Published online 5 November 2008 | Nature | doi:10.1038/news.2008.1206

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Growing up under the guidance of bacteria

Scientists discover how microbes help the mouse gut to mature.

Woman's bare midriffEven 'friendly' bacteria need to be kept in check.Punchstock

The gut is home to a host of 'friendly' bacteria as well as being at risk from harmful invaders that can cause anything from mild upset to death. But even the friendly microbes need to be kept under control, and, a study finds, the presence of some of these bacteria seems to be necessary for normal development of immune mechanisms that do just that.

Gérard Eberl of the Pasteur Institute in Paris and his colleagues report in Nature1, that immune tissues in the mouse gut will only mature if fragments of a bacterial molecule called peptidoglycan are present.

The researchers focused on clusters of cells called cryptopatches that form in the intestines of newborn mice. Normally, as a healthy mouse grows, these cryptopatches develop into 'isolated lymphoid follicles', which are made up of antibody-producing cells. But mice raised in a sterile environment keep their cryptopatches into adulthood.

Eberl and his co-workers have found that pieces of peptidoglycan — a polymer made of sugars and amino acids that is found in the cell walls of bacteria — activate a receptor called NOD1 in cells that line the gut wall. When NOD1 'sees' a fragment of peptidoglycan, it triggers the production of chemical signals that activate a second receptor, CCR6, which is found in cryptopatches and is required for them to mature.

Crucially, pieces of peptidoglycan only appear in the gut when bacteria of a class known as 'Gram negative' divide. "We can replace the [many thousands of] bacteria in our gut with just this little piece of bacterial cell wall, and still induce the same phenomenon," says Eberl.

Finally, Eberl and his colleagues demonstrated that the lymphoid follicles also control the growth of bacteria. When they stopped the follicles from forming in the intestines of otherwise healthy mice, the researchers found that the total number of harmless gut bacteria jumped tenfold.

"What is brilliant about this paper is that they have described the cascade of signals from the wall of the bacterium right to the lymphocyte [antibody-producing cells]," says Francisco Guarner, a researcher at the Digestive System Research Unit of the Vall d'Hebron University Hopital in Barcelona, Spain, who was not involved in the study.

"If you know which molecules are involved, you have many tools to improve the system, and eventually you can see how to improve it in different medical conditions."

He notes that one of the molecules involved in this signalling, a peptide called β-defensin 3, is the mouse version of a molecule that has been linked to Crohn's disease in humans.

"I think these findings may be applicable to Crohn's disease and to ulcerative colitis," adds Guarner, who has shown that people with these conditions have gut ecosystems that vary unusually over time. "Because in these situations the immune system is fighting the normal bacteria of the gut."

But Dennis Kasper, a microbiologist at Harvard Medical School, points out that NOD1 is found only inside gut cells, so it is unclear how the receptor can detect fragments of peptidoglycan floating in the intestine. And, he adds, there are clusters of immune-system cells in the intestine other than the isolated lymphoid follicles.

"My suspicion is that different compliments of the gut flora impact on different aspects of the immune system," says Kasper. "Overall, the field needs to lay down the basic principles of how different diseases are associated with different lymphoid tissues." 

  • References

    1. Bouskra, D. et al. Nature doi:10.1038/nature07450 (2008).
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