The latest discovery of Science: the brain can talk directly with intestinal bacteria!

In our body, more than half of the cells are not human cells, but symbiotic microorganisms. Among them, the intestinal tract becomes the most important gathering place for microorganisms. Trillions of microbial communities dominated by bacteria have shaped our health here, and the imbalance of microbial communities has been proved to be closely related to a variety of diseases - from intestinal diseases to metabolic diseases such as diabetes and obesity, and even nervous system diseases. The key link between microorganisms and many diseases is the brain gut axis.

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More and more evidence shows that the host and intestinal microorganisms are interdependent, and the brain gut axis connecting the central nervous system and the gastrointestinal tract plays an important role in it. The compounds released by the microbial community regulate the host's immune response, metabolism, brain function and other physiological functions through the brain gut axis with the blood circulation. However, it is still unknown whether the brain neurons can directly sense the components of bacteria and whether bacteria can regulate physiological processes by regulating neurons.
In the latest issue of science, scientists from the Pasteur Institute in France and other institutions have revealed the mysterious connection between the brain and intestinal bacteria. They found in the mouse model that hypothalamic neurons can directly detect the changes of intestinal bacterial activity and regulate physiological processes such as appetite and body temperature according to their changes. This discovery proves that there is direct communication between intestinal microorganisms and brain neurons, which may provide new treatment ideas for metabolic disorders such as diabetes and obesity.

The research team focused on the nucleotide oligomerization domain 2 (NOD2) receptor. This pattern recognition receptor exists in most immune cells and can help the immune system recognize the fragment of bacterial cell wall, cell wall peptide. Previous studies have found that mutations in the gene encoding NOD2 receptor are related to metabolic diseases such as Crohn's disease, as well as nervous system diseases and emotional disorders. However, these studies are insufficient to prove that there is a direct relationship between neuronal activity in the brain and bacterial activity in the gut.
In the latest paper, the research team used brain imaging technology to observe that neurons in different regions of the mouse brain (especially the hypothalamus) express NOD2 receptors. Further experiments showed that when contacting with the cell wall peptide of intestinal bacteria, the electrical activity of neurons was inhibited.
And when NOD2 is inhibited in the hypothalamus γ- When GABA neurons are specifically knocked out, these neurons are no longer inhibited by cell wall peptides. At this time, the brain loses its control over food intake and body temperature. As a result, mice (especially older females) gained weight and were more likely to develop type 2 diabetes.

▲ schematic diagram of mouse experiment of this study (picture source: reference [1])
Thus, this study proved that neurons can directly sense bacterial cell wall peptides. Previously, it was thought that this process requires the participation of immune cells. Dr. Pierre Marie LLEDO of Pasteur Institute, the corresponding author of the paper, said: "as the brain center, the hypothalamus is responsible for regulating key processes such as body temperature, fertility, hunger and thirst, and we found that bacterial cell wall peptides can directly act on the hypothalamus, which is a surprising discovery."
This study shows that neurons can detect the activities of bacteria, such as reproduction and death, so as to directly judge the impact of food intake on intestinal balance. Excessive intake of certain foods may stimulate the disproportionate growth of certain bacteria or pathogens, thus endangering the balance of the intestinal microbiome.

▲ hypothalamic NOD2 is involved in the regulation of body weight and body temperature (picture source: reference [1])
The effect of cell wall peptide on hypothalamic neurons and metabolism has also attracted people's attention to its potential impact on other brain functions, and is expected to help us understand the relationship between specific brain diseases and NOD2 gene mutations. This discovery also points out the direction for other interdisciplinary research in neuroscience, immunology and microbiology. Based on this breakthrough, we can expect that more brain diseases and metabolic disorders may usher in new therapies.
Reference material:
[1] Ilana Gabanyi et al., Bacterial sensing via neuronal Nod2 regulates appetite and body temperature. Science (2022) DOI: 10.1126/science. abj3986
[2] Decoding a direct dialog between the gut microbiota and the brain. Retrieved Apr. 15, 2022 from https://medicalxpress.com/news/2022-04-decoding-dialog-gut-microbiota-brain.html
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