GATA4 controls regionalization of tissue immunity and commensal-driven immunopathology

Zachary M. Earley, Wioletta Lisicka, Joseph J. Sifakis, Raúl Aguirre-Gamboa, Anita Kowalczyk, Jacob T. Barlow, Dustin G. Shaw, Valentina Discepolo, Ineke L. Tan, Saideep Gona, Jordan D. Ernest, Polly Matzinger, Luis B. Barreiro, Andrey Morgun, Albert Bendelac, Rustem F. Ismagilov, Natalia Shulzhenko, Samantha J. Riesenfeld, Bana Jabri

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)43-57.e10
JournalImmunity
Volume56
Issue number1
DOIs
StatePublished - 10 Jan 2023
Externally publishedYes

Keywords

  • GATA4
  • IgA
  • bacterial colonization
  • celiac disease
  • immunopathology
  • infection
  • intestinal epithelial cells
  • intestinal regionalization
  • retinoic acid
  • segmented filamentous bacteria

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