(W1170) HUMAN BREAST MILK PRESERVES FATTY TRANSPORT AND INTESTINAL INTEGRITY IN MODELING NECROTIZING ENTEROCOLITIS USING HUMAN SMALL INTESTINAL ORGANOIDS
Resident Physician / PhD Student University of Saskatchewan, Canada
Abstract: Necrotizing enterocolitis (NEC) is a deadly disease for preterm neonates, with mortality up to 50% and significant long-term complications, despite many modern medical and surgical advancements. Although human breast milk reduces the incidence of NEC and appears to promote intestinal adaptation, the underlying molecular mechanisms are not fully understood nor replicated by formula feeds. Moreover, enteral feeding is often restricted in neonates with NEC due to ileus, bowel rest, or perioperative consideration. As there are a lack of specific treatments for NEC, elucidating these adaptive processes may reveal novel therapeutic targets that mimic the benefits of breast milk, offering a promising strategy to reduce NEC-associated morbidity and mortality.
Human organoids are established models of both the intestinal system and the NEC disease process. Mature iPSC-derived human small intestinal organoids were cultured in growth media supplemented with either human breast milk, Enfamil A+ formula or 1X D-PBS (control) at 1:10 ratio. To simulate NEC-inducing inflammatory conditions, groups were exposed to a 24 h treatment of TNF-alpha and LPS, administered before or after exposure to the supplemented media. Immunocytochemistry assessed the integrity of tight-junctions, enterocyte abundance, and preservation of goblet cells, all key components of epithelial barrier function. Concurrent RT-qPCR analysis focused on the expression of critical fatty acid transport proteins.
Our results demonstrate that when compared to formula, human breast milk uniquely upregulates lipid transport-associated genes FABP1, SCARB2, and FATP4. Goblet cell populations and tight junction integrity is also better preserved in breast milk-treated NEC organoids, as compared to formula-fed ones. These molecular adaptations offer insight into the potent protective effects of breast milk, underscoring its role in promoting intestinal homeostasis under inflammatory stress.
These results expose promising molecular targets for drug discovery, such as fatty acid transporters, laying the groundwork for the development of targeted therapies capable of replicating the adaptive benefits of human breast milk. Such strategies may be leveraged to improve intestinal function in neonates afflicted by intestinal diseases.
Funding Source: University of Saskatchewan Department of Surgery - Resident Research Award
