Guest column: The communication between the gut and the brain – The gut-brain axis

This is a column by Catharina Lavebratt, who is a lecturer in medical genetics at the Institute for Molecular Medicine and Surgery at the Karolinska Institute. Catharina also leads the research group, Translational Psychiatry, and works at the Centre for Molecular Medicine at Karolinska University Hospital. Catharina’s research is focused on understanding the molecular mechanisms behind psychiatric disorders in order to enable better diagnosis as well as preventive and individualised treatment. At the time of writing, Catharina is leading a clinical study into ADHD and gut flora at the Karolinska Institute. Her co-author is Catharina’s doctoral student, Miranda Stiernborg, M.Sc. in Biotechnology.

We live in a microbiotic world, where we’re constantly surrounded by microbes such as bacteria, viruses and fungi. Our bodies are also home to several billion microbes and 99% of the human body’s genetic code belongs to microbes that have inhabited in our bodies, with the intestines constituting the largest microbial community. In fact, we humans have never existed without having microbes living inside us – for hundreds of thousands of years we’ve been coexisting and we’ve therefore developed a very important partnership with these organisms. If this partnership doesn’t work, or the microbes in our guts are unbalanced, this has an effect on the rest of the body. Because the billions of tiny organisms in our gut affect much more than just their homes, they can affect our bodies in many ways, far beyond the walls of the gut.

What is the gut-brain axis?

Researchers have long been able to see a connection between an upset stomach and conditions that affect the brain, e.g. mental and neurodegenerative diseases [1], but they could not explain this link. Because what do the stomach and the brain really have to do with each other? The stomach and the brain having a direct connection may seem surprising. They’re far apart from each other and have different principal functions. However, the situation in the stomach, and specifically the microbes that live in our intestines, the microbiota, actually affects our brain. How this takes place is explained at present by the gut-brain axis, among other things.

The gut-brain axis is a collective name for the communication pathways between the intestines and the brain. The communication takes place via the nervous system, the blood, and the immune system, among others. The approximately 2kg of microbes in our guts have a bigger effect on this communication than we previously believed, and we know the most about the role of bacteria. However, we’re currently far from having a comprehensive image of their actual effect.

The microbes in the gut having an effect on the brain has been shown, for example, through studies where researchers have created so-called bacteria-free mice and rats. These animals have shown altered behaviours in terms of how active they are, their social interaction, and displaying behaviours similar to anxiety and depression [2]. Furthermore, researchers on several studies of mice and rats have observed that even taking antibiotics, which significantly reduce the number of microbes, causes similar behavioural changes. Effects on behaviour have been observed, especially when the gut microbes have been reduced in young animals [3]. But even though studies suggest a communication between intestinal microbes and the brain in mice and rats, it’s not yet completely clear how this happens. To understand this, we need to go deeper, to a molecular level.

But how does the communication between the gut and the brain actually take place?

The gut-brain axis is, as I said, comprised of the different ways the gut and the brain communicate, some modes of communication are more direct than others. The vagus nerve, which is one of 10 nerves whose roots are located in the brain, is the fastest and most direct link between the intestine and the brain. The fibres of the vagus nerve extend into the intestinal wall where they can be reached by molecules from the microbes, among others. These molecules, such as serotonin, dopamine, glutamate and GABA, can affect the signals that travel to the brain through the fibres of the vagus nerve and thus have an effect on the nerve cells in the brain. For example, researchers added a bacterial strain to the guts of the mice and observed increased communication between the nerve cells in certain parts of the brain, as well as the mice being more resistant to stress and showing fewer depressive behaviours. But when the mice had their vagus nerve cut, these traits were no longer seen[4].

The gut-brain axis also features indirect communication, which mostly happens via waste products from the microbes. Like us humans, many of the microbes in our guts have a metabolism. Different microbes produce different kinds of small molecules from the broken-down food in our intestines. These small molecules can be transported through as well as communicating with the cells of the intestinal wall, which means that these molecules can reach or initiate reactions that affect the body. One fairly thoroughly studied waste product of the bacteria in our gut is short-chain fatty acids (SCFAs), whose primary source is the bacteria that break down fibre in the gut. These fatty acids can be transported through the intestinal wall and found in small amounts in the blood and spinal fluid. SCFA’s affect a lot of processes such as the intestinal wall’s impermeability, stimulation of the vagus nerve, and the processes of the immune system.

The neuroendocrine system is the interplay between hormones and the nervous system, where the HPA axis is the part of the neuroendocrine system that takes care of the body’s stress signals after psychological and physical stressors. The microbiota and the HPA axis appear to have two-way communication, in which an activated HPA axis, i.e. increased stress, for example, appears to be capable of causing increased permeability of the intestinal wall and microbe-driven inflammation [5, 6].

What does the gut-brain axis mean for the human body?

You now know what the gut-brain axis is and how the intestinal flora communicate with the brain, but what does this really mean? As you may have noticed, a lot of the studies presented in this piece are about animal tests. These studies may demonstrate molecular mechanisms, underlying communications and relationships in controlled environments, but say less about how this relates to humans. Mice, rats and humans are so different that it’s not possible to draw conclusions about the human gut-brain axis based solely on mouse/rat studies. These studies could instead be the basis for questions and hypotheses to be later tested in studies on humans.

So how much does the microbiota affect our behaviour? A lot of the studies on the possible effects of intestinal microbes on mental health or neurodegeneration in humans have been quite small-scale, i.e. based on measurements from just a few people. But even small-scale studies can reveal possible connections [5]. Studies have shown that when transferring faeces from patients with depression, for example, to the intestines of mice/rats, these animals develop behaviours and chemical blood markers that are observed in people with depression. In the same way, symptoms of schizophrenia and autism could be created by giving mice/rats faeces from these patients. This suggests that the microbes can cause core symptoms similar to those from depression, autism, and schizophrenia [7-9]. In line with this, several studies have found differences in the intestinal bacteria between healthy individuals and individuals with depression, autism, schizophrenia, bipolar disorder and Parkinson’s disease, for example [5].

So far, we’ve only scratched the surface regarding the role of microbes in the gut-brain axis. In the last decade, research on gut microbes has exploded, and as mentioned, a lot of animal tests and small-scale human studies have been done which show surprising connections. However, the findings from the different studies are not always consistent and many aspects are unclear such as differences between animal species, covariance versus causality, gender differences, impact on our diet, genetic makeup of microbes colonising the gut, and above all that the mechanisms are largely unknown. But the more studies that are done, the more we’ll be able to unravel the ambiguities and understand our complex partnership with the microbes that control communication between the gut and the brain, which may give us new methods for diagnosing and treating diseases.

Authors:

Catharina Lavebratt and Miranda Stiernborg

Referenser

1. Cryan, J.F., et al., The gut microbiome in neurological disorders. Lancet Neurol, 2019.
2. Sherwin, E., et al., Microbiota and the social brain. Science, 2019. 366(6465): p. eaar2016.
3. Codagnone, M.G., et al., Programming Bugs: Microbiota and the Developmental Origins of Brain Health and Disease. Biol Psychiatry, 2019. 85(2): p. 150-163.
4. Bonaz, B., T. Bazin, and S. Pellissier, The Vagus Nerve at the Interface of the Microbiota-Gut-Brain Axis. Frontiers in Neuroscience, 2018. 12(49).
5. Cryan, J.F., et al., The Microbiota-Gut-Brain Axis. Physiol Rev, 2019. 99(4): p. 1877-2013.
6. Farzi, A., E.E. Frohlich, and P. Holzer, Gut Microbiota and the Neuroendocrine System. Neurotherapeutics, 2018. 15(1): p. 5-22.
7. Kelly, J.R., et al., Transferring the blues: Depression-associated gut microbiota induces neurobehavioural changes in the rat. J Psychiatr Res, 2016. 82: p. 109-18.
8. Zheng, P., et al., The gut microbiome from patients with schizophrenia modulates the glutamate-glutamine-GABA cycle and schizophrenia-relevant behaviors in mice. Sci Adv, 2019. 5(2): p. eaau8317.
9. Sharon, G., et al., Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice. Cell, 2019. 177(6): p. 1600-1618.e17.