohn's disease are the two major forms of chronic idiopathic... more Abstract Ulcerative colitis and Crohn's disease are the two major forms of chronic idiopathic inflammatory bowel disease. They are relapsing inflammatory conditions of the gastrointestinal tract with characteristic extra-intestinal manifestations. Accurate diagnosis depends on integration of clinical, endoscopic, radiological and histopathological features. The two conditions cannot be accurately diagnosed in some patients if only colonic disease is present; such cases are termed ‘equivocal chronic idiopathic inflammatory bowel disease’. This contribution discusses the pathology of Crohn's disease and ulcerative colitis.
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Papers by Jean-pierre Hugot