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

• Published in: Nature communications Vol. 15; no. 1; pp. 8623 - 16
• Main Authors: Perruzza, Lisa, Heckmann, Julia, Rezzonico Jost, Tanja, Raneri, Matteo, Guglielmetti, Simone, Gargari, Giorgio, Palatella, Martina, Willers, Maike, Fehlhaber, Beate, Werlein, Christopher, Vogl, Thomas, Roth, Johannes, Grassi, Fabio, Viemann, Dorothee
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.10.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 13/51; 14/19; 14/34; 38/1; 38/77; 45/91; 631/250/256/2515; 64/60; 692/4020/1503/1501; 692/4020/1503/1702/295; Animal models; Animals; Animals, Newborn; Breast milk; Breastfeeding & lactation; Calgranulin A - genetics; Calgranulin A - metabolism; Calgranulin B - genetics; Calgranulin B - metabolism; Children; Colonization; Dietary Supplements; Digestive system; Disease Models, Animal; Female; Gastrointestinal Microbiome; Gastrointestinal tract; Homeostasis; Humanities and Social Sciences; Humans; Immunity, Mucosal; Imprinting; Intestinal Diseases - metabolism; Intestinal Diseases - microbiology; Intestinal Diseases - pathology; Intestinal Mucosa - immunology; Intestinal Mucosa - metabolism; Intestinal Mucosa - microbiology; Intestinal Mucosa - pathology; Intestine; Intestines - immunology; Intestines - microbiology; Intestines - pathology; Leukocytes (neutrophilic); Male; Malnutrition; Malnutrition - complications; Malnutrition - metabolism; Mice; Mice, Inbred C57BL; Mucosal immunity; multidisciplinary; Neonates; Neutrophils - immunology; Neutrophils - metabolism; Offspring; Phenotypes; Postpartum period; Pregnancy; Risk factors; Science; Science (multidisciplinary); Suckling behavior; Weaning
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-52829-x

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. Malnutrition is a key risk factor affecting children’s health and development. Here, the authors report long-term protection against malnutrition-induced enteropathy by a neonatal S100a8/a9 nutritional supply in mice.