Lactotransferrin reduction as a target mechanism of postnatal intestinal vulnerability in murine preeclampsia models

Fetal growth restriction (FGR) and preeclampsia (PE) are associated with placental insufficiency. Although FGR increases the risk of postnatal intestinal disorders, the mechanisms by which intrauterine stress causes these disorders and the intestinal alterations underlying their pathogenesis remain unclear. In this study, we investigated the underlying molecular mechanisms and potential preventive strategies. Pregnant mice were administered angiotensin II or recombinant soluble fms-like tyrosine kinase-1 to induce PE with FGR. Offspring intestines were collected on embryonic day 18.5 for RNA sequencing and on postnatal days (P) 7 and 21 for histological analyses. At P21, enteritis was induced using lipopolysaccharide and platelet-activating factors. Offspring from the PE model (PE offspring) exhibited shorter intestinal lengths and fewer secretory cells than the controls. RNA sequencing identified 226 differentially expressed genes, with lactotransferrin (Ltf), a protective secretory protein, downregulated in PE offspring. Immunohistochemistry demonstrated increased epithelial Ltf expression from P7 to P21, which was impaired in PE offspring. Following enteritis induction, the PE offspring showed increased severity, which was markedly mitigated by prophylactic LTF supplementation. These findings highlight the importance of risk-based preventive strategies for postnatal intestinal disorders in infants exposed to placental insufficiency-induced intrauterine stress.NEW & NOTEWORTHY Children born to mothers with preeclampsia are at an increased risk of postnatal intestinal vulnerability, yet the mechanisms of such disorders remain unclear. In murine preeclampsia models with fetal growth restriction, offspring exhibited impaired intestinal epithelial differentiation and markedly reduced lactotransferrin expression from fetal to postnatal stages. Prophylactic oral lactotransferrin mitigated experimental enteritis, highlighting a risk-based preventive strategy for postnatal intestinal disorders in infants exposed to intrauterine stress.