April 26, 2022
Written by: Vanessa B. Sanchez
The human gut microbiota is home to over trillions (~ 1014) of different types of bacteria, and every time you eat, you expand how dynamic this population can get1. Your brain relies on this diverse microbiome to properly function, as the absence of a healthy microbiome has been shown to lead to changes in brain chemistry, function, and behavior2. To read more about the intimate relationship between your gut and the brain (“gut-brain axis”) check out this PNK article!
The bacterial composition of your gut is constantly changing when you eat, and so are the different by-products of these bacteria. Some of these by-products include the building blocks of bacteria cell walls, called muropeptides. Every time bacteria reproduce, grow, or die, muropeptides shed off. In the gut, muropeptides are recognized by cellular receptors like Nod2,3,4. Interestingly, Nod2 is involved with many digestive disorders (e.g., Crohn’s disease), psychiatric disorders (e.g., bipolar disorder and Schizophrenia), and neurodegenerative diseases (e.g., Alzheimer’s disease and Parkinson’s disease), suggesting that the same receptors that recognize muropeptides in the gut also play a role in these disorders3. Meanwhile, muropeptides have been detected in mouse brains and influence the brain activity and function of female flies5. Because of the link between Nod2 and brain disorders, and muropeptides’ ability to influence brain activity, a team of scientists asked: can neurons detect muropeptides?
While it was known that Nod2 is found in immune cells and plays a role in the immune system, researchers wanted to determine where Nod2 is found in the brain of mice. Using a combination of mouse genetics and imaging techniques, they found Nod2 to be abundant in neurons of a specific brain region that is implicated in feeding behavior and body temperature regulation called the hypothalamus3. Because muropeptides are found in the gut, scientists wanted to see if muropeptides are also found in the brains of mice. To do so, mice were given an oral dose of muropeptides that had a radioactive tag. In this way, scientists were able to visualize where these muropeptides ended up in the brain using imaging techniques that could detect the radioactive tags. Here, they confirmed that muropeptides are detected in the brains of mice. To see if there are any differences between age (younger vs older) and sex (male vs female), scientists took a closer look and found that muropeptides are more abundant in older female mice brains. These findings coincide with previous work, such that muropeptides have been detected and can influence the brain neuronal activity of female flies3,5.
To look for a connection between muropeptides and brain activity in mice, scientists used tiny electrodes to record the activity of hypothalamic neurons (remember: these neurons express Nod2, which recognizes muropeptides). Upon closer examination, scientists found that activity of inhibitory (“turn off”) neurons decreased when mice were given muropeptides3. What these findings suggests is that inhibitory neurons can sense how much you eat based on how much muropeptides there are (i.e., the more you eat, the more muropeptides there will be). By detecting these muropeptides, hypothalamic inhibitory neurons will decrease their activity or turn off, which in turn makes you feel full3!
Because the hypothalamus is important for behaviors such as feeding and temperature regulation, scientists wanted to better understand how do muropeptides influence hypothalamic neurons in mice? To do so, they gave an oral dose of muropeptides and closely monitored hypothalamus-dependent behaviors. Here, it was found that only older female mice in comparison to younger female or male mice were affected by this dose, such that they rarely if ever built their nests, which is a behavioral trait that is associated with body temperature regulation and heat conservation3-4. These findings suggests that muropeptides can influence hypothalamic inhibitory neurons, which leads to changes in appetite (excessive eating resulting in gaining weight) and body temperature control (failure to build nests). Scientists speculate that one reason why females are particularly affected my muropeptides is because their appetites constantly change to reflect their sexual maturity or pregnancy status3.
Is there a way to reverse this effect? YES. By using a broad spectrum of antibiotics, you can reduce the amount bacteria in the gut, and thereby reduce the amount of muropeptides in mice. When older female mice were given an oral dose of muropeptides and later antibiotics, they did not eat as much, gain weight, and were back to building their nests.
In summary, scientists found that muropeptides 1-are abundant in the hypothalamus, 2-can inhibit hypothalamic inhibitory neurons, 3-influence eating and temperature regulation behavior, and 4-that antibiotics can reverse these effects by depleting muropeptides, which can allow inhibitory neurons to do their job and regulate such behaviors. Want to see a neat schematic created by the scientists from this study? Check it out here! Moreover, this new study can inform the way we think about what and how we eat since it clearly influences our downstream behaviors and metabolism! More importantly, this study informs the way physicians can develop and prescribe more targeted treatments for patients with specific metabolic or neurological disorders, ultimately, changing and contributing to the ever-evolving field of the gut-brain axis.
- Thursby, E., & Juge, N. (2017). Introduction to the human gut microbiota. Biochemical Journal, 474(11), 1823-1836.
- Cryan, J. F., & Dinan, T. G. (2012). Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nature reviews neuroscience, 13(10), 701-712.
- Gabanyi, I., Lepousez, G., Wheeler, R., Vieites-Prado, A., Nissant, A., Wagner, S., … & Lledo, P. M. (2022). Bacterial sensing via neuronal Nod2 regulates appetite and body temperature. Science, 376(6590), eabj3986.
- Institut Pasteur. (2022, April 15). Decoding a direct dialog between the gut microbiota and the brain. ScienceDaily. Retrieved April 18, 2022 from www.sciencedaily.com/releases/2022/04/220415100551.htm
- Masuzzo, A., Manière, G., Viallat-Lieutaud, A., Avazeri, E., Zugasti, O., Grosjean, Y., … & Royet, J. (2019). Peptidoglycan-dependent NF-κB activation in a small subset of brain octopaminergic neurons controls female oviposition. Elife, 8, e50559.