The Brain-Gut-Microbiome Axis
How researchers now have more than just a ‘gut feeling’
Biology is like a ball of string; as researchers unravel one aspect of the vast bundle that constitutes their field of work, they reach another tangle. To cope with this complexity – and as scientific understanding advances – scientists and physicians have become increasingly specialized within particular areas of research, which have themselves grown incredibly sophisticated. The result has been a huge leap forward in the ability of researchers to study specific aspects of biology, and of physicians to treat specialized conditions as never before. These scientific advances are influencing all areas of research and healthcare, from neuroscience and immunology, to endocrinology and gastroenterology.
Perhaps predictably, and fuelled by advances in ‘big data’ and genomic technologies, recent discoveries have reiterated that specialized areas of biology are, in fact, interconnected – they are knots made on the same ball of string. To build upon advances in individual fields of research, scientists and physicians must now adapt and learn to understand the ways in which their fields interact. One such area of study is the relationship between the brain and the gastrointestinal tract, and the communication that takes place between the two through the brain-gut axis.
The Brain and the Gut Do Not Exist in Isolation
Many aspects of the brain and the central nervous system are unique. The complex organization of neurons within our brains account for our very consciousness, our ability to perceive the world around us, to learn, and to form relationships.1 The brain also enjoys a level of physical isolation from the rest of the body; a barrier separates the brain from circulating blood, providing protection for its delicate neurons.2 External pathogens such as bacteria, and even the body’s immune response against such pathogens, have limited access to the brain through this barrier. For many years, scientists had considered the brain to be completely isolated from the body’s immune response – a view that is now changing. In reality, and in spite of its unique nature, the brain and the central nervous system serve many functions that require close communication with the rest of the body: from the conscious contraction of our muscles, to the unconscious beating of our hearts, and the regulation of our temperature.3,4 One particular line of communication from the brain that researchers have been focusing on in recent years is that with the gut.
The gut contains neuronal connections with the brain and the central nervous system throughout its length, with perhaps the most interesting region of interaction being at the intestinal tract.5 The intestines have their own specialized functions, including the absorption of nutrients from digested material within the small intestine, and extraction of water in the large intestine. From the point of view of the nervous system, many intestinal functions are controlled by the enteric nervous system – a collection of neurons that is able to function separately, at least to an extent, from the brain and the central nervous system, and so is sometimes referred to as the body’s ‘second brain’.5,6 The very existence of an enteric nervous system, as well as the connections that exist with the brain, exemplify how gastroenterology and neuroscience cannot be considered truly distinct areas of study.
Microbiome: The human microbiome is a community of trillions of microbes – different species of bacteria, archaea, fungi, viruses, and protists – living in and on various areas of the body.
The Microbiome Resides Largely Within the Colon
Interest in the interactions that take place between the gut and the brain has grown with the discovery of the important role that intestinal communities of microbes play in human health. A healthy human gastrointestinal tract contains over 1 kg of microorganisms, corresponding to more than 100 trillion in number – the most studied of which are bacteria.7,8 To put this number in perspective, our guts contain significantly more bacteria (which are extremely small), than our bodies contain human cells. The vast majority of these microorganisms are present in the large intestine, and together constitute what is known as the human microbiome.8 While the microbiome is flexible, changing with age and in response to factors such as diet, it can also be considered stable, in that healthy communities of different bacterial species become established – co-existing, and supporting both each other and their human host. In this way, the microbiome is dominated by ‘friendly’ species of bacteria which include Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria.9
The presence of a healthy, balanced microbiome is not just important to our development, but also in the prevention of infection by pathogenic bacteria. By forming stable communities of healthy bacteria within a well-balanced microbiome, pathogenic bacteria have a much harder time becoming established within the gut, so the very presence of intestinal microbiota improves resistance of the gastrointestinal tract to harmful infection.10 Interestingly, a much-publicized treatment to some harmful gastrointestinal infections involves ingesting a sample of microbiota from a healthy donor in order to effectively displace pathogenic bacteria with a healthy microbiome. Such treatment is known as a fecal transplant, although it has gained much publicity as a so-called ‘poop pill’.11
Multiple Paths, Multiple Directions
While the brain is largely isolated from microorganisms, the intestinal tract is the opposite. This has led researchers to develop their understanding of the interactions of the brain and the gut to incorporate the microbiota and establish the concept of the brain-gut-microbiome axis. As a result, a new appreciation of the interconnectivity of the microbiome and the brain has developed among researchers, with effects of the microbiome seen upon the brain and, conversely, effects of the brain and its activity seen upon the microbiome. This interconnectivity is achieved through multiple paths of communication.
Nervous Connections
Nervous connections allow our bodies to communicate information rapidly over long distances in the form of electrical impulses – acting like a form of biological broadband. The vagus nerve consists of two bundles of neurons that run on either side of the body, from the base of the brain to the abdomen; connections with the vagus nerve are made all over the body, including to the intestinal tract.12 Stimulation of the vagus nerve can be achieved efficiently by signals derived from specialized cells of the gut, but scientists now know that this communication can also be triggered by signals from the bacteria of the microbiome.8 Neurons of the brain use chemicals called neurotransmitters to communicate with each other, and these are affected by stimulation of the vagus nerve at the intestinal tract, and by the intestinal microbiota.13-15 This means that bacteria of the microbiome are able to indirectly contribute to neuronal function within the brain.
Communication also occurs through the vagus nerve in the direction of the brain to the gut. Stimulation of the vagus nerve in this direction increases the integrity of the intestinal tract by encouraging cells which form the lining of the intestine to adhere to each other more tightly.16 As the intestinal tract plays host to the bacteria of the microbiome, and any microorganisms that may be ingested with our food, intestinal integrity is important to avoid infections that may occur by breaching the intestinal wall.
The Circulatory System
As well as rapid neuronal connections, the brain-gut-microbiome axis also involves less direct methods of communication through the circulation of molecules in the blood. If neuronal communication can be described as biological broadband, communication via this circulatory system is perhaps more akin to a message in a bottle – but is by no means less important.
Hormones are molecules that specialize in using the circulatory system to communicate over long distances and are a major component of brain-gut-microbiome communication. A prime example of this is the regulation of stress hormones in the blood. Adrenocorticotropic hormone and corticosterone are mouse stress hormones which are partly regulated by a region of the brain called the hypothalamus, however, after a short period of stress, these hormones can become elevated in mice that lack a microbiome.17 This elevated stress response can be brought back to normal by introducing these mice to even a single species of bacteria at an early age, which suggests that the gut microbiome not only affects the bodily response to stress, but also the very development of the hormonal stress response and its coordination within the brain. In developed mice, the introduction of stress has also been shown to work in the other direction, with just a short period of stress able to cause a measurable difference in the composition of bacteria within the microbiome.18,19
Bacteria of the microbiome, just like the cells of our own bodies, break down and build up molecules to survive, with many of these molecules sourced from the food that we eat. This process is known as metabolism, and many of the resulting metabolites proceed to circulate within the blood, where, like hormones, they can act as a method of long-distance communication.20 Short-chain fatty acids are metabolites that intestinal bacteria can produce from dietary fibre, and are particularly interesting in brain-gut-microbiome communication as they may circulate in the blood or activate the vagus nerve directly.13,21,22 Mice that lack a microbiome also have raised levels of an amino acid called tryptophan in their blood. In the context of the nervous system, tryptophan is a vital ingredient for the production of the important neurotransmitter, serotonin. By restricting the availability of tryptophan in the blood, intestinal microbiota can therefore affect neurotransmitter production and neuronal function in the brain.23
The Immune System
For the gut to host a healthy microbiome without an inappropriate or potentially damaging immune response, the intestinal tract has developed a specialized immunological environment.24 The vagus nerve makes a contribution to this anti-inflammatory environment by promoting intestinal integrity, but also by actively dampening the activation of immune cells at the gut.25 This anti-inflammatory effect of the vagus nerve is regulated, in part, by the aforementioned hormonal stress response that is coordinated at the hypothalamus of the brain, and that is also affected by the microbiota.17,25 While it is important that the immune system at the intestinal tract remains active enough to respond appropriately to an infection, the importance of appropriate regulation of this response is best demonstrated by what happens when regulation goes wrong, such as in inflammatory bowel disease (IBD).
The effects of inflammation are not restricted to the gut, as immune cells and their inflammatory signals are highly adapted to circulating within the blood in order to bring about whole-body responses to infection. Researchers also know that excessive inflammation can have a particularly detrimental effect upon the delicate neurons of the brain. Even this relatively new area of study of neuroinflammation cannot be considered in isolation, as the microbiome plays an important role in ‘training’ the general immune response, but also in the development of specialized immune cells known as microglia that are found exclusively within the brain.24,26
Role of the Gut and Microbiome Axis in Neurological Disease
As bacteria of the microbiome are in such close contact with the intestinal tract, it is unsurprising that changes in the microbiome are found in individuals with inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis, as well as the functional bowel disorder, irritable bowel syndrome (IBS).27-31 However, as we have discussed, the gut and the brain do not exist in isolation, and are, in fact, connected through multiple paths. Researchers now know that the microbiome can be perturbed not just in conditions of the bowel, but in a whole range of diseases and disorders, including those of the brain.32
Psychiatric Disorders
In spite of the nervous connections between the microbiome and the brain, it still seems staggering that experiments performed in mice indicate that the microbiome can affect our very behaviour. Specifically, mice lacking a microbiome display changes in how they behave that can be described as ‘anxiety-like’ and ‘depression-like’.33 Similar experiments have even shown that the microbiome affects the very development of the brain, with physical differences seen at the connections between neurons of mice that lack a microbiome.34Results such as these raise the interesting possibility that a subtle effect of the microbiome upon the development of the brain could affect an individual’s behaviour and mental wellbeing over time. Scientists realize that using mice to investigate complex human mental illnesses has its limitations – a depressed mouse will only resemble a depressed human to a certain extent – but the change in both behaviour and neurodevelopment that stem from the microbiome are nevertheless striking.
“The initial skepticism about reports suggesting a profound role of an intact gut microbiota in shaping brain neurochemistry and emotional behavior has given way to an unprecedented paradigm shift in the conceptualization of many psychiatric and neurological diseases.”35
Corresponding with results collected using mice, patients diagnosed with IBS or IBS-associated disorders (such as chronic pelvic pain or overactive bladder) also present with psychiatric problems such as depression more commonly than the wider population.27,36 Gastrointestinal problems and a disrupted microbiome also occur in individuals with autism spectrum disorder, with gastrointestinal and autistic symptoms even appearing linked in severity.37-39 These observations suggest that mental health and behaviour are linked to the gastrointestinal tract and the microbiome, not just by mouse experiments, but in humans also.
Neurodegenerative Disease
The brain-gut-microbiome axis is not only important in the development and function of the brain, but also in the death of neurons that occurs during neurodegenerative disease. Scientists have shown that patients with Parkinson’s disease, and more recently Alzheimer’s disease, also have an altered microbiome that signifies a link between neurodegenerative disease and the gastrointestinal tract.40,41 To Parkinson’s patients, involvement of the gastrointestinal tract in their condition will be of little surprise, as Parkinson’s can present with well-documented gastrointestinal symptoms; however, recent evidence suggests that the gastrointestinal tract and the brain-gut-microbiome axis may be more important to the condition than previously thought.
Constipation is a common gastrointestinal symptom that presents at a very early stage of Parkinson’s, often before the movement-related issues that define the condition.42 Constipation occurs as a result of damage to the enteric nervous system of the intestinal tract; however, scientists have also found that the risk of developing Parkinson’s can be estimated from the severity of constipation and the frequency of bowel movements.43,44 Building upon this, in Parkinson’s patients, physical signs of pathology can be found at the gastrointestinal tract up to 20 years prior to diagnosis of the disease.45 Experiments in mice have even demonstrated that such pathology can spread from the intestinal tract to the brain through the vagus nerve.46 There is also evidence of the active involvement of the microbiome in Parkinson’s. In experiments performed using a mouse model of the disease, removal of the gut microbiome reduced movement-associated symptoms, while the introduction of gut microbes taken from human Parkinson’s patients increased them.41
Together, these findings give credence to the idea that Parkinson’s disease may actually originate in the gut, and spread to the brain through the brain-gut-microbiome axis. A hypothesis that aligns with the finding that in humans, severing the vagus nerve, and therefore one of the major channels of the brain-gut axis, reduces the risk of developing Parkinson’s.47
Future Perspectives and Treatments
The routes of communication that are part of the brain-gut-microbiome axis provide a mechanism by which diseases traditionally thought of as entirely neurological, or entirely gastrointestinal, may be related. Correspondingly, the numerous and wide-ranging conditions linked to a disrupted microbiome suggest that the microbiome and this communication axis might play an important role in promoting health, and potentially also in diagnosing and treating disease.
One approach toward utilizing the microbiome in healthcare is to supplement (probiotics), or provide nutrition to promote the growth of (prebiotics), healthy gastrointestinal bacteria as a method of preventing disease or alleviating symptoms in conditions such as irritable bowel syndrome.8,9,21,27 Interest in this approach has built a global probiotics dietary supplements market that is expected to grow from $4.11 billion in 2016 to $6.95 billion by 2022 (USD).48 However, in spite of this growth, there is currently little evidence regarding specific type, dosage, duration, and mode of delivery when it comes to treating individual conditions with probiotics, although we are consistently seeing more research in this area.
Fecal transplant may also play a role in future treatment of disease, not just for gastrointestinal conditions, but also for neurological and psychiatric ones. As an example, through a small clinical trial, researchers recently showed that transfer of healthy microbiota to individuals with autism spectrum disorder improved both gastrointestinal and behavioural symptoms.49 In the brain to gut direction, the anti-inflammatory and pro-intestinal integrity effect of vagal nerve stimulation may have potential in the alleviation of intestinal inflammation in inflammatory bowel disease through the restoration of a healthy balance of bacteria in the microbiome.8
“The past decade has shown a potent hidden organ. This next decade will see widespread inclusion of this newly discovered organ into diagnostic consideration and in targeted manipulation for therapeutic intervention of many diseases”21
We live in an exciting time for research with new discoveries providing more opportunities for interventions in the treatment and prevention of disease. The wide repertoire of interactions that exist simply between the brain, the gut, and the microbiome are just one example of the complex and interconnected nature of biology. To adapt, medical research is undergoing an exciting and unprecedented cultural shift toward collaboration between specialities that had previously been considered distinct. Perhaps there is no better example of this shift than in the study of the brain-gut-microbiome axis; however, the phenomenon is not limited to this area of study, with exciting new developments being made across the board, from the role of inflammation in psychiatric conditions, to the relationship between dental care and heart disease.50,51