Antenatal ureaplasma infection impairs development of the fetal ovine gut in an IL-1-dependent manner

Abstract

Ureaplasma infection of the amniotic cavity is associated with adverse postnatal intestinal outcomes. We tested whether interleukin-1 (IL-1) signaling underlies intestinal pathology following ureaplasma exposure in fetal sheep. Pregnant ewes received intra-amniotic injections of ureaplasma or culture media for controls at 3, 7, and 14 d before preterm delivery at 124 d gestation (term 150 d). Intra-amniotic injections of recombinant human interleukin IL-1 receptor antagonist (rhIL-1ra) or saline for controls were given 3 h before and every 2 d after Ureaplasma injection. Ureaplasma exposure caused fetal gut inflammation within 7 d with damaged villus epithelium and gut barrier loss. Proliferation, differentiation, and maturation of enterocytes were significantly reduced after 7 d of ureaplasma exposure, leading to severe villus atrophy at 14 d. Inflammation, impaired development and villus atrophy of the fetal gut was largely prevented by intra-uterine rhIL-1ra treatment. These data form the basis for a clinical understanding of the role of ureaplasma in postnatal intestinal pathologies.

Selective IL-1α exposure to the fetal gut, lung, and chorioamnion/skin causes intestinal inflammatory and developmental changes in fetal sheep

“…Development of the fetal intestine was shown to be impaired in an IL-1-dependent manner in the context of chorioamnionitis. 17 Therefore, these results indicate that disturbed maturation of the intestinal epithelium during antenatal inflammation is the result of direct IL-1α effects to the GI mucosa. Alternatively, increased vacuolization and shortened villi at 6 days after IL-1α exposure to the fetal gut could also be interpreted as indicators of mucosal injury.…”

“…17 In the present study, we evaluated the impact of IL-1α signaling on intestinal inflammation and injury when different epithelial organs were selectively exposed to IL-1α. Our findings indicate that the adverse outcomes of the fetal gut in the course of chorioamnionitis are the combined result of selective IL-1α-driven signaling of the lung, gut, and chorioamnion/skin.…”

“…Maturation of the fetal gut was assessed by immunohistochemical staining of I-FABP 30 and by the size of vacuoles in the intestinal epithelium. In control animals (Figure 4a), I-FABP expression was detected along the villus, which is characteristic for animals of this GA. 17 In contrast, 6 days after IL-1α exposure to the gut, I-FABP expression was primarily localized in the crypts (Figure 4b) and large …”

“…15 Importantly, inhibition of IL-1 signaling with an IL-1 receptor antagonist in our chorioamnionitis model largely prevented fetal organ inflammation and its negative sequelae. 16,17 IL-1 signaling is central to antenatal inflammation in multiple animal models, [18][19][20] and IA IL-1α administration in fetal sheep caused inflammation in the chorioamnion with injury to the respiratory and gastrointestinal tract. [21][22][23] However, it remains unstudied whether local (i.e.…”

Isolation of Separate Ureaplasma Species From Endotracheal Secretions of Twin Patients

“…Ureaplasma has been detected in gastric aspirate samples from preterm human neonates, and experimental intrauterine Ureaplasma infection in pregnant sheep was found to impair development of the fetal ovine gut in an IL-1-dependent manner. 12,13 In addition, Okogbule-Wonodi et al, 14 have reported a 2-fold increased NEC prevalence in Ureaplasma-infected neonates born <33 weeks and a 3.3-fold increase in those born <28 weeks with Ureaplasma infection.…”