According to a team of researchers at Baylor College of Medicine, Tongji University and collaborating institutions, weaning or switching from milk to solid food in early life doesn’t just change what babies eat, it helps reprogram the gut’s immune defenses to mount faster and stronger responses that can last into adulthood.
The researchers report in Nature Microbiology that weaning reshaped the gut microbiome – the vast community of gut microorganisms – in mice, which in turn ‘trained’ intestinal stem cells to respond better to microbes later in life and appears to protect against inflammatory diseases long after childhood has passed.
“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 co-corresponding author Dr. Lanlan Shen, professor of pediatrics – nutrition and member of the Dan L Duncan Comprehensive Cancer Center at Baylor. “This change of microbial diversity triggers a brief, controlled inflammatory response known as the weaning reaction.”
While inflammation often is viewed as harmful, in this context it acts like a training drill – intense, temporary and essential for preparing the gut’s immune system for future challenges. What remained unclear was how this short training leaves such a lasting impression.
“We focused on intestinal stem cells, the long-lived cells that constantly renew the gut lining every few days,” said first author Dr. Li Yang, instructor of pediatrics – nutrition in the Shen lab at Baylor. “Because these stem cells persist for life, durable changes to them could shape gut health for decades.”
Weaning-related microbial signals
Researchers discovered that weaning-related microbial signals changed how intestinal stem cells regulate immune genes. The microbes reprogramed these stem cells by changing their DNA methylation patterns. These are patterns of methyl chemical tags in the DNA, also called epigenetic markers. DNA methylation patterns act like a switch that can turn genes up or down. Changing the pattern changes gene expression.
“One group of genes, MHC class II, stood out,” Shen said. “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.”
“This process creates an epithelial immune memory that is embedded directly in the gut lining,” Yang said. “Even after stem cells matured into fully differentiated intestinal cells, they retained this epigenetic imprint. When exposed to immune signals later in life, these cells remembered their training and responded faster and more robustly than untrained ones.”
Training effect
The training effect depends strongly on the types of microbes that colonize the gut after weaning. Gram positive bacteria stimulate IFN γ production and generate compounds, such as short chain fatty acids and alpha ketoglutarate, that directly support epigenetic reprogramming.
“Giving young mice a low dose of antibiotic penicillin during early life eliminated many of these beneficial bacteria. As a result, the epigenetic reprogramming of intestinal stem cells did not occur,” Shen said. “As adults, antibiotic-exposed mice had lower MHC class II expression in the gut, weaker immune defenses and far greater susceptibility to colitis and colon cancer when challenged.”
And timing is everything. “When epithelial stem cell reprogramming took place during early life, training persisted into adulthood. But when reprogramming was attempted after weaning, the training was much weaker or absent,” Yang said. “This suggests a critical window when the gut microbiome can shape long term immunity. Once that window closes, intestinal stem cells become harder to change.”
Implications for people
Although this study was conducted in mice, it has important implications for people. Inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis often emerge in adolescence or young adulthood, but the study suggests that their roots may extend back to early childhood.
“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. 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.”
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Other contributors to this work include Robert C. Peery, Shirui Zhou, Xiaomin Chen, Leah M. Farmer, Fabiola Gutierrez, Stephanie Fowler, Lanjing Zhang, Julia M. Salamat, Karen Riggins and Jiejun Shi. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, Tongji University, Princeton Medical Center and Rutgers University.
This work was funded by the March of Dimes (6-FY18-135), the US Department of Agriculture (CRIS 3092-51000-060), and the National Institutes of Health (R21HD101035, R01CA233472, and R01HD100914). This study was supported in part by the National Institute of Diabetes and Digestive and Kidney Diseases T32 fellowship T32DK07664 and the following grants: NIH/NIDDK P30 DK056338, NIH/NIEHS P30ES030285 and NIH/NCI P30CA125123.
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