Prenatal Diagnosis of Myhre Syndrome in Two Cases: Further Delineation of the Cardiac and External Phenotype.

Myhre syndrome is a rare genetic disease caused by recurrent gain-of-function variants in SMAD4 (Ile500Thr, Ile500Val, Arg496Cys, and Ile500Met) characterized by postnatal short stature with pseudo-muscular build, joint stiffness, variable intellectual disability, hearing loss, and a distinctive pattern of dysmorphic facial features. The course can be severe in some cases, with life-threatening cardiac and pulmonary complications caused by connective tissue involvement. These progressive features over time make early clinical diagnosis difficult but possible by astute clinicians who evaluate young children with autism or short stature and unusual appearance.

Diet-induced obesity alters intestinal monocyte-derived and tissue-resident macrophages and increases intestinal permeability in female mice independent of tumor necrosis factor.

Macrophages are essential for homeostatic maintenance of the anti-inflammatory and tolerogenic intestinal environment, yet monocyte-derived macrophages can promote local inflammation. Proinflammatory macrophage accumulation within the intestines may contribute to the development of systemic chronic inflammation and immunometabolic dysfunction in obesity. Using a model of high-fat diet-induced obesity in C57BL/6J female mice, we assessed intestinal paracellular permeability by in vivo and ex vivo assays and quantitated intestinal macrophages in ileum and colon tissues by multicolor flow cytometry after short (6 wk), intermediate (12 wk), and prolonged (18 wk) diet allocation.

Psychological stress impairs IL22-driven protective gut mucosal immunity against colonising pathobionts.

Crohn's disease is an inflammatory disease of the gastrointestinal tract characterized by an aberrant response to microbial and environmental triggers. This includes an altered microbiome dominated by Enterobacteriaceae and in particular adherent-invasive E. coli (AIEC).

Aryl hydrocarbon receptor ligand production by the gut microbiota is decreased in celiac disease leading to intestinal inflammation.

Metabolism of tryptophan by the gut microbiota into derivatives that activate the aryl hydrocarbon receptor (AhR) contributes to intestinal homeostasis. Many chronic inflammatory conditions, including celiac disease involving a loss of tolerance to dietary gluten, are influenced by cues from the gut microbiota. We investigated whether AhR ligand production by the gut microbiota could influence gluten immunopathology in nonobese diabetic (NOD) mice expressing DQ8, a celiac disease susceptibility gene.

Lactobacilli Degrade Wheat Amylase Trypsin Inhibitors to Reduce Intestinal Dysfunction Induced by Immunogenic Wheat Proteins.

Background & Aims: Wheat-related disorders, a spectrum of conditions induced by the ingestion of gluten-containing cereals, have been increasing in prevalence. Patients with celiac disease have gluten-specific immune responses, but the contribution of non-gluten proteins to symptoms in patients with celiac disease or other wheat-related disorders is controversial.

Methods: C57BL/6 (control), Myd88, Ticam1, and Il15 mice were placed on diets that lacked wheat or gluten, with or without wheat amylase trypsin inhibitors (ATIs), for 1 week.

Inflammation-related differences in mucosa-associated microbiota and intestinal barrier function in colonic Crohn's disease.

Crohn's disease (CD), characterized by discontinuous intestinal injury and inflammation, has been associated with changes in luminal microbial composition and impaired barrier function. The relationships between visual features of intestinal injury, permeability, and the mucosa-associated microbiota are unclear. Individuals undergoing routine colonoscopy (controls) and patients with CD were evaluated by clinical parameters and confocal laser scanning endomicroscopic colonoscopy (CLE).

A Commensal Bifidobacterium longum Strain Prevents Gluten-Related Immunopathology in Mice through Expression of a Serine Protease Inhibitor.

Microbiota-modulating strategies, including probiotic administration, have been tested for the treatment of chronic gastrointestinal diseases despite limited information regarding their mechanisms of action. We previously demonstrated that patients with active celiac disease have decreased duodenal expression of elafin, a human serine protease inhibitor, and supplementation of elafin by a recombinant strain prevents gliadin-induced immunopathology in the NOD/DQ8 mouse model of gluten sensitivity. The commensal probiotic strain NCC2705 produces a serine protease inhibitor (Srp) that exhibits immune-modulating properties.

Age-Associated Microbial Dysbiosis Promotes Intestinal Permeability, Systemic Inflammation, and Macrophage Dysfunction.

Levels of inflammatory mediators in circulation are known to increase with age, but the underlying cause of this age-associated inflammation is debated. We find that, when maintained under germ-free conditions, mice do not display an age-related increase in circulating pro-inflammatory cytokine levels. A higher proportion of germ-free mice live to 600 days than their conventional counterparts, and macrophages derived from aged germ-free mice maintain anti-microbial activity.

Duodenal Bacteria From Patients With Celiac Disease and Healthy Subjects Distinctly Affect Gluten Breakdown and Immunogenicity.

Background & Aims: Partially degraded gluten peptides from cereals trigger celiac disease (CD), an autoimmune enteropathy occurring in genetically susceptible persons. Susceptibility genes are necessary but not sufficient to induce CD, and additional environmental factors related to unfavorable alterations in the microbiota have been proposed. We investigated gluten metabolism by opportunistic pathogens and commensal duodenal bacteria and characterized the capacity of the produced peptides to activate gluten-specific T-cells from CD patients.

Mechanisms of innate immune activation by gluten peptide p31-43 in mice.

Celiac disease (CD) is an immune-mediated enteropathy triggered by gluten in genetically susceptible individuals. Innate immunity contributes to the pathogenesis of CD, but the mechanisms remain poorly understood. Although previous in vitro work suggests that gliadin peptide p31-43 acts as an innate immune trigger, the underlying pathways are unclear and have not been explored in vivo.

Ecobiotherapy Rich in Firmicutes Decreases Susceptibility to Colitis in a Humanized Gnotobiotic Mouse Model.

Background: Alterations in the intestinal microbiota, characterized by depletion of anti-inflammatory bacteria, such as Firmicutes, in patients with ulcerative colitis (UC) have prompted interest in microbiota-modulating strategies for this condition. The aim of this study was to evaluate the role of fecal and synthetic human microbial ecosystems, low or enriched in Firmicutes, on colitis susceptibility and host immune responses.

Methods: The microbiota of selected healthy and UC human donors was characterized by culture method and 16S rRNA-based sequencing.

Faecalibacterium prausnitzii prevents physiological damages in a chronic low-grade inflammation murine model.

Background: The human gut houses one of the most complex and abundant ecosystems composed of up to 10(13)-10(14) microorganisms. The importance of this intestinal microbiota is highlighted when a disruption of the intestinal ecosystem equilibrium appears (a phenomenon called dysbiosis) leading to an illness status, such as inflammatory bowel diseases (IBD). Indeed, the reduction of the commensal bacterium Faecalibacterium prausnitzii (one of the most prevalent intestinal bacterial species in healthy adults) has been correlated with several diseases, including IBD, and most importantly, it has been shown that this bacterium has anti-inflammatory and protective effects in pre-clinical models of colitis.

BL-7010 demonstrates specific binding to gliadin and reduces gluten-associated pathology in a chronic mouse model of gliadin sensitivity.

Celiac disease (CD) is an autoimmune disorder in individuals that carry DQ2 or DQ8 MHC class II haplotypes, triggered by the ingestion of gluten. There is no current treatment other than a gluten-free diet (GFD). We have previously shown that the BL-7010 copolymer poly(hydroxyethyl methacrylate-co-styrene sulfonate) (P(HEMA-co-SS)) binds with higher efficiency to gliadin than to other proteins present in the small intestine, ameliorating gliadin-induced pathology in the HLA-HCD4/DQ8 model of gluten sensitivity.

Novel role of the serine protease inhibitor elafin in gluten-related disorders.

Objectives: Elafin, an endogenous serine protease inhibitor, modulates colonic inflammation. We investigated the role of elafin in celiac disease (CD) using human small intestinal tissues and in vitro assays of gliadin deamidation. We also investigated the potential beneficial effects of elafin in a mouse model of gluten sensitivity.

Efficacy of Bifidobacterium breve NCC2950 against DSS-induced colitis is dependent on bacterial preparation and timing of administration.

Probiotics have been proposed as a therapy for inflammatory bowel disease, but variations in strains, formulations, and protocols used in clinical trials have hindered the creation of guidelines for their use. Thus, preclinical insight into the mechanisms of specific probiotic strains and mode of administration would be useful to guide future clinical trial design. In this study, live, heat inactivated (HI), and spent culture medium preparations of the probiotic Bifidobacterium breve NCC2950 were administered to specific pathogen free C57BL/6 mice before or during colitis, as well as before colitis reactivation.

Differential induction of antimicrobial REGIII by the intestinal microbiota and Bifidobacterium breve NCC2950.

The intestinal microbiota is a key determinant of gut homeostasis, which is achieved, in part, through regulation of antimicrobial peptide secretion. The aim of this study was to determine the efficiency by which members of the intestinal microbiota induce the antimicrobial peptide REGIII and to elucidate the underlying pathways. We showed that germfree mice have low levels of REGIII-γ in their ileum and colon compared to mice with different intestinal microbiota backgrounds.