The brain is the central information center and constantly monitors the state of every organ present in a body. Previous research has shown that the brain also receives signals from the gut microbiota.
in a new Immunity journal study, researchers discuss Gabanyi’s work et al. (2022), published in a recent issue of Sciencewhich reveals that hypothalamic gamma-aminobutyric acid (GABAergic) neurons recognize microbial muropeptides via the cytosolic receptor NOD2, which regulates food intake and body temperature.
Study: When the brain senses insects. Image Credit: Inkoly/Shutterstock.com
The brain and the gut microbiota
Previous research indicates that structural components of gut bacteria can trigger pro-inflammatory responses in the body and therefore have an indirect effect on the brain. This phenomenon occurs through peripheral neurons or molecules that are released by immune cells after exposure to bacterial cells circulating in the blood.
In 2022 Science study, Gabanyi and colleagues discuss microbiome-brain communication. Here, the researchers report that certain neurons in the brain can directly identify components of the bacterial cell wall and subsequently initiate altered feeding behavior and temperature regulation.
The hypothalamus is a region of the brain that connects the central nervous system (CNS) to the endocrine system through the pituitary gland. Additionally, the hypothalamus regulates various functions such as thirst, hunger, reproduction, sleep, body temperature, and circadian rhythms by inhibiting or stimulating neurons. To date, there is little research on how the hypothalamus recognizes the state of the gastrointestinal lumen and senses the microbes it harbors.
Commensal microorganisms are generally recognized by pattern recognition receptors (PRRs) of the innate immune system. For example, NOD2 is involved in the identification of muramyl dipeptide (MDP), which is a peptidoglycan fragment of the bacterial cell wall.
Previous studies have highlighted functions of NOD2 beyond those related to innate immunity. However, the mechanisms responsible for the connection between bacterial peptidoglycans and neuronal functions in the brain remain largely unknown.
What happens when microbial compounds reach the brain?
Gabanyi and his team filled this research gap by studying the NOD2-GFP reporter gene in mice, which helped them to study the function of NOD2 in different parts of the CNS. Although microglia and endothelial cells were found to express NOD2 in all areas of the brain, NOD2 expression in neurons only occurred in specific regions, such as the striatum, thalamus, and hypothalamus. .
The researchers also observed that the muropeptides were able to cross the intestinal barrier and reach the systemic circulation system in mice. These peptides were then detected in the brain tissues of all the mice. Notably, the extent of their expression was higher in female mice than in males.
The researchers also generated a novel mouse model lacking NOD2 in inhibitory GABAergic neurons (VgatDNod2 mice) and excitatory neurons expressing calcium/calmodulin-dependent protein kinase II (CamKIIDNod2 mice). Aged female VgatDNod2 mice gained weight, had altered body temperature and increased diet. These phenotypic events were caused by MDP, as mice treated with MDP showed reduced food intake compared to mice that received treatment with MDP isomers, which cannot activate NOD2.
Scientists have also identified brain regions affected by MDP. In this context, they mapped the expression of the neuronal activity marker Fos in different areas of the brain in male and female mice of different age groups and treated them with MDP or the control isomer. The arcuate nucleus of the hypothalamus exhibited reduced expression of Fos in aged female mice compared to males.
Studies have shown that within the arcuate nucleus, the GABAergic population is responsible for food intake, which consists of AgRP+ NPY+ neurons. These genes are active during fasting and are silenced upon exposure to food.
Interestingly, Gabanyi et al. observed that these neurons express NOD2 and that exposure to MDP suppresses their activity. A decrease in the activity of GABAergic neurons of the arcuate nucleus was also identified in both mice.
How does NOD2 expression regulate food intake?
The researchers also infected NOD2fl/fl mice with a Cre-expressing virus in their hypothalamus to locally target GABAergic NOD2+ neurons. Altered phenotypes, such as differential food intake and weight gain in both groups of mice, which included one group treated with MDP and the other with control, returned to normal when treated with antibiotics broad spectrum.
This finding implies that a decrease in the gut microbiome occurred after antibiotic treatment. This resulted in a reduction in the number of circulating muropeptides which then impaired neuronal sensing by its activity on NOD2.
In this study, Gabanyi and his research team highlight the possibility that bacterial components can directly regulate the appetite of individuals. These findings presented the potential of PRR biology in the brain, which could be harnessed to combat the growing global problem of obesity.
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