Study: When the brain feels the bugs. Image Credit: Inkoly / Shutterstock.com

Gut microbiome acts on the brain to control appetite

The brain is the central information center and constantly monitors the condition of every organ in a body. Previous research has shown that the brain also receives signals from the gut microbiota.

in a new one Immunity journal study, researchers discuss Gabanyi .’s work et al. (2022), published in a recent issue of Scienceshowing 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 the insects. Image Credit: Inkoly/Shutterstock.com

The brain and gut microbiome

Previous research indicates that structural components of gut bacteria can trigger pro-inflammatory responses in the body and thereby have an indirect effect on the brain. This phenomenon occurs through peripheral neurons or molecules released by immune cells after exposure to bacterial cells circulating in the blood.

In the 2022 Science study, Gabanyi and colleagues discuss microbiome-brain communication. Herein, the researchers report that some neurons in the brain can directly identify bacterial cell wall components and subsequently initiate altered feeding behavior and temperature regulation.

The hypothalamus is an area of ​​the brain that connects the central nervous system (CNS) to the endocrine system through the pituitary gland. In addition, the hypothalamus regulates various functions such as thirst, hunger, reproduction, sleep, body temperature and circadian rhythms by inhibiting or stimulating neurons. To date, there has been a limited amount of research into how the hypothalamus recognizes the state of the gastrointestinal tract and perceives the microbes it harbors.

Commensal microorganisms are typically recognized by pattern recognition receptors (PRRs) of the innate immune system. For example, NOD2 has been implicated in the identification of muramyl dipeptide (MDP), a peptidoglycan fragment of the bacterial cell wall.

Previous studies have highlighted NOD2’s functions beyond those associated with innate immunity. However, the mechanisms responsible for the link between bacterial peptidoglycans and neuronal functions of the brain remain largely unknown.

What happens when microbial components reach the brain?

Gabanyi and her team addressed this research gap by studying the NOD2-GFP reporter gene in mice, which helped them investigate the function of NOD2 in different parts of the CNS. Although microglia and endothelial cells were found to express NOD2 in all parts of the brain, NOD2 expression in neurons occurred only in specific regions, such as the striatum, thalamus and hypothalamus.

The researchers also saw that muropeptides could cross the gut barrier and reach the systemic circulatory system in mice. These peptides were later detected in the brain tissues of all mice. Notably, the extent of their expression was greater in female mice compared to males.

The researchers also generated a new mouse model that lacked NOD2 in inhibitory GABAergic neurons (VgatDNod2 mice) and excitatory neurons expressing calcium/calmodulin-dependent protein kinase II (CamKIIDNod2 mice). Older female VgatDNod2 mice gained weight, had altered body temperature and fed more. These phenotypic events were mediated by MDP, as mice treated with MDP showed a reduction in food intake compared to mice given an MDP isomer treatment, which cannot activate NOD2.

The scientists also identified the 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 both male and female mice of different age groups and treated them with MDP or the control isomer. The arcuate nucleus of the hypothalamus showed reduced Fos expression in older female mice compared to males.

Studies have shown that within the arcuate nucleus, the GABAergic population is responsible for food intake, which is formed by AgRP+ NPY+ neurons. These genes are active during fasting and are silenced when exposed to food.

Interestingly, Gabanyi et al. observed that these neurons express NOD2 and that exposure to MDP suppresses their activity. Reduced activity of GABAergic arcuate nucleus neurons was also noted 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 target NOD2+ GABAergic neurons locally. Altered phenotypes, such as differential food intake and weight gain in both groups of mice, including one group treated with MDP and the other with control, returned to normal after treatment with broad-spectrum antibiotics.

This finding implies that there was a decrease in the gut microbiome after antibiotic treatment. This resulted in a reduction in the number of circulating muropeptides which subsequently altered neuronal perception through its activity on NOD2.

conclusions

In this study, Gabanyi and her research team highlight the possibility that bacterial components may directly regulate individuals’ appetites. These findings have presented the potential of PRR biology in the brain that could be exploited to combat the increasing global problem of obesity.

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