The neonatal period is a critical phase for the development of the intestinal immune system, marked by rapid adaptation to the external environment and unique nutritional demands. Breast milk plays a pivotal role in this transition, yet the mechanisms by which it influences neonatal mucosal immunity remain unclear. This review examines the potential mechanisms by which cell-free DNA (cfDNA) in breast milk may impact neonatal immune development, particularly through Toll-like receptor 9 (TLR9) signalling and gut microbiota interactions. We propose that cfDNA in breast milk interacts with TLR9 on the apical surface of neonatal intestinal epithelial cells, potentially serving as an initial anti-inflammatory stimulus before the establishment of commensal bacteria. This hypothesis is supported by the high concentration and stability of cfDNA in breast milk, as well as the known activation of TLR9 by mitochondrial DNA in breast milk. The review emphasises the need for further empirical research to validate these interactions and their implications for neonatal health, suggesting that understanding these dynamics could lead to improved strategies for neonatal care and disease prevention.
Keywords: TLR9; cfDNA; mucosal immunity.