GUT-BRAIN AXIS: When Muropeptides Talk to the Hypothalamus

A growing body of evidence shows the degree of interdependence between hosts and their gut microbiota, illustrating the importance of the gut-brain axis to human health. Byproducts of the gut microbiota are known to circulate in the bloodstream and regulate host physiological processes, including immunity, metabolism, but also brain function. This is a first established connection between the microbiota and the brain. The Institut Pasteur team with colleagues from Inserm and CNRS showed in an animal model that hypothalamic neurons directly detect changes in bacterial activity and adjust appetite and body temperature accordingly. These discoveries also illustrate the direct dialogue that takes place between the gut microbiota and the brain, and suggest new therapeutic approaches against metabolic diseases such as diabetes and obesity.

A receptor involved in both bacterial activity in the gut and neural activity in the brain

Scientists are focusing here on a receptor, NOD2, that is present in most immune cells. This receptor detects the presence of muropeptides, building blocks of the bacterial cell membrane. In addition, variants in the gene encoding the NOD2 receptor are known to be associated with digestive disorders, including Crohn’s disease, as well as neurological and mood disorders. Thus, NOD2 appears to be involved in bacterial activity in the gut and neuronal activity in the brain.

The study: Using brain imaging in mice, scientists observed that:

  • NOD2 is expressed in mice by neurons in various regions of the brain, particularly the hypothalamus;
  • these hypothalamic neurons are involved in regulating appetite and body temperature;
  • however, their electrical activity is suppressed when they come into contact with bacterial gut muropeptides;
  • but if the NOD2 receptor is missing, the activity of these neurons is no longer inhibited by muropeptides and the brain loses control of food intake and body temperature: the study shows that mice gain weight and are more likely to develop type 2 diabetes.

It is therefore the demonstration of a direct dialogue between neurons and bacteria: Neurons directly sense bacterial muropeptides and that these bacterial fragments act directly on the hypothalamus, an area known to control vital functions such as body temperature, reproduction, hunger and thirst. Bacterial activity “serves” the brain as a direct indicator of the effects of food intake on the gut ecosystem.

These muropeptides, which could exert further influences on the neurons of the hypothalamus and ultimately on other cerebral and metabolic functions, will lead to new therapeutic approaches… brain diseases and metabolic disorders.

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