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The Gut–Brain Axis May Not Operate as Previously Thought

An illustration of interactions between the gut and the brain.
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New information on how the gut and brain communicate has been uncovered by Flinders University researchers in a development that could influence how we make and use certain drugs, such as antidepressants.

The study is published in Cell and Tissue Research.

Understanding signaling between the brain and gut

The gut–brain axis is a complex neural pathway that sends signals to aid communication between the brain and the gut. The vagal sensory nerves are a major part of this communication system, sending signals from the gut to the brain to promote health and well-being.

The majority of the body’s serotonin – the “feel-good hormone” – is produced in the gut by specialized hormone-secreting cells called enteroendocrine cells (EECs). Serotonin is a hugely important neurotransmitter that sends signals between neurons and plays a key role in many bodily functions.

However, despite the importance of the gut–brain axis, how serotonin activates these sensory vagal nerve endings in the gut wall has been a mystery.

“It had once been proposed that EECs make physical synaptic connections with the sensory nerve endings of the vagus and use fast neurotransmitters to activate vagal sensory endings,” said Professor Nick Spencer, senior author of the study and a Matthew Flinders Professor in the College of Medicine and Human Health.

“However, the results of our new research uncover that any substances (including serotonin) released from EEC cells must communicate via a process of diffusion to the sensory nerve endings of the vagus nerve, that lie in the colon (large intestine).”

No close contacts

The researchers investigated communication between EECs and vagal nerve endings in mouse models using a method called anterograde neuronal tracing. This revealed that the serotonin-producing EECs and vagal efferent nerve endings were spaced too far apart in the mouse gut to communicate via synaptic transmission.

What is synaptic transmission?

Synaptic transmission is the process by which neurotransmitters are used to communicate with a target cell or cells. This involves the neurotransmitter molecules crossing a very short distance to their target cell(s) via synapses.

“The mean distances between vagal nerve endings and the nearest serotonin-containing EECs were hundreds of times greater than known distances that underlie synaptic transmission in vertebrates. This rules out any possible mechanism of fast synaptic transmission,” said Spencer.

Instead, the findings suggest that substances produced from EECs – like serotonin – must reach the colon’s vagal sensory nerve endings by diffusion. This is the net movement of molecules over any distance from one region to another.

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“This is a major discovery for our understanding of gut–brain communication which has profound implications for drug developments, treatments of anxiety and depression and other digestive problems such as irritable bowel symptoms (IBS), all of which involve serotonin in some way,” Spencer explained.

This could change the way we think about the gut–brain axis and influence future drug development. This includes selective serotonin reuptake inhibitors (SSRIs) – a common type of antidepressant – as around 95% of serotonin is produced in the gut. This therefore represents a great opportunity to study how serotonin from EECs acts on vagal sensory nerve endings in the gut wall.

“Our understanding of how the gut communicates with the brain, via sensory nerves has been substantially improved based on the findings of this study, and we look forward to exploring this topic further,” Spencer added.

Reference: Spencer NJ, Kyloh MA, Travis L, Hibberd TJ. Identification of vagal afferent nerve endings in the mouse colon and their spatial relationship with enterochromaffin cells. Cell Tissue Res. 2024. doi: 10.1007/s00441-024-03879-6

This article is a rework of a press release issued by Flinders University. Material has been edited for length and content.