Project description:Systemic sclerosis (SSc) is a complex and still unclear rare disease associated with fibrosis in multiple organs. Microbiota has recently emerged as an important environmental factor in SSc pathogenesis, either at gut, oral and skin level.
Project description:The more aggressive clinical disease course of Pediatric Onset Multiple Sclerosis(POMS) as compared to Adult Onset Multiple Sclerosis(AOMS) during the first year disease is supported by higher inflammatory potential promoted by transcriptional level of age-associated genes and transcription factors involved in Cell Cycle, B Cell proliferation and senescent mechanisms. Herein, we compared the blood mononuclear cell transcriptome of POMS and AOMS patients during first year disease. Pediatric Healthy and Adult subjects (PHC, AHC) were used as controls. Correlation analysis of the gene expression with the radiological sign, upstream regulators analysis and clinical assesment were also evaluated.
Project description:In the presented study, in order to unravel gut microbial community multiplicity and the influence of maternal milk nutrients (i.e., IgA) on gut mucosal microbiota onset and shaping, a mouse GM (MGM) was used as newborn study model to discuss genetic background and feeding modulation on gut microbiota in term of symbiosis, dysbiosis and rebiosis maintenance during early gut microbiota onset and programming after birth. Particularly, a bottom-up shotgun metaproteomic approach, combined with a computational pipeline, has been compred with a culturomics analysis of mouse gut microbiota, obtained by MALDI-TOF mass spectrometry (MS).
Project description:Microbial dysbiosis has been identified in adult inflammatory bowel disease (IBD) patients. However, microbial composition and functional interplay between host genetics and microorganisms in early IBD onset remain poorly defined. Here, we identified and demonstrated the causal effect of Atopobium parvulum and the gut microbiota in pediatric IBD. Microbiota and proteomic profiling revealed that the abundance of A. parvulum, a potent H2S producer, was associated with increased disease severity and a concurrent reduction in the expression of the host H2S detoxification pathway. In the Il10-/- mouse model of inflammation, A. parvulum induced severe pancolitis that was dependent on the presence of the gut microbiota. In addition, we demonstrated that administration of bismuth, an H2S scavenger, prevented A. parvulum-induced colitis. Our findings identified Atopobium parvulum as a major mediator of inflammation severity, and revealed an alteration of the balance between the production and detoxification of H2S in the gastrointestinal tract.
Project description:Intestinal microbial dysbiosis is associated with Crohn’s disease (CD). However, the mechanisms leading to the chronic mucosal inflammation that characterizes this disease remain unclear. To evaluate causality and mechanisms of disease, we conducted a systems level study of the interactions between the gut microbiota and host in new-onset pediatric patients. We report an altered host proteome in CD patients indicative of impaired mitochondrial functions. A downregulation of mitochondrial proteins implicated in H2S detoxification was observed, while the relative abundance of H2S microbial producers was increased. Network correlation analysis identified Atopobium parvulum as the central hub of H2S producers. Gnotobiotic and conventionalized colitis-susceptible interleukin-10-deficient (Il10-/-) mice demonstrated that A. parvulum induced colitis, a phenotype requiring the presence of the intestinal microbiota. Administration of bismuth, a H2S scavenger, prevented A. parvulum-induced colitis in Il10-/- mice. This study identified host-microbiota interactions that are disturbed in CD patients providing mechanistic insights on CD pathogenesis.
Project description:Disruption of gut barrier function and intestinal immune cell homeostasis are increasingly considered critical players in pathogenesis of extra-intestinal inflammatory diseases, including multiple sclerosis (MS) and its prototypical animal model, theexperimental autoimmune encephalomyelitis (EAE). Breakdown of epithelial barriers increases intestinal permeability and systemic dissemination of microbiota-derived molecules. However,whetherthe gut-vascular barrier (GVB) is altered during EAE has not been reported. Here, we demonstrate that endothelial cell proliferation and vessel permeability increase before EAE clinical onset, leadingto vascular remodelingand expansion of intestinal villi capillary bed during disease symptomatic phasein an antigen-independent manner. Concomitant to onset of angiogenesis observed prior to neurological symptoms, we identify an increase of intestinal perivascular immune cells characterized by the surface markerlymphatic vessel endothelial hyaluronic acid receptor 1 (LYVE-1). LYVE-1+is expressed more frequently on B cells that show high levels of CD73 and have proangiogenic properties. B cell depletion was sufficient tomitigate enteric blood endothelial cell proliferation following immunization for EAE. In conclusion, we propose that altered intestinal vasculature driven by a specialized LYVE-1+B cell subset promotes angiogenesis and that loss of GVB function is implicated in EAE development and autoimmunity.
Project description:The pathogenesis of multiple sclerosis (MS) remains to be elucidated. Pediatric-onset MS (POMS) represents the earliest stage of the disease. CSF proteins in POMS may therefore provide causal information. Therefore, the aim of the current study was to analyze CSF proteins in children with an initial CNS acquired demyelinating syndrome (ADS) and to make a comparison between POMS and monophasic ADS (mADS). Patients were selected from two prospective pediatric ADS studies. Liquid chromatography-mass spectrometry was performed in a Dutch discovery cohort (POMS n=28; mADS n=39). Parallel reaction monitoring-mass spectrometry was performed on selected proteins more abundant in POMS with ≥ 8 unique peptides in a combined Dutch and Canadian validation cohort (POMS n=48; mADS n=106).
Project description:The pathogenesis of multiple sclerosis (MS) remains to be elucidated. Pediatric-onset MS (POMS) represents the earliest stage of the disease. CSF proteins in POMS may therefore provide causal information. Therefore, the aim of the current study was to analyze CSF proteins in children with an initial CNS acquired demyelinating syndrome (ADS) and to make a comparison between POMS and monophasic ADS (mADS). Patients were selected from two prospective pediatric ADS studies. Liquid chromatography-mass spectrometry was performed in a Dutch discovery cohort (POMS n=28; mADS n=39). Parallel reaction monitoring-mass spectrometry was performed on selected proteins more abundant in POMS with ≥ 8 unique peptides in a combined Dutch and Canadian validation cohort (POMS n=48; mADS n=106).