A team of researchers from Baylor College of Medicine, Tongji University, and other institutions announced on Mar. 19 that the process of weaning—transitioning from milk to solid food in early life—not only changes diet but also reprograms the gut’s immune defenses, potentially influencing health into adulthood.
The study, published in Nature Microbiology, highlights how weaning alters the gut microbiome in mice. This shift trains intestinal stem cells to respond more effectively to microbes later in life and may protect against inflammatory diseases long after childhood. The findings could have implications for understanding and preventing conditions such as Crohn’s disease and ulcerative colitis.
“Weaning is a major transition for babies. As milk gives way to solid food, the gut is suddenly exposed to a much wider variety of microbes,” said Dr. Lanlan Shen, professor of pediatrics – nutrition at Baylor College of Medicine. “This change of microbial diversity triggers a brief, controlled inflammatory response known as the weaning reaction.” Shen explained that while inflammation is often seen as harmful, this temporary response acts like a training drill for the gut’s immune system.
Dr. Li Yang, instructor of pediatrics – nutrition at Baylor and first author on the study, said: “We focused on intestinal stem cells, the long-lived cells that constantly renew the gut lining every few days. Because these stem cells persist for life, durable changes to them could shape gut health for decades.” The research found that microbial signals during weaning changed DNA methylation patterns in these stem cells—epigenetic markers that influence gene expression.
Shen noted: “One group of genes, MHC class II, stood out. These genes allow intestinal epithelial cells to communicate with immune cells and to help distinguish friendly microbes from threats. During weaning, MHC class II genes in intestinal stem cells lost methylation at key sites. This change made the genes easier to activate later, even long after the initial microbial signals were gone.”
Yang added: “This process creates an epithelial immune memory that is embedded directly in the gut lining... When exposed to immune signals later in life, these cells remembered their training and responded faster and more robustly than untrained ones.” The effect depended on specific types of bacteria present after weaning; antibiotics given early eliminated beneficial bacteria and prevented this reprogramming.
The study suggests there is a critical window during which exposure to certain microbes can establish lasting immunity through epigenetic changes in stem cells—a process less effective if attempted after this period has passed.
“Epidemiological studies already link antibiotic use in infancy with higher risk of these diseases later,” Shen said. “This research provides an explanation – early life disruptions to the microbiome may prevent the gut from establishing protective immune memory.”
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Looking ahead, Shen said: “Our findings also suggests that if we can identify the right microbial communities or their products that promote healthy immune intestinal training during early life, we might one day design dietary strategies to reduce lifelong disease risk.”
