Deep phenotyping of health-disease continuum in the Human Phenotype Project.

The Human Phenotype Project (HPP) is a large-scale deep-phenotype prospective cohort. To date, approximately 28,000 participants have enrolled, with more than 13,000 completing their initial visit. The project is aimed at identifying novel molecular signatures with diagnostic, prognostic and therapeutic value, and at developing artificial intelligence (AI)-based predictive models for disease onset and progression.

A Mushroom Based Prebiotic Supplement Pilot Study Among Patients with Crohn's Disease.

Data on a mushroom based prebiotic supplementation in patients with Crohn's disease (CD) in western population is scarce. In this pilot trial, we aimed to assess the clinical efficacy and fecal microbial compositional and functional alterations associated with 'Mycodigest,' a commercial prebiotic supplement composed of three mushroom extracts. Patients with mild to moderate CD were recruited to a single center, randomized, double-blind, placebo-controlled pilot induction trial.

Immune dysregulation in glycogen storage disease 1b extends beyond neutropenia.

Glycogen Storage Disease type 1b (GSD1b) is a rare disease manifesting as hypoglycemia, recurrent infections and neutropenia, resulting from deleterious mutations in the SLC37A4 gene encoding the glucose-6-phosphate transporter. Classic treatment strategies in GSD1b focus on restoring neutrophil numbers and function; however, the immune defect is believed to be multifactorial and extensive immunophenotyping characterization is currently missing. Here we apply a systems immunology approach utilizing Cytometry by Time of Flight (CyTOF) to map the peripheral immune landscape of 6 GSD1b patients.

Economic and Chronologic Optimization of Fecal Donors Screening Process.

Unlabelled: Fecal microbial transplantation (FMT) is the delivery of fecal microbiome, isolated from healthy donors, into a patient's gastrointestinal tract. FMT is a safe and efficient treatment for recurrent infection. Donors undergo strict screening to avoid disease transmission.

Single-cell atlas of the human neonatal small intestine affected by necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is a gastrointestinal complication of premature infants with high rates of morbidity and mortality. A comprehensive view of the cellular changes and aberrant interactions that underlie NEC is lacking. This study aimed at filling in this gap.

Immune dysregulation in Glycogen Storage Disease 1b - a CyTOF approach.

Glycogen Storage Disease type 1b (GSD1b) is a rare disease manifesting as hypoglycemia, recurrent infections and neutropenia, resulting from deleterious mutations in the gene encoding the glucose-6-phosphate transporter. The susceptibility to infections is thought to be attributed not only to the neutrophil defect, though extensive immunophenotyping characterization is currently missing. Here we apply a systems immunology approach utilizing Cytometry by Time Of Flight (CyTOF) to map the peripheral immune landscape of 6 GSD1b patients.

A somatic hypermutation-based machine learning model stratifies individuals with Crohn's disease and controls.

Crohn's disease (CD) is a chronic relapsing-remitting inflammatory disorder of the gastrointestinal tract that is characterized by altered innate and adaptive immune function. Although massively parallel sequencing studies of the T cell receptor repertoire identified oligoclonal expansion of unique clones, much less is known about the B cell receptor (BCR) repertoire in CD. Here, we present a novel BCR repertoire sequencing data set from ileal biopsies from pediatric patients with CD and controls, and identify CD-specific somatic hypermutation (SHM) patterns, revealed by a machine learning (ML) algorithm trained on BCR repertoire sequences.

RIPK1 mutations causing infantile-onset IBD with inflammatory and fistulizing features.

Purpose: Receptor-interacting serine/threonine-protein kinase 1 RIPK1) is an important regulator of necroptosis and inflammatory responses. We present the clinical features, genetic analysis and immune work-up of two patients with infantile-onset inflammatory bowel disease (IBD) resulting from mutations.

Methods: Whole exome and Sanger sequencing was performed in two IBD patients.

Mucus sialylation determines intestinal host-commensal homeostasis.

Intestinal mucus forms the first line of defense against bacterial invasion while providing nutrition to support microbial symbiosis. How the host controls mucus barrier integrity and commensalism is unclear. We show that terminal sialylation of glycans on intestinal mucus by ST6GALNAC1 (ST6), the dominant sialyltransferase specifically expressed in goblet cells and induced by microbial pathogen-associated molecular patterns, is essential for mucus integrity and protecting against excessive bacterial proteolytic degradation.

CD16+CD163+ monocytes traffic to sites of inflammation during necrotizing enterocolitis in premature infants.

Necrotizing enterocolitis (NEC) is a severe gastrointestinal complication of prematurity. Using suspension and imaging mass cytometry coupled with single-cell RNA sequencing, we demonstrate severe inflammation in patients with NEC. NEC mucosa could be subtyped by an influx of three distinct neutrophil phenotypes (immature, newly emigrated, and aged).

T and B Cell Receptor Immune Repertoire Analysis using Next-generation Sequencing.

Immunological memory, the hallmark of adaptive immunity, is orchestrated by T and B lymphocytes. In circulation and different organs, there are billions of unique T and B cell clones, and each one can bind a specific antigen, leading to proliferation, differentiation and/or cytokine secretion. The vast heterogeneity in T and B cells is generated by random recombination of different genetic segments.

Mucosal IL-10 and IL-10 receptor expression patterns in paediatric patients with ulcerative colitis.

Interleukin-10 (IL-10) is a key anti-inflammatory cytokine. We aimed to assess IL-10 and IL-10 receptor (IL-10R) expression in the gut, and determine whether these patterns are altered in patients with ulcerative colitis (UC). Formalin-fixed paraffin-embedded rectal and transverse colon sections were collected from three groups of patients: (a) control subjects with normal colonoscopy and without history of inflammatory bowel disease; (b) UC patients with extensive colitis or pancolitis (E3/E4 phenotype); and (c) UC patients with limited distal disease (E1/E2 phenotype; n = 8-10 subjects per group).

Distinct extracellular-matrix remodeling events precede symptoms of inflammation.

Identification of early processes leading to complex tissue pathologies, such as inflammatory bowel diseases, ‎poses a major scientific and clinical challenge that is imperative for improved diagnosis and treatment. Most studies of inflammation onset focus on cellular processes and signaling molecules, while overlooking the environment in which they take place, the continuously remodeled extracellular matrix. In this study, we used colitis models for investigating extracellular-matrix dynamics during disease onset, while treating the matrix as a complete and defined entity.

Enhanced Collagen Deposition in the Duodenum of Patients with Hyaline Fibromatosis Syndrome and Protein Losing Enteropathy.

Hyaline fibromatosis syndrome (HFS), resulting from mutations, is an ultra-rare disease that causes intestinal lymphangiectasia and protein-losing enteropathy (PLE). The mechanisms leading to the gastrointestinal phenotype in these patients are not well defined. We present two patients with congenital diarrhea, severe PLE and unique clinical features resulting from deleterious mutations.

Circulating α4β7 Memory T Cells in Pediatric IBD Patients Express a Polyclonal T Cell Receptor Repertoire.

Background: The integrin α4β7 is highly expressed on activated T cells and is thought to direct homing of lymphocytes to the intestine. Since ulcerative colitis (UC) and Crohn's disease (CD) are characterized by mucosal oligoclonal T cells' expansion, we aimed to assess whether similar repertoire features are identified in circulating gut-specific memory T cells.

Methods: Memory CD3 T cells were isolated from blood samples of control subjects and patients with active UC or CD and then FACS-sorted into α4β7 and α4β7 populations.

Monogenic Inflammatory Bowel Disease: It's Never Too Late to Make a Diagnosis.

More than 50 different monogenic disorders have been identified as directly causing inflammatory bowel diseases, typically manifesting in the first years of life. We present the clinical course and immunological work-up of an adult patient who presented in adolescent years with an atypical gastrointestinal phenotype and was diagnosed more than two decades later with a monogenic disorder with important therapeutic implications. Whole exome sequencing was performed in a 37-years-old patient with a history of diarrhea since adolescence.

In utero human intestine harbors unique metabolome, including bacterial metabolites.

Symbiotic microbial colonization through the establishment of the intestinal microbiome is critical to many intestinal functions, including nutrient metabolism, intestinal barrier integrity, and immune regulation. Recent studies suggest that education of intestinal immunity may be ongoing in utero. However, the drivers of this process are unknown.

Antibodies Against Glycoprotein 2 Are Specific Biomarkers for Pediatric Crohn's Disease.

Background: Serological markers can assist in accurate differentiation between Crohn's disease (CD) and ulcerative colitis (UC). One such marker is anti-glycoprotein 2 (anti-GP2) which was shown to be a specific marker for CD in adult patients. The aim of our study was to assess the utility of anti-GP2 and GP2 as biomarkers for pediatric CD, and determine whether they correlate with disease activity.

An RTEL1 Mutation Links to Infantile-Onset Ulcerative Colitis and Severe Immunodeficiency.

Purpose: More than 50 different monogenic disorders causing inflammatory bowel disease (IBD) have been identified. Our goal was to characterize the clinical phenotype, genetic workup, and immunologic alterations in an Ashkenazi Jewish patient that presented during infancy with ulcerative colitis and unique clinical manifestations.

Methods: Immune workup and whole-exome sequencing were performed, along with Sanger sequencing for confirmation.

Alterations in T and B Cell Receptor Repertoires Patterns in Patients With IL10 Signaling Defects and History of Infantile-Onset IBD.

Patients with loss-of-function mutations in IL10 or IL10 receptor (IL10R) genes develop severe, medical-refractory, infantile-onset inflammatory bowel disease (IBD). We have previously reported significant alterations in innate and adaptive immune responses in these patients. Next generation sequencing platforms enable a comprehensive assessment of T cell receptor (TCR) and B cell receptor (BCR) repertoire patterns.

Maturation of the Human Intestinal Immune System Occurs Early in Fetal Development.

There are limited data on fetal and early life development of human intestinal immunity. Using mass cytometry (CyTOF) and next-generation sequencing of B and T cell receptor (BCR and TCR) repertoires, we demonstrate complex intestinal immunity from 16 weeks' gestational age (GA). Both BCR and TCR repertoires are diverse with CDRH and CDR3β length increasing with advancing GA.

A Unique Presentation of Infantile-Onset Colitis and Eosinophilic Disease without Recurrent Infections Resulting from a Novel Homozygous CARMIL2 Variant.

Purpose: This study aimed to characterize the clinical phenotype, genetic basis, and consequent immunological phenotype of a boy with severe infantile-onset colitis and eosinophilic gastrointestinal disease, and no evidence of recurrent or severe infections.

Methods: Trio whole-exome sequencing (WES) was utilized for pathogenic variant discovery. Western blot (WB) and immunohistochemical (IHC) staining were used for protein expression analyses.

Intestinal epithelial cells and T cells differentially recognize and respond to Candida albicans yeast and hypha.

Inflammatory bowel diseases (IBD) are a multifactorial disorder. Our understanding of the role of bacteria in the pathogenesis of IBD has increased substantially; however, only scarce data exist regarding the role of commensal fungi in maintaining intestinal homeostasis and triggering IBD. Candida albicans (C.

Genetic and Structural Analysis of a SKIV2L Mutation Causing Tricho-hepato-enteric Syndrome.

Background: Advances in genomics have facilitated the discovery of monogenic disorders in patients with unique gastro-intestinal phenotypes. Syndromic diarrhea, also called tricho-hepato-enteric (THE) syndrome, results from deleterious mutations in SKIV2L or TTC37 genes. The main features of this disorder are intractable diarrhea, abnormal hair, facial dysmorphism, immunodeficiency and liver disease.

Impaired IL-10 Receptor-mediated Suppression in Monocyte From Patients With Crohn Disease.

Objectives: Interleukin-10 (IL-10) is an immunoregulatory cytokine that has a central role in suppressing proinflammatory responses. Patients with deleterious mutations in interleukin (IL)-10 or IL-10 receptor (IL-10R) genes develop severe colitis and perianal disease in the first months of life. Whether IL-10R expression and signaling in pediatric- or adult-onset Crohn disease (CD) are altered is unknown.