MaternalInfection Perturbs Foetal and Maternal Foetal Interface Metabolism, Exposing the Foetus to Kynurenine.

Abstract

INTRODUCTION: infection during pregnancy can result in abortion or congenital infection. Events in the maternal-foetal interface, which form a selective barrier between the maternal and foetal circulations and where critical immunological adaptations occur, are critical in determining the pregnancy outcome. Recent studies have demonstrated thatinfection can alter host metabolism, but howinfection alters the placenta or the foetus metabolome has not been reported. METHODS: Herein, for the first time, we use liquid chromatography mass spectrometry (LCMS) in the BALB/c murine model of congenitalto address this shortcoming. RESULTS: Maternal infection resulted in dysregulation of free amino acids with significant decreases in the levels of arginine, proline, threonine, methionine, leucine, glycine and glutamine detected in the decidua. Similar changes were noted in the placenta, although differences were less pronounced. In contrast, amino acid levels were not significantly altered in the foetal extracts. Results demonstrate thatinfection induces the highest number of metabolite changes in the maternal serum. However, a subset of these changes was also found in the maternal-foetal interface and in the developing foetus. Maternal infection resulted in changes to arginine metabolism and downregulation of the urea cycleSpecifically, ornithine, arginosuccinate and citrulline were significantly decreased in all three tissues following maternal infection. Increased levels of spermidine were evident in the placenta and foetal extracts and not in the decidua from maternally infected mice. This indicates that maternalinfection downregulates the urea cycle, while increasing flux into polyamine biosynthesis in the decidua, placenta and foetus. Maternal infection resulted in an alteration to the tryptophan degradation pathway. Significantly decreased levels of kynurenine were seen in the decidua and placenta of maternally infected mice in comparison with the uninfected controls. In contrast, there was a significant increase in kynurenine in foetal extracts from maternally infected mice. Some metabolites from microbiome origin, including indoxylsulfate and 4-guanidinobutanoate, were changed compared with the controls, suggesting the potential ofto change the host microbiome. DISCUSSION: The data presented herein demonstrate thatinfection during pregnancy alters the metabolome of the maternal-foetal interface and developing foetus. Notably increased kynurenine and decreased tryptophan levels were found in the foetal tissue. As kynurenine is known to be produced during maternal immune activation and has been implicated in the development of psychoneurological diseases these changes could have important implications for the offspring over their lifetime.