The gut microbiota represents the body’s largest reservoir of bacteria. The relationship between the microbiota and the human body is mediated through the gut-central nervous system axis, more commonly referred to as the gut-brain axis. Composed of billions of microorganisms living in the digestive tract, the gut microbiota plays a crucial role in overall health—including brain health.
Several mechanisms have been proposed to explain how the gut microbiota can influence the brain. These mechanisms include the production of neurotransmitters, modulation of inflammation, regulation of intestinal permeability, and direct communication with the central nervous system via the vagus nerve, which connects the brain to the gut. One particularly interesting aspect for studying the gut-brain axis is the analysis of the NOD2 (Nucleotide Oligomerization Domain) receptor found inside cells, especially immune cells. This receptor detects the presence of muropeptides—components of bacterial cell walls that are byproducts of the gut microbiota.
Numerous studies have suggested that certain genetic variants of the gene coding for the NOD2 receptor are associated with gastrointestinal diseases such as Crohn’s disease, as well as with neurological and psychiatric disorders, including Parkinson’s disease, mood disorders (anxiety, depression), and autism. Research also suggests that modulating the gut microbiota—through probiotics, prebiotics, or dietary changes—could have a positive impact on mental health. However, until recently, these studies had not demonstrated a direct connection between brain neuron function and gut bacterial activity. That changed with a 2022 study by a group of European researchers.
Using brain imaging techniques, scientists observed in mice that the NOD2 receptor is expressed by neurons in various brain regions, especially in an area known as the hypothalamus. The hypothalamus is a key brain structure involved in many vital functions, including appetite regulation, metabolism, sleep, body temperature, stress response, and endocrine system control through hormone production and release—thereby also playing a role in reproduction. The researchers discovered that these neurons cease their electrical activity when exposed to bacterial muropeptides from the gut. These muropeptides are released when bacteria proliferate. Conversely, when the NOD2 receptor is defective, the neurons are no longer inhibited by the muropeptides. As a result, the brain loses control over food intake and body temperature. Consequently, the mice gain weight and become more prone to developing type 2 diabetes, particularly in older females.
What makes this discovery remarkable is that it is the neurons—rather than immune cells—that directly detect the bacterial muropeptides. This suggests that neurons are capable of sensing bacterial growth or death to monitor the impact of food intake on the intestinal ecosystem. It can therefore be assumed that excessive eating or certain types of food may promote the disproportionate expansion of specific bacteria or pathogens, thereby endangering intestinal balance.
This bidirectional communication between the gut microbiota and the hypothalamus is crucial for regulating many physiological functions and may play a role in conditions such as obesity, diabetes, metabolic and neurological disorders, and other diseases related to hypothalamic dysfunction. Understanding this complex interaction may lead to the development of new therapeutic approaches targeting the gut microbiota or the gut-brain axis.
Reference:
Ilana Gabanyi et al. Bacterial sensing via neuronal Nod2 regulates appetite and body temperature. Science 376, eabj3986 (2022). DOI: 10.1126/science.abj3986