New PILOT publication in PNAS

PILOT members Anna-Lena Ullrich, Thomas Clavel, Aline Dupont and Mathias W. Hornef have published a new paper in PNAS:

Salmonella infection accelerates postnatal maturation of the intestinal epithelium

Significance

Postnatal establishment of metabolic, host–microbial, and immune homeostasis is the result of precisely timed and tightly regulated developmental and adaptive processes. Tissue damage during this “neonatal window of opportunity” may disrupt these processes explaining human epidemiological data associating early life events with persistent adverse effects on mucosal physiology, host metabolism, growth, and intellectual development. Here, we show that early life enteric infection leads to an accelerated tissue maturation and the premature emergence of antimicrobial, metabolic, developmental, and regenerative properties of the adult gut. Our findings link immune activation and postnatal tissue development, explain the exacerbated disease course in the newborn host, and provide promising targets for future therapeutic strategies.

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.

Full article: https://doi.org/10.1073/pnas.2403344122