Year: 2024
Type: article
Abstract: Postnatal establishment of enteric metabolic, host–microbial and immune homeostasis is the result of precisely timed and tightly regulated developmental and adaptive processes. Here, we show that infection with the invasive enteropathogen Salmonella Typhimurium results in accelerated maturation of the neonatal epithelium with premature appearance of antimicrobial, metabolic, developmental, and regenerative features of the adult tissue. Using conditional Myd88-deficient mice, we identify the critical contribution of immune cell-derived mediators. Cytokine stimulation of neonatal intestinal epithelial stem cell organoids suggests a network of synergistic and antagonistic cytokine effects with a significant contribution of IL-22, IL-4/IL-13, TNF, and IL-6 to infection-induced enterocyte reprogramming. Our findings demonstrate that the infection-associated immune cell activation disrupts physiological postnatal tissue maturation and may thereby worsen clinical outcomes and alter the neonatal-adult transition.
Authors: Stefan Schlößer, Anna-Lena Ullrich, Nastaran Fazel Modares, Matthias A. Schmitz, Johannes Schöneich, Kaiyi Zhang, Isabel Richter, Laura Robrahn, Sarah Schraven, James S. Nagai, Sven-Bastiaan Haange, Susan A. V. Jennings, Thomas Clavel, Ulrike Rolle-Kampczyk, Fabian Kiessling, Ivan G. Costa, Vanesa Muncan, Urska Repnik, Martin von Bergen, Aline Dupont, Mathias W. Hornef
Institutions: Universitätsklinikum Aachen, RWTH Aachen University, Medizinische Hochschule Hannover, Helmholtz Centre for Environmental Research, Amsterdam University Medical Centers, Amsterdam Gastroenterology Endocrinology Metabolism, University of Amsterdam, Christian-Albrechts-Universität zu Kiel
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Funders: Amsterdam University Medical Centers, Deutsche Forschungsgemeinschaft, Universiteit van Amsterdam, Bundesministerium für Bildung und Forschung, Helmholtz-Zentrum für Umweltforschung, Medizinischen Hochschule Hannover, RWTH Aachen University, Novo Nordisk Fonden, Medizinische Fakultät, RWTH Aachen University, H2020 European Research Council, HORIZON EUROPE European Research Council
Awards: G1284162446, G1852760606, G2506462028, Gut epithelial dynamics and function at the nexus of early life infection and long-term health, G3367582530, G3570765224, G3750051246, G3843702472, TRR 359: Perinatale Entwicklung der ImmunzellTopologie (PILOT), G5663219190, G7155641737, SFB 1382: Die DarmLeber Achse – Funktionelle Zusammenhänge und therapeutische Strategien
OpenAlex ID: W4405896120