GATA4 controls regionalization of tissue immunity and commensal-driven immunopathology

• DOI: 10.1016/j.immuni.2022.12.009
• Publication Date: 2023-01-10T18:10:10Z
• Authors: 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. Riese...; Bana Jabri
• Keywords: 0301 basic medicine; bacterial colonization; Immunology; 610; segmented filamentous bacteria; GATA4; IgA; bacterial colonization; celiac disease; immunopathology; infection; intestinal epithelial cells; intestinal regionalization; retinoic acid; segmented filamentous bacteria; GATA4; Mice; 03 medical and health sciences; Intestine, Small; retinoic acid; Immunology and Allergy; immunopathology; Animals; Humans; Intestinal Mucosa; Symbiosis; Immunity, Mucosal; Interleukin-17; Enterobacteriaceae Infections; 600; Actinobacillus; infection; 3. Good health; Gastrointestinal Microbiome; GATA4 Transcription Factor; Infectious Diseases; intestinal epithelial cells; intestinal regionalization; IgA; celiac disease

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.