• Weaning reaction
• Triggering the immune system

  • What is already known on this topic
    The gut microbiota make-up of newborns is determined first by the bacteria acquired from the mother and then by the composition of breast milk and the introduction of solid foods.

  • What this research adds
    During weaning, changes in the gut microbiota of newborn mice cause an immune response that is important for preventing allergies and other inflammatory disorders in adulthood.

  • Conclusions
    The findings highlight the importance of an early exposure to microbiota for the development of a normal immune system.

More evidence backs up the “hygiene hypothesis” – or the idea that exposure to bacteria early in life builds a healthy immune system. Researchers have found that when newborn mice start to get solid foods, changes in their gut microbiota trigger an immune reaction that is important for preventing allergies and other inflammatory diseases later in life.

Ziad Al Nabhani of the Institute Pasteur in Paris and his colleagues explored how the intestinal immune system of newborn mice reacts to microbial colonization. The first response to microbes occurs during weaning and is important for educating the immune system, the researchers report in Immunity.

Weaning reaction

The researchers started off by tracking the number and type of intestinal bacteria in newborn mice. Soon after birth, the mouse gut is colonized by γ-Proteobacteria and then by Lactobacillales, which are adapted to the milk environment. But during weaning, the number of bacteria such as Clostridia and Bacteroidia increases up to 100-fold, leading to the standard composition of the adult gut microbiota.

Weaning caused changes in the microbiota composition, which in turn resulted in the expression of genes that contribute to anti-microbial immunity, including the inflammatory molecules tumor necrosis factor alpha and interferon γ.

Mice treated with antibiotics that kill anaerobic bacteria such as Clostridia didn’t develop a weaning reaction, suggesting that these bacteria are necessary for the immune response induced by weaning. Indeed, segmented filamentous bacteria, which are a type of Clostridia, were sufficient to induce the weaning reaction.

When the researchers transferred the gut microbiota from healthy mice to germ-free mice before germ-free mice were weaned, the levels of inflammatory molecules increased. The same immune response didn’t happen after germ-free mice were weaned, suggesting that the weaning reaction has to occur during a defined time window: between two and four weeks in mice, which corresponds to three to six months in humans.

Indeed, when the researchers delayed weaning by feeding newborn mice milk only for more than four weeks, the weaning reaction was delayed too.

Triggering the immune system

To test whether the weaning reaction had an impact on the immune system, the researchers induced gut inflammation in newborn mice. The animals that had been exposed to microbiota before weaning developed a mild inflammation, while those that had been exposed to the microbes after weaning developed severe inflammation.

Similarly, mice treated with antibiotics during weaning developed inflammatory disorders such as intestinal allergies and colorectal cancer, whereas those treated with antibiotics before weaning didn’t.

The researchers also found that weaning-mediated changes in the gut microbiota trigger specific immune cells that are important for a balanced immune reaction. Without these cells, immune responses are exacerbated and can lead to inflammatory diseases.

The findings highlight the importance of an early exposure to microbiota for the development of a normal immune system. Limiting the exposure of children to microbes through increased hygiene and antibiotics overuse could contribute to a heightened susceptibility to inflammatory disorders such as allergy and inflammatory bowel disease later in life, the scientists say.