Can genetically modified gut bacterial help manage mood disorders

Summary: Gut-brain axis plays a vital role in brain health and preventing mood disorders. The gut produces many neuroactive compounds and even neurotransmitters. One of the most crucial neurotransmitters for emotional health, serotonin, is primarily produced in the gut. Thus, altering the gut production of neuroactive compounds may help manage mood disorders. Researchers are developing genetically modified bacteria that can sense the level of specific compounds and, if needed, increase or reduce their production in the gut. Thus, these genetically modified gut bacteria may help manage mood disorders by sensing and altering the production of neuroactive compounds.

 Science has discovered the truth behind a “gut feeling.” It appears that mood changes cause gastrointestinal distress and thus changes in the gut. 

Although the ability of the brain to alter gut health is well recognized now, what has surprised researchers is the ability of the gut to influence brain function. It is now evident that this relationship is dual-sided and is now called the “gut-brain axis”1,2.

It appears that the gut has a much greater role in mood and brain health than imagined earlier. There are many discoveries that led to this new understanding.

Firstly, it is now known that the gut has a large number of neurons. In addition, the gut has the largest number of neurons outside the brain. Thus, researchers are now calling the gut the second brain.

Secondly, researchers found that the vagal nerve innervating the gut has more ascending fibers than descending fibers. It means that the gut sends much more information to the brain than believed earlier. It is now evident that the role of the vagal nerve is not limited to controlling intestinal function and motility. The vagal nerve also sends signals from the gut to the brain, thus influencing mood.

Thirdly, researchers know that one of the most important neurotransmitters, serotonin, is primarily produced in the gut. It is known that more than 90% of serotonin is made in the gut. Since serotonin plays a central role in emotional responses, the gut has a lot of say in controlling human emotions3.

However, the gut also produces some lesser-known or poorly understood neuropeptides. Thus, having a broader say in the brain’s health. Moreover, it seems that many of the neurotransmitters are produced by microbes residing in the gut, or they play a vital role in their production. Thus, the gut microbiota has an important role in maintaining brain health.

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It means that there must be a way of using these microbes to manage mood disorders and boost brain health. What if we could create microbes that can sense minor changes in the gut and then respond accordingly. For example, sensing serotonin levels and then regulating its production.

Recently, Tae Seok Moon et al. published their findings in the journal Cell Systems. They think that creating such genetically engineered gut microbes is possible. They have also made a proof of concept by creating microbes that can sense certain molecules4.

Till now, the challenge has been in understanding how these microbes sense various chemicals. Thus, it was challenging to create a bacteria that could sense specific molecules, act as biosensors, and also initiate a particular response when the levels of those chemicals change.

In the study, researchers created genetically modified Escherichia coli Nissle 1917 (EcN) with the ability to sense specific chemical compounds. For example, it can differentiate between structurally similar molecules like phenylalanine (Phe) and tyrosine (Tyr). 

Since they found that these sensors work, they now need to produce actuators, that is, developing a mechanism that can carry out some functions after detecting specific molecules.

For example, this may ultimately help them create a bacterium that may produce serotonin if its levels are low in the gut or degrade the targeted chemical if its levels are too high.

Of course, if this technology is mastered, it may have many uses, from monitoring food quality to producing certain chemicals when and as needed. This could play a significant role in reducing human suffering and delivering novel treatments for mood disorders.

References

1. That gut feeling. https://www.apa.org. Accessed February 2, 2022. https://www.apa.org/monitor/2012/09/gut-feeling
2. Carabotti M, Scirocco A, Maselli MA, Severi C. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol. 2015;28(2):203-209.
3. Terry N, Margolis KG. Serotonergic Mechanisms Regulating the GI Tract: Experimental Evidence and Therapeutic Relevance. Handb Exp Pharmacol. 2017;239:319-342. doi:10.1007/164_2016_103
4. Rottinghaus AG, Xi C, Amrofell MB, Yi H, Moon TS. Engineering ligand-specific biosensors for aromatic amino acids and neurochemicals. cels. 2021;0(0). doi:10.1016/j.cels.2021.10.006