Dataset Information

Single-cell census of the colonic epithelium reveals goblet cell drivers of barrier breakdown in inflammatory bowel disease

ABSTRACT: Colonic epithelial cells facilitate host-microbe interactions to control mucosal immunity, and they also coordinate recycling and forming the mucus barrier. Epithelial barrier breakdown underpins inflammatory bowel disease (IBD). However, we do not know the specific contributions of each epithelial cell subtype to this process. Here, we profiled single colonic epithelial cells in health and IBD. Our results identified previously unknown subtypes and crypt gradients of progenitors, colonocytes and goblet cells. We also revealed a novel specialized metal ion storage and chloride secretory cell. In IBD, we discovered a unique cluster of disease associated goblet cells that remodels the barrier. We found downregulated WFDC2, a novel goblet cell expressing anti-protease that inhibited bacterial growth. Our in vivo studies demonstrated WFDC2 preserved tight junction integrity and prevented commensal invasion and mucosal inflammation. We delineate markers and transcriptional states, identify a new colonic epithelial cell and uncover fundamental principles of epithelial plasticity and barrier breakdown in IBD. Thus, our study reveals new therapeutic targets and disease-related mechanisms in IBD

OTHER RELATED OMICS DATASETS IN: GSE116222

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Colon

DISEASE(S): Inflammatory Bowel Disease

SUBMITTER: Simon Davis

LAB HEAD: Roman Fischer

PROVIDER: PXD011655 | Pride | 2019-02-16

REPOSITORIES: Pride

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Publications

Colonic epithelial cell diversity in health and inflammatory bowel disease.

Parikh Kaushal K Antanaviciute Agne A Fawkner-Corbett David D Jagielowicz Marta M Aulicino Anna A Lagerholm Christoffer C Davis Simon S Kinchen James J Chen Hannah H HH Alham Nasullah Khalid NK Ashley Neil N Johnson Errin E Hublitz Philip P Bao Leyuan L Lukomska Joanna J Andev Rajinder Singh RS Björklund Elisabet E Kessler Benedikt M BM Fischer Roman R Goldin Robert R Koohy Hashem H Simmons Alison A

Nature 20190227 7746

The colonic epithelium facilitates host-microorganism interactions to control mucosal immunity, coordinate nutrient recycling and form a mucus barrier. Breakdown of the epithelial barrier underpins inflammatory bowel disease (IBD). However, the specific contributions of each epithelial-cell subtype to this process are unknown. Here we profile single colonic epithelial cells from patients with IBD and unaffected controls. We identify previously unknown cellular subtypes, including gradients of pr ...[more]

PMID: 30814735

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Project description:Leber2015 - Mucosal immunity and gut microbiome interaction during C. difficile infection This model is described in the article: Systems Modeling of Interactions between Mucosal Immunity and the Gut Microbiome during Clostridium difficile Infection. Leber A, Viladomiu M, Hontecillas R, Abedi V, Philipson C, Hoops S, Howard B, Bassaganya-Riera J. PLoS ONE 2015; 10(7): e0134849 Abstract: Clostridium difficile infections are associated with the use of broad-spectrum antibiotics and result in an exuberant inflammatory response, leading to nosocomial diarrhea, colitis and even death. To better understand the dynamics of mucosal immunity during C. difficile infection from initiation through expansion to resolution, we built a computational model of the mucosal immune response to the bacterium. The model was calibrated using data from a mouse model of C. difficile infection. The model demonstrates a crucial role of T helper 17 (Th17) effector responses in the colonic lamina propria and luminal commensal bacteria populations in the clearance of C. difficile and colonic pathology, whereas regulatory T (Treg) cells responses are associated with the recovery phase. In addition, the production of anti-microbial peptides by inflamed epithelial cells and activated neutrophils in response to C. difficile infection inhibit the re-growth of beneficial commensal bacterial species. Computational simulations suggest that the removal of neutrophil and epithelial cell derived anti-microbial inhibitions, separately and together, on commensal bacterial regrowth promote recovery and minimize colonic inflammatory pathology. Simulation results predict a decrease in colonic inflammatory markers, such as neutrophilic influx and Th17 cells in the colonic lamina propria, and length of infection with accelerated commensal bacteria re-growth through altered anti-microbial inhibition. Computational modeling provides novel insights on the therapeutic value of repopulating the colonic microbiome and inducing regulatory mucosal immune responses during C. difficile infection. Thus, modeling mucosal immunity-gut microbiota interactions has the potential to guide the development of targeted fecal transplantation therapies in the context of precision medicine interventions. This model is hosted on BioModels Database and identified by: BIOMD0000000583. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Dataset Information

Single-cell census of the colonic epithelium reveals goblet cell drivers of barrier breakdown in inflammatory bowel disease

Publications

Colonic epithelial cell diversity in health and inflammatory bowel disease.

Similar Datasets

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