GATA4 controls regionalization of tissue immunity and commensal-driven immunopathology

There is growing recognition that regionalization of bacterial colonization and immunity along the intestinal tract has an important role in health and disease. Yet, the mechanisms underlying intestinal regionalization and its dysregulation in disease are not well understood. This study found that r...

Full description

Saved in:
Bibliographic Details
Published in:Immunity (Cambridge, Mass.) Mass.), 2023-01, Vol.56 (1), p.43-57.e10
Main Authors: Earley, Zachary M., Lisicka, Wioletta, Sifakis, Joseph J., Aguirre-Gamboa, Raúl, Kowalczyk, Anita, Barlow, Jacob T., Shaw, Dustin G., Discepolo, Valentina, Tan, Ineke L., Gona, Saideep, Ernest, Jordan D., Matzinger, Polly, Barreiro, Luis B., Morgun, Andrey, Bendelac, Albert, Ismagilov, Rustem F., Shulzhenko, Natalia, Riesenfeld, Samantha J., Jabri, Bana
Format: Article
Language:English
Subjects:
Actinobacillus
Animals
bacterial colonization
celiac disease
Enterobacteriaceae Infections
Gastrointestinal Microbiome - immunology
GATA4
GATA4 Transcription Factor - metabolism
Humans
IgA
Immunity, Mucosal
immunopathology
infection
Interleukin-17 - immunology
Interleukin-17 - metabolism
intestinal epithelial cells
Intestinal Mucosa - immunology
Intestinal Mucosa - microbiology
intestinal regionalization
Intestine, Small
Mice
retinoic acid
segmented filamentous bacteria
Symbiosis
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:There is growing recognition that regionalization of bacterial colonization and immunity along the intestinal tract has an important role in health and disease. Yet, the mechanisms underlying intestinal regionalization and its dysregulation in disease are not well understood. This study found that regional epithelial expression of the transcription factor GATA4 controls bacterial colonization and inflammatory tissue immunity in the proximal small intestine by regulating retinol metabolism and luminal IgA. Furthermore, in mice without jejunal GATA4 expression, the commensal segmented filamentous bacteria promoted pathogenic inflammatory immune responses that disrupted barrier function and increased mortality upon Citrobacter rodentium infection. In celiac disease patients, low GATA4 expression was associated with metabolic alterations, mucosal Actinobacillus, and increased IL-17 immunity. Taken together, these results reveal broad impacts of GATA4-regulated intestinal regionalization on bacterial colonization and tissue immunity, highlighting an elaborate interdependence of intestinal metabolism, immunity, and microbiota in homeostasis and disease. [Display omitted] •GATA4 prevents small intestinal inflammation by restricting bacterial colonization•GATA4 regulates bacterial colonization in part by regulating IgA and retinol metabolism•GATA4 deficiency, SFB, and Citrobacter rodentium synergize to drive immunopathology•Th17 immunity is found in celiac patients with GATA4 deficiency and Actinobacillus Regulators of intestinal regionalization are vital, yet poorly understood. Here, Earley et al. demonstrate how the transcription factor GATA4 regulates metabolic pathways and luminal IgA to control adherent bacteria colonization. Proper gut regionalization and commensal colonization is critical in preventing dysregulated Th17 responses and immunopathology in humans and mice.
ISSN:1074-7613
1097-4180
DOI:10.1016/j.immuni.2022.12.009