Prophylactic Intra-Uterine β-Cyclodextrin Administration during Intra-Uterine Ureaplasma parvum Infection Partly Prevents Liver Inflammation without Interfering with the Enterohepatic Circulation of the Fetal Sheep.

Cathelijne Heymans,Marcel Den Dulk,Mhamed Hadfoune,Tim G.A.M Wolfs,Owen B Spiller,Michael L Beeton,Chantal Van Heugten,Matthew W Kemp,Matthew S Payne,Alan H Jobe,Lara R Heij,Boris W Kramer,Jogchum Plat,Sarah J Stock,Kaatje Lenaerts,Wim G Van Gemert

doi:10.3390/nu12051312

Abstract

Chorioamnionitis can lead to inflammation and injury of the liver and gut, thereby predisposing patients to adverse outcomes such as necrotizing enterocolitis (NEC). In addition, intestinal bile acids (BAs) accumulation is causally linked to NEC development. Plant sterols are a promising intervention to prevent NEC development, considering their anti-inflammatory properties in the liver. Therefore, we investigated whether an intra-amniotic (IA) Ureaplasma parvum (UP) infection affected the liver and enterohepatic circulation (EHC) and evaluated whether an IA administered plant sterol mixture dissolved in β-cyclodextrin exerted prophylactic effects. An ovine chorioamnionitis model was used in which liver inflammation and the EHC were assessed following IA UP exposure in the presence or absence of IA prophylactic plant sterols (a mixture of β-sitosterol and campesterol dissolved in β-cyclodextrin (carrier)) or carrier alone. IA UP exposure caused an inflammatory reaction in the liver, histologically seen as clustered and conflated hepatic erythropoiesis in the parenchyma, which was partially prevented by IA administration of sterol + β-cyclodextrin, or β-cyclodextrin alone. In addition, IA administration of β-cyclodextrin prior to UP caused changes in the expression of several hepatic BAs transporters, without causing alterations in other aspects of the EHC. Thereby, the addition of plant sterols to the carrier β-cyclodextrin did not have additional effects.

Highlights

Preterm birth, birth before 37 weeks of gestation, is the leading cause of morbidity and mortality among infants worldwide [1]
The increased expression of the apical sodium-dependent bile acid transporter (ASBT) in the terminal ileum, a protein involved in the uptake of conjugated bile acids (BAs) into the enterocytes, was reported in preterm infants with necrotizing enterocolitis (NEC)
We previously showed that fetal gut inflammation and mucosal damage following IA Ureaplasma parvum (UP) exposure were prevented by prophylactic plant sterol supplementation in the amniotic fluid [16]

Summary

Introduction

Birth before 37 weeks of gestation, is the leading cause of morbidity and mortality among infants worldwide [1]. The intraluminal accumulation of conjugated BAs resulted in intestinal epithelial damage, similar to the histopathological findings in NEC [11] These high concentrations of intraluminal BAs might be the result of increased BA synthesis, as was shown in a rat NEC model [12]. The increased expression of the apical sodium-dependent bile acid transporter (ASBT) in the terminal ileum, a protein involved in the uptake of conjugated BAs into the enterocytes, was reported in preterm infants with NEC and in an experimental NEC model with rodents which correlated with the location of intestinal damage, suggesting increased BAs uptake by enterocytes [13,14]. The important role of the liver and the gut-liver axis in NEC pathogenesis is further underlined by the presence of increased hepatic inflammation in neonatal rats with NEC, which correlated with the progression of intestinal damage during disease development [15]

Objectives

Results

Conclusion