If you have ever experienced “butterflies” before a presentation, had no appetite during a stressful week, or experienced gut discomfort when your sleep is off, you are familiar with the effects of the bidirectional gut-brain connection. Over the last two decades, there has been intense research into understanding this gut-brain axis and the role that the millions of microbes that inhabit our gut can play in health and disease. To call it the gut-brain axis is somewhat oversimplifying this complex network that involves the gut microbiome, inflammatory, metabolic and immune responses, satiety and stress hormones, neurotransmitters and other chemical messengers; as well as factors involved in sleep, exercise, and diet amongst others. In short, it is a complex system that enables the brain to influence digestion, appetite, satiety, and bowel movements (amongst others) and for the gut to influence mood, stress, sleep and various other daily functions.
For health and nutrition products, this is an exciting but nuanced space to engage with. We cannot control genetics, nor our previous life experiences, but we can all make choices about what and when we eat, how much we exercise, our sleep patterns, and how we might manage our stress levels. Interestingly, all these factors can influence the microbiome, and the microbiome in turn can influence these factors. Thus, the diet and the microbiome represent targetable means to influence mood, sleep, stress and exercise, and the restoration of certain microbes in our gut has been linked with several beneficial health outcomes.
There is no shortage of scientific reviews on the gut-brain axis, but one landmark review by Cryan and colleagues in Physiological Reviews provides an excellent overview of the gut-brain axis and the role of the microbiome if one wishes to dive deeper into the subject (REF). The review highlights the ways in which the microbiota and the brain communicate, which include the neuroendocrine-immune system, tryptophan metabolism, the vagus nerve, the enteric nervous system, and microbial metabolites.
Table of Contents
How Do the Gut and Brain Communicate?
The gut has its own nervous system that can act independently of the brain called the enteric nervous system (ENS) consisting of millions of neurons embedded in the intestinal walls that play a role in digestion, motility, secretion, blood flow, and the sensation of fullness or discomfort in the stomach or intestines and it responds to changes in the local environment. Due to its complexity, the ENS is sometimes referred to as the “second brain,” but it does not have higher-level cognitive functions.
The vagus nerve, which is part of the parasympathetic nervous system, is one of the key direct communication methods between the gut and the brain. It controls many autonomic functions, including digestion, heart rate, and breathing, and it sends sensory information from the gut directly to the brain about the status of the gastrointestinal tract. In the opposite direction, neural communication can travel from the brain to the gut to directly impact digestion, motility, and the secretion of neurotransmitters and gut hormones.
As well as containing millions of neurons throughout the ENS, the intestinal lining contains millions of immune cells that together with the physical epithelial lining of the gut serve as a barrier against invading pathogens and toxins from entering the bloodstream. Interestingly, the microbiota in our gut also plays a key role in the development, priming, maintenance and function of the immune cells in the gut from early life and throughout our lifespan, helping to train them to respond to threats.
One key role of these immune cells is an inflammatory response to infection or injury, but current hypotheses is that there is a constant low grade inflammatory tone maintained at the level of the gut in response to microbial by-products and biological debris from the diet. These cytokines and chemokines can enter the circulatory system and travel to the brain and other organs, providing indirect communication on gut status. Indeed, these circulating inflammatory markers can communicate across the blood-brain barrier to influence neuroinflammatory markers and thus influence centrally mediated function.
As well as influencing immune function and inflammatory response, the microbiota plays a key role in metabolism. We, as humans, sometimes do not possess the necessary enzymatic machinery to efficiently break down complex food macromolecules, and we are dependent on the microbes in our digestive tract to catabolise these dietary products into simpler fats, sugars and proteins so that we can then process these metabolites for nutritional value. A classic example would be the breakdown of certain fibres or certain vegetables that are often fermented by microbes in the large intestine. The breakdown of fibres by these microbiota can result in the production of short-chain fatty acids (SCFAs), which in turn influence the gut barrier function, immune response, and can indirectly communicate with the brain to influence centrally mediated events.
After eating, the distension of the gut, the arrival of food and the sensing of nutrients results in the release of a number of hormones and chemical messengers from the pancreas and intestines, while the cessation of food is modulated by the release of other hormones at the level of the gut by centrally-mediated control. These include glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 and -2 (GLP-1; GLP-2), cholecystokinin (CCK), peptide YY (PYY), oxyntomodulin and neurotensin, insulin, amylin, glucagon, orexin, and ghrelin amongst others that can enter the bloodstream and communicate with the brain and gut about hunger and satiety status.
As well as hunger hormones, the stress response and associated biochemical messengers (cortisol amongst them) represent another indirect mechanism by which the gut and brain can communicate. The hypothalamic-pituitary-adrenal (HPA) axis which regulates our response to stress influences a variety of bodily functions, including digestion, metabolism, immune response, and mood. Furthermore, stress can influence the gut microbiota, which in turn can influence the HPA axis, creating a feedback loop that can contribute to the development of mood disorders. Much research has been conducted around the gut-brain axis in irritable bowel syndrome, inflammatory bowel disease and other ailments of the gut, and the potential role of the microbiota in the aetiology and potential treatment of these disorders.
What Could This Mean for Mood, Stress, and Sleep?
The most common question that arises when discussing the gut-brain axis is whether and how it influences mood, stress, and sleep. While the mechanisms are not fully understood, it is obvious that our diet and/or any discomfort to the gut can influence these parameters and vice versa.
There are thousands of research papers looking at diet, and targeting the microbiome, but many studies are observational or preclinical, and further human interventional trials are needed to establish causality and demonstrate efficacy.
A common approach to studying the effect of the gut-brain axis on mood involves dietary manipulations (e.g., high-fat, low-fat, vegan, vegetarian, ketone, FODMAP, Mediterranean diet) and microbiome-targeted supplements (e.g., probiotics, prebiotics, synbiotics, and postbiotics), and assessing their impact on mood and behavior. However, the results are mixed, and it is still unclear which dietary strategies or dietary supplements, if any, have a consistent effect on mood, and the mechanisms behind these effects require further study. One of the most researched gut-brain connection areas is in relation to stress/anxiety, as both can influence each other in a feedback loop. Stress can lead to changes in appetite, digestion, and the composition of the microbiome, while gastrointestinal issues and narrowing of microbiome diversity have been associated with certain symptoms of anxiety disorders.
As well as stress and anxiety, sleep deprivation can also disrupt gut-brain communication and the microbiome, while evidence suggests that changes in our microbiome can influence our sleep-wake cycles.
However, it must be noted that mood, stress and sleep are complex constructs that can be measured in a variety of ways, from self-reported questionnaires to objective biomarkers. This means that when designing a study, it is important to consider the endpoints, the population, the diet, and the interventions. A common understanding is that everyone’s microbiome is unique, so a dietary supplement that works for you may not necessarily demonstrate efficacy in another individual. In general, the consensus is that such manipulations are effective if one can supplement what is lacking from the diet, or replenish keystone microbes that may be absent from one’s microbiome that they have evolved with since childhood.
Promising Science or Gut-Health Hype?
The gut-brain communication and the role of the microbiome therein is a fascinating area of research, but it is important to separate hype from reality. Preclinical studies have provided some evidence whereby dietary and microbiome manipulation can influence mood, behaviour, and cognition, while human studies have had mixed results in demonstrating efficacy in mood, stress and sleep. One must be cautious in interpreting the information to distinguish between the mechanisms and the effects, and there is a growing argument for personalized dietary and/or microbiome interventions for improving mood, stress and sleep.
What Has Not Been Proven?
Every person’s microbiome is unique, and it is shaped by a variety of factors, including genetics, environment, diet, and lifestyle. Every individual’s microbiome is influenced by the mode of delivery at birth (C-section vs. vaginal birth), breastfeeding vs. formula feeding, and the use of antibiotics in early childhood. The microbiome also evolves over time, and the composition in early adulthood is only one snapshot of a lifelong journey. In short, there is no single “ideal” microbiome, and there is no supplement or diet that will improve everyone’s mood, stress levels, or sleep.
It is also important to note that a microbiome-targeted intervention might not have any effect on a person’s mood or mental health. A person’s mood or mental health might improve for reasons unrelated to the microbiome, such as changes in diet, sleep, or stress levels. This is why it is important to design studies that control these factors and use appropriate endpoints to measure the effects of a microbiome-targeted intervention.
Success Story:
One recent success story in the gut-brain communication space is the rise of GLP-1 receptor agonists. Our natural GLP-1 binds to the GLP-1 receptor to communicate the sensation of feeling full and thus suppresses appetite, and once it has mediated its effects, it is degraded by the enzyme DPP-IV in the body. Commercially sold GLP-1 receptor agonists have been developed to be resistant to DPP-IV degradation, allowing them to stay active for longer and have more sustained effects, thus contributing to weight loss by suppressing appetite for longer. These drugs have been a game-changer for many patients, as they can help manage weight and related conditions and improve their quality of life and mental well-being.
Everyday Habits That May Support Gut and Mental Wellbeing
Supplements and medications will always have their place in healthcare, but for most people, the best way to support gut and mental wellbeing is to focus on controllable aspects of daily life such as eating a healthy, balanced diet, taking regular exercise, getting good quality sleep, and taking measures to reduce stressful events. These are the cornerstones of a healthy lifestyle, and they can have a profound effect on both the gut and the brain.
Why Human Clinical Studies Are Still Needed
The gut-brain axis is a fascinating area of research, but it is important to acknowledge the limitations of the current evidence. At this point, most studies are either preclinical or observational, and there is a need for more human interventional studies to demonstrate efficacy.
Endpoint selection is critical when designing such studies. The choice of endpoints will depend on the sponsor’s objectives, but it is important to choose biomarkers that are relevant to the condition in combination with assessments that capture how the study participant feels.
The choice of population and the inclusion/exclusion criteria are also important, as the results of a study in healthy volunteers or restricted populations may not translate to the general population. Many clinical studies exploring the gut-brain axis are in homogeneous populations (e.g. within a narrow age range, or restricted by BMI, sex, or distinct symptomology), which limits the ability to draw conclusions about the effects of an intervention in the broader population. This is an important consideration for sponsors who may wish to bring a dietary supplement to market, as regulatory agencies may request evidence from diverse populations to support a broader health claim.
In Atlantia Clinical Trials, we collaborate with our sponsors to design and deliver excellence in clinical studies with clear objectives, based on over 15 years’ experience in dietary supplements, pharma products, cosmetics and medical devices in the nutrition and health space.
Conclusion:
The take-home message is that the gut-brain axis and the role of each individual’s microbiome is complex, and is influenced by a variety of factors, including diet, medication, health, age, geography, sleep, stress, and hormones. This means that when designing a study targeting the gut-brain axis or a microbiome-targeted intervention, it is important to consider these factors and account for them in the study design.