The gut-brain pathway has been the center of many studies in the past few years, but the mechanisms driving this interaction are still poorly understood. In our work we reveal how parts of a bacterium’s cell wall are able to reach the brain and decrease the activity of certain neurons controlling appetite.
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published on Jan 30, 2023
Our gut microbial community is not as stable as one might think. Our diet has a big impact on the type and amount of bacteria we have in our gut. Every time we eat, we are not only satisfying our nutritional needs, but we are also feeding our intestinal bacteria. This works both ways though—the gut microbiota also releases a wide range of bacterial products back into our gut.
In this work we wanted to understand if and how the gut bacteria could influence our day-to-day life.
Some of the products released by our gut bacteria are able to cross the intestinal barrier and reach distant organs. One type of these bacterial-derived products are the muropeptides, which are small fragments of a bacterium’s cell wall that is released every time it grows, divides or dies.
We first wanted to see whether or not brain neurons could sense and respond to these muropeptides. Therefore, we first set out to answer two questions: 1) Do the neurons express the receptor for muropeptides? And 2), are the muropeptides capable of traveling from the gut to the brain?
One of the receptors capable of sensing and triggering a response to a muropeptide is the Nod2 receptor. We used mice that expressed a fluorescent protein where it had a Nod2 receptor, and then checked for the fluorescence. We saw that brain neurons of different types and from many different regions expressed the Nod2 receptor.
After showing that the neurons had the machinery to detect and respond to muropeptides, we evaluated whether there were any muropeptides from the gut present in the brain. We added bacteria with radioactive markers to the guts of the mice, and then we looked for these markers in the brain. When we saw these markers there, we could then demonstrate that the muropeptides were able to move from the intestine to the brain.
Together, these results strongly indicated that the neurons in the brain can sense and respond to bacterial products from the gut. But what do these detectors and muropeptides actually do?
To investigate, we generated mice that lacked the Nod2 receptor in a specific type of neurons, the inhibitory neurons, and observed these mice until they were 12 months old. To our surprise we noted that female mice (and only females, not males) would eat more and gain more weight than control mice, starting at around 6 months old.
This was a strong indication that the neuronal Nod2 was involved in appetite control. It is known that one of the main brain regions that control our feeding behavior is the region of the hypothalamus called the Arcuate nucleus (ARC). Activation and inhibition of the neurons present in that area play a prominent role in responding to the nutrients (or lack thereof) circulating in our body to regulate our appetite. Knowing that, we went on and analyzed the role of the inhibitory neurons in the ARC.
We used a fluorescent protein called GcamP to look at neuronal activity in real time, and could see changes in the activity of the ARC when a hungry mouse received food. We understand that these changes are a signal for the mouse that it is full, and to stop eating. We also found a similar “fullness signal” when our control mice were fed muropeptides. However, the mice that had the Nod2 receptors removed seemed to lack the fullness signal and kept on eating. This further suggested that the muropeptides really did help control hunger.
Finally, we treated mice with antibiotics to deplete its gut microbiota. We saw that, without the gut bacteria, mice with or without the neuronal Nod2 receptor would have the same weight and eat the same amount as each other. When we removed the antiobiotics and the gut microbiota could recover, the weight and appetite differences were detected again.
This work revealed that our gut microbiota is involved in the regulation of appetite, but intriguingly only in female mice after a certain age. Future work should reveal why such a sex and age specificity exists in this gut-brain pathway.
Gabanyi, I., Lepousez, G., Wheeler, R., Vieites-Prado, A., Nissant, A., Wagner, S., Moigneu, C., Dulauroy, S., Hicham, S., Polomack, B., Verny, F., Rosenstiel, P., Renier, N., Boneca, I. G., Eberl, G., & Lledo, P.-M. (2022). Bacterial sensing via neuronal Nod2 regulates appetite and body temperature. Science, 376(6590). https://doi.org/10.1126/science.abj3986