Scientists have sought to demonstrate a direct relationship between neuronal activity in the brain and bacterial activity in the gut. In a new study, researchers uncovered that hypothalamic neurons in an animal model directly detect variations in bacterial activity and adapt appetite and body temperature accordingly. These findings demonstrate that a direct dialog occurs between the gut microbiota and the brain, a discovery that could lead to new therapeutic approaches for tackling metabolic disorders such as diabetes and obesity.

Their findings are published in the journal Science in a paper titled, “Bacterial sensing via neuronal Nod2 regulates appetite and body temperature,” and led by researchers at the Institut Pasteur, neurobiologists from the perception and memory unit (Institut Pasteur/CNRS), immunobiologists from the microenvironment and immunity unit (Institut Pasteur/Inserm), and microbiologists from the biology and genetics of the bacterial cell wall unit (Institut Pasteur/CNRS/Inserm).

“Compounds released by the microbiota are found in the bloodstream and can modulate physiological processes in the host, such as immunity, metabolism, and brain functions. Microbial metabolites, including short-chain fatty acids and tryptophan derivatives, regulate many processes through receptors that are widely expressed,” the researchers wrote. “However, the structural components of microbes are detected by pattern recognition receptors (PRRs) that signal the presence of viruses, bacteria, or fungi on mucosal surfaces, in tissues, and in cells. Bacterial components have been found to modulate brain activity, and PRRs are associated with brain disorders. Whether brain neurons can directly sense bacterial components and whether bacteria can regulate physiological processes through regulation of brain neurons remains to be demonstrated.”

The scientists focused on the NOD2 (nucleotide oligomerization domain) receptor which is mostly found inside 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 coding for the NOD2 receptor are associated with digestive disorders, including Crohn’s disease, as well as 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 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 subsequently discovered that these neurons’ electrical activity is suppressed when they come into contact with bacterial muropeptides from the gut.

“Muropeptides in the gut, blood, and brain are considered to be markers of bacterial proliferation,” explained Ivo G. Boneca, PhD, head of the biology and genetics of the bacterial cell wall unit at the Institut Pasteur (CNRS/Inserm).

“It is extraordinary to discover that bacterial fragments act directly on a brain center as strategic as the hypothalamus, which is known to manage vital functions such as body temperature, reproduction, hunger, and thirst,” commented Pierre-Marie Lledo, PhD, CNRS scientist and head of the Institut Pasteur’s perception and memory unit.

This discovery paves the way for new interdisciplinary projects at the frontier between neurosciences, immunology, and microbiology, and ultimately, for new therapeutic approaches to brain diseases and metabolic disorders such as diabetes and obesity.