The development and maintenance of a balanced microbiota is crucial for human health. Milk contains immune factors that not only protect offspring from infectious diseases but also play an important role in promoting the development and maintenance of the microbiota. However, the persisting effects of milk-derived immune factors on the maintenance of the microbiota after weaning have not been carefully examined. In this study, a cross-fostering model was employed using immunocompetent (IC) and immunodeficient (ID) mice in which one-half of the pups born from two dams were replaced. As a result, breast milk from the IC dam (IC milk) affected the development of the microbiota during lactation and maintained it even after weaning in the large intestine of the ID pups. The large intestinal microbiota of ID pups raised on IC milk remained similar to that of normal IC pups. Under normal conditions, the genus Mucispirillum was closely associated with other bacteria, forming a diverse bacterial community in the large intestine. In the small intestine, there were no differences in the microbiota before weaning, regardless of whether IC or ID milk was consumed. By contrast, significant differences were observed in the small intestinal microbiota between IC and ID mice after weaning
however, this was dependent on the immune-related characteristics of offspring (rather than milk-derived immune factors). These results indicate that breast milk plays an important role in the large (not small) intestine of offspring to create and maintain a diverse microbiota with a balanced bacterial network even after weaning.