Postnatal supplementation with alarmins S100a8/a9 ameliorates malnutrition-induced neonate enteropathy in mice

Lisa Perruzza (), Julia Heckmann, Tanja Rezzonico Jost, Matteo Raneri, Simone Guglielmetti, Giorgio Gargari, Martina Palatella, Maike Willers, Beate Fehlhaber, Christopher Werlein, Thomas Vogl, Johannes Roth, Fabio Grassi and Dorothee Viemann ()
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Lisa Perruzza: Università della Svizzera Italiana (USI)
Julia Heckmann: University Hospital Würzburg
Tanja Rezzonico Jost: Università della Svizzera Italiana (USI)
Matteo Raneri: Università della Svizzera Italiana (USI)
Simone Guglielmetti: University of Milano-Bicocca
Giorgio Gargari: University of Milan
Martina Palatella: Università della Svizzera Italiana (USI)
Maike Willers: Hannover Medical School
Beate Fehlhaber: Hannover Medical School
Christopher Werlein: Hannover Medical School
Thomas Vogl: University of Münster
Johannes Roth: University of Münster
Fabio Grassi: Università della Svizzera Italiana (USI)
Dorothee Viemann: University Hospital Würzburg

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Malnutrition is linked to 45% of global childhood mortality, however, the impact of maternal malnutrition on the child’s health remains elusive. Previous studies suggested that maternal malnutrition does not affect breast milk composition. Yet, malnourished children often develop a so-called environmental enteropathy, assumed to be triggered by frequent pathogen uptake and unfavorable gut colonization. Here, we show in a murine model that maternal malnutrition induces a persistent inflammatory gut dysfunction in the offspring that establishes during nursing and does not recover after weaning onto standard diet. Early intestinal influx of neutrophils, impaired postnatal development of gut-regulatory functions, and expansion of Enterobacteriaceae were hallmarks of this enteropathy. This gut phenotype resembled those developing under deficient S100a8/a9-supply via breast milk, which is a known key factor for the postnatal development of gut homeostasis. We could confirm that S100a8/a9 is lacking in the breast milk of malnourished mothers and the offspring’s intestine. Nutritional supply of S100a8 to neonates of malnourished mothers abrogated the aberrant development of gut mucosal immunity and microbiota colonization and protected them lifelong against severe enteric infections and non-infectious bowel diseases. S100a8 supplementation after birth might be a promising measure to counteract deleterious imprinting of gut immunity by maternal malnutrition.

Date: 2024
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DOI: 10.1038/s41467-024-52829-x

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