Gut microbiota byproducts circulate in the bloodstream, regulating physiological processes in the host, including immunity, metabolism, and brain function. Scientists from the Institut Pasteur (partner research organization of Université Paris Cité), Inserm and CNRS have discovered that hypothalamic neurons in an animal model directly detect variations in bacterial activity and adapt the appetite and body temperature accordingly. These results demonstrate that a direct dialogue occurs between the gut microbiota and the brain, a finding that could lead to new therapeutic approaches to combat metabolic disorders such as diabetes and obesity. The findings should be published in Science April 15, 2022.
The intestine is the largest reservoir of bacteria in the body. A growing body of evidence reveals the degree of interdependence between hosts and their gut microbiota, and highlights the importance of the gut-brain axis. At the Institut Pasteur, neurobiologists from the Perception and Memory Unit (Institut Pasteur/CNRS)[1]immunobiologists from the Microenvironment and Immunity Unit (Institut Pasteur/Inserm) and microbiologists from the Biology and Genetics of the Bacterial Wall Unit (Institut Pasteur/CNRS/Inserm)[2] shared their expertise to study how gut bacteria directly control the activity of certain neurons in the brain.
The scientists focused on the NOD2 receptor (nucleotide oligomerization domain) which is found inside most immune cells. This receptor detects the presence of muropeptides, which are the building blocks of the bacterial cell wall. Moreover, it has previously been established that variants of the gene encoding the NOD2 receptor are associated with digestive disorders, including Crohn’s disease, as well as with neurological diseases and mood disorders. However, these data were insufficient to demonstrate a direct relationship between neuronal activity in the brain and bacterial activity in the gut. This was revealed by the consortium of scientists in the new study.
Using brain imaging techniques, the scientists first observed that the NOD2 receptor in mice is expressed by neurons in different regions of the brain, and in particular in a region known as the hypothalamus. They then discovered that the electrical activity of these neurons is suppressed when they come into contact with bacterial muropeptides from the gut. “Muropeptides in the intestine, blood and brain are considered markers of bacterial proliferation, explains Ivo G. Boneca, head of the Biology and Genetics of the Bacterial Wall Unit at the Institut Pasteur (CNRS/Inserm ). Conversely, if the NOD2 receptor is absent, these neurons are no longer suppressed by the muropeptides. As a result, the brain loses control over food intake and body temperature. The mice gain weight and are more likely to develop type 2 diabetes, especially in older females.
In this study, the scientists highlighted the surprising fact that neurons directly perceive bacterial muropeptides, whereas it was thought that this task was mainly devolved to immune cells. “It is extraordinary to discover that bacterial fragments act directly on such a strategic brain center as the hypothalamus, known to manage vital functions such as body temperature, reproduction, hunger and thirst”, comments Pierre-Marie Lledo, CNRS researcher and director of the Perception and Memory Unit at the Institut Pasteur.
Neurons thus seem to detect bacterial activity (proliferation and death) as a direct indicator of the impact of food intake on the intestinal ecosystem. ” Excessive consumption of a specific food can stimulate the disproportionate growth of certain bacteria or pathogens, thus compromising the intestinal balance, says Gérard Eberl, head of the Microenvironment and Immunity Unit at the Institut Pasteur (Inserm).
The impact of muropeptides on hypothalamic neurons and metabolism raises questions about their potential role in other brain functions, and may help us understand the link between certain brain diseases and genetic variants of NOD2. This discovery opens the way to new interdisciplinary projects at the border between neurosciences, immunology and microbiology, and ultimately to new therapeutic approaches to brain diseases and metabolic disorders such as diabetes and obesity.
[1] This research unit is also known as the “Genes, Synapses and Cognition Laboratory” (Institut Pasteur/CNRS). The Paris Brain Institute (CNRS/Inserm/Sorbonne University/AP-HP) also contributed to these results.
[2] The name of the CNRS unit is “Integrative and Molecular Microbiology Unit” and the Inserm unit is “Host-Microbe Interactions and Physiopathology Unit” (Pasteur Institute/CNRS/Inserm).
Source of the story:
Materials provided by Pastor Institute. Note: Content may be edited for style and length.