Exploring the Immunomodulatory Potential of Human Milk: Aryl Hydrocarbon Receptor Activation and Its Impact on Neonatal Gut Health
Naomi V. Wieser,
Mohammed Ghiboub,
Caroline Verseijden,
Johannes B. van Goudoever,
Anne Schoonderwoerd,
Tim G. J. de Meij,
Hendrik J. Niemarkt,
Mark Davids,
Antoine Lefèvre,
Patrick Emond,
Joep P. M. Derikx,
Wouter J. de Jonge,
Bruno Sovran
Affiliations
Naomi V. Wieser
Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Center, University of Amsterdam, 1105 BK Amsterdam, The Netherlands
Mohammed Ghiboub
Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Center, University of Amsterdam, 1105 BK Amsterdam, The Netherlands
Caroline Verseijden
Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Center, University of Amsterdam, 1105 BK Amsterdam, The Netherlands
Johannes B. van Goudoever
Department of Pediatrics, Emma Children’s Hospital, Dutch National Human Milk Bank, Amsterdam University Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Anne Schoonderwoerd
Department of Pediatrics, Emma Children’s Hospital, Dutch National Human Milk Bank, Amsterdam University Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Tim G. J. de Meij
Amsterdam Gastroenterology, Endocrinology, Metabolism (AGEM), 1105 AZ Amsterdam, The Netherlands
Hendrik J. Niemarkt
Department of Neonatology, Maxima Medical Center, De Run 4600, 5504 DB Veldhoven, The Netherlands
Mark Davids
Department of Experimental Vascular Medicine, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
Antoine Lefèvre
UMR 1253, iBrain, University of Tours, Inserm, 37044 Tours, France
Patrick Emond
UMR 1253, iBrain, University of Tours, Inserm, 37044 Tours, France
Joep P. M. Derikx
Department of Pediatric Surgery, Emma Children’s Hospital, Amsterdam University Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Wouter J. de Jonge
Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Center, University of Amsterdam, 1105 BK Amsterdam, The Netherlands
Bruno Sovran
Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Center, University of Amsterdam, 1105 BK Amsterdam, The Netherlands
Several metabolites of the essential amino acid tryptophan have emerged as key players in gut homeostasis through different cellular pathways, particularly through metabolites which can activate the aryl hydrocarbon receptor (AHR). This study aimed to map the metabolism of tryptophan in early life and investigate the effects of specific metabolites on epithelial cells and barrier integrity. Twenty-one tryptophan metabolites were measured in the feces of full-term and preterm neonates as well as in human milk and formula. The ability of specific AHR metabolites to regulate cytokine-induced IL8 expression and maintain barrier integrity was assessed in Caco2 cells and human fetal organoids (HFOs). Overall, higher concentrations of tryptophan metabolites were measured in the feces of full-term neonates compared to those of preterm ones. Within AHR metabolites, indole-3-lactic acid (ILA) was significantly higher in the feces of full-term neonates. Human milk contained different levels of several tryptophan metabolites compared to formula. Particularly, within the AHR metabolites, indole-3-sulfate (I3S) and indole-3-acetic acid (IAA) were significantly higher compared to formula. Fecal-derived ILA and milk-derived IAA were capable of reducing TNFα-induced IL8 expression in Caco2 cells and HFOs in an AHR-dependent manner. Furthermore, fecal-derived ILA and milk-derived IAA significantly reduced TNFα-induced barrier disruption in HFOs.
