The gastrointestinal tract is regionally compartmentalized to coordinate digestion and metabolism of nutrients. This metabolic compartmentalization impacts host regional tissue immunity and bacterial communities. However, the mechanisms underlying intestinal regionalization and its impact on the mucosal immune response in homeostasis and disease are unclear. We hypothesized that intestinal epithelial cells coordinate regional metabolic and immune functions through the transcription factor GATA4. We generated conditional GATA4 deficient mice in intestinal epithelial cells to test this hypothesis. We found that GATA4 controlled the regionalization of lipid metabolism and inflammatory T cell responses in the small intestine. In the absence of GATA4, Segmented filamentous bacteria changed its regionalization to colonize the jejunum and drive IFNγ and IL17 T cell responses. We observed that GATA4 controlled levels of luminal IgA through regulating retinoic acid metabolism in intestinal epithelial cells. The increased capacity of the proximal intestine to produce luminal IgA in wild type mice protects the epithelium from bacteria adhesion by Segmented filamentous bacteria and limits inflammatory immune responses. Finally, we tested the role of GATA4 deficiency and intestinal regionalization in the host response to pathogen infection or human autoimmune disease. We observed that the GATA4 controlled the regionalization of Citrobacter rodentium colonization and survival from the infection. In the context of human disease, we observed a loss of GATA4 in active celiac patients coupled with higher IL17 signaling and decreased retinol metabolism. The presence of Actinobacillus in active celiac patients was associated with lower GATA4 expression, higher IL17 signaling, and increased tissue destruction. These data identify GATA4 as critical regulator of regional metabolism, bacterial colonization, and the host immune response.




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