Proline Alleviates Low-Protein Diet-Induced Adverse Pregnancy Outcomes by Enriching <i>Akkermansia</i> and Activating Placental Wnt/Igf1 Signaling

Alterations in gut microbiota and its metabolites are associated with placental and fetal development. Although proline has been shown to enhance placental function and improve pregnancy outcomes, its interaction with the gut microbiota remains poorly understood. In this study, a gestational low-protein diet (LPD) leads to decreased fetal birth weight and impaired placental vascular development, as well as increased embryonic resorption rates; these effects are mitigated by dietary proline supplementation. Mechanistically, proline enhances the abundance of <i>Akkermansia</i> and the production of butyrate in the gut, thereby promoting placental angiogenesis by activating the placental Wnt/insulin-like growth factor 1 (Igf1) signaling pathway, ultimately alleviating fetal developmental impairment caused by LPD. Moreover, in an in vitro porcine vascular endothelial cell model under amino acid-restricted conditions, butyrate enhances angiogenesis by activating the Wnt/Igf1 signaling pathway. These findings reveal that targeting the dietary proline supply and gut microbiota may open new avenues for the prevention of intrauterine growth restriction.