The intrinsic link between our nervous system and the gut
I Have a Gut Feeling
In 2004, pioneering experimental research conducted by Sudo et al., demonstrated that germ-free mice, born with no commensal microbiota, exhibited measurably exaggerated hormonal responses to a physical stressor, compared to controls. More interestingly, the exaggerated hypothalamic-pituitary-adrenal (HPA) stress response was reversed when the germ-free mice were given Bifidobacterium infantis, a “friendly” or “good” strain of bacteria.
This sparked interest in the concept named the ‘gut-brain axis’ (GBA). Particularly the idea that the gut microbiota could influence the neuroendocrine HPA axis, our stress response system.
Over the following two decades numerous experimental findings added to this evidence, elucidating that a compromised microbiota may affect behaviour, mood and neurodevelopment and more astonishingly that our gut microbiota could transfer behavioural phenotypes to donor recipients (e.g., transplanting the microbiota from mice fed a high fat diet to a non-obese mouse fed a control or standard diet).
Sudo et al. were not the first to postulate the potential modulating effect of our inherent microbial communities on disorders of the nervous system. The earliest evidence dates to the early 1900s, when physicians and scientists theorised that the contents of the colon, primarily unwelcome or “bad” microbial species, could potentially contribute to melancholiac depression, a form of major depressive disorder, and to neurosis.
More recently, microbiologists and immunologists have investigated this theory further and studies have resulted in the identification of numerous mechanisms for which our gut bacteria, namely our gut microbiome, could play an important role in communication between the gut and the brain and the development of chronic disease. This GBA has since been upgraded by many, to the ‘gut-brain-microbiota axis’.
Side Bar: Gut Terminology
Reading about this field means inevitably coming across various terms, some of which may be used interchangeably, which is not always accurate.
- “Microbiome”: the term for the ‘extended genome’ provided by the bacteria in the human gut, i.e. what functions do the exert?
- “Microbiota”: the term for the different bacteria in the ecosystem, i.e. what bacteria are there, and in what proportions?
- “Microbe”: microscopic organisms, including bacteria, archaea, fungi, protozoa, algae, and viruses.
- “Bacteria”: single-cell organisms that are highly adaptable.
- “Dysbiosis”: the term for disturbances in the composition of the microbiota, influencing disease states.
- “Prebiotic”: defined as “a selectively fermented ingredient that allows specific changes, both in the composition and/or activity of the gastrointestinal microbiota that confers benefits.”
- “Probiotic”: defined as “a live microorganism that, when administered in adequate amounts, confers a health benefit on the host.”
- “Contrabiotic”: types of plant fibres which block the adherence and translocation of potentially pathogenic strains of bacteria to the intestinal mucosa.
Understanding the Gut-Brain Connection
Much progress has been made in describing the bidirectional exchanges between the central nervous system, the enteric nervous system, and the gastrointestinal tract.
In humans (and all vertebrates), the nervous system has two divisions:
- Central nervous system (CNS) - comprising the brain and spinal cord
- Peripheral nervous system (PNS) - comprising the network of neurons that exist outside the CNS.
The PNS is further divided into two main systems:
- Autonomic nervous system (ANS)
- Somatic nervous system (SNS)
Our gut-brain connection relies on bidirectional communication via the ANS, specifically our enteric nervous system (the digestive systems unique nervous system), and the sympathetic (‘fight-or-flight’) and the parasympathetic (‘rest and digest’) arms/branches of the ANS.
The gut-brain axis of the ANS drives both 'afferent' (sensory) and 'efferent' (motor) neural signals between the gut and the brain. Simply put, after ingesting a meal, the presence of nutrients in the gastrointestinal (GI) tract initiates a neural and hormonal response. The ANS gathers information from its surrounding environment, from the walls of the digestive tract (extending from the esophagus to the anus). It then relays this information to the brain, which then acts on the signals or decisions that the CNS returns.
This enteric nervous system (ENS), embedded in the wall of the gastrointestinal system, contains an extensive distribution of neurons, about the same as the spinal cord. Whilst the ENS can function independently, digestive function is dependent on communication between this system and the CNS. To fulfil this role, the ENS produces an abundance of neurotransmitters. These hormones (e.g., ghrelin) are then released into the bloodstream and cross the tightly regulated blood–brain barrier with help from the vagus nerve.
In addition to holding its own specialised nervous system, the gut has its own immune system too. Interactions between the microbiota and immune cells have been shown to affect the renewal of gut epithelial cells. The neuro-immuno endocrine mediators of the GBA also allow the brain to influence intestinal function. This communication pathway is more of an integrated system, beyond the components of the nervous system, as it also integrates the immune and endocrine system.
The hypothalamic-pituitary-adrenal axis (HPA axis) is another mechanism by which the brain can communicate with the gut to help control digestion through the action of hormones. This pathway connects the emotional and cognitive regions in the brain with the peripheral GI functions. We know that impaired HPA axis activity leads to severe chronic diseases, including melancholic depression, anorexia nervosa, panic disorders and obsessive-compulsive disorders, to name a few (details here and here).
The microbiota is seen as an important factor of this gut-brain axis, and disturbances in the homeostasis of these integrated systems has been implicated in various neurological and psychiatric conditions.
What is the Gut Microbiota?
The microbiome includes all microorganisms (bacteria, fungi, and viruses) and their genetic material, in or on their host. Whereas the microbiota defines or classifies the microbe population in a certain ecosystem, for example the gut microbiota, which is the largest and most diverse community of microorganisms. Other microbial communities are found on the skin, nasal passage, lungs, and the urogenital tract.
Microbes that survive in the gastrointestinal (GI) tract outnumber us by 10-fold, and the microbial genome is hypothesised to be 100 times larger than our own. To a varying extent, the nutrient density and energy availability of food is affected by the digestive capacity of a person’s microbiota. Furthermore, an increasing body of evidence suggests the microbiota also influence drug metabolism and bioavailability. This is particularly notable in pharmacology treatments for neuropsychological disorders and obesity.
From: Clarke et al., Pharmacological Reviews April 2019, 71 (2) 198-224
Copyright: American Society for Pharmacology and Experimental Therapeutics.
The Human Microbiome Project, an extension of the Human Genome project was established in 2007 to investigate its relationship to health and various diseases. The project provides big data which can be utilised to link microbial sequences with the human phenotype. This area of research has been largely driven by the development of highly specific next-generation sequencing technology to help characterise the gut microbiome. Using this bioinformatics, researchers can isolate different populations and target potential groups for interventions. This is incredibly important as the presence and abundance of bacterial species can vary significantly from one person to the next, and can rapidly change under certain conditions, for example:
- Pharmaceutical agents (particularly antibiotics)
- Changes in diet and lifestyle
- Exposure to pathogens
The initial acquisition of microbiota at birth is formed by a number of intrinsic and environmental factors. It is well established that exposure to the mothers vaginal microbiota has a measurable protective effect from various adverse health outcomes in later life, such as risk of asthma and obesity, compared to those born via caesarean section.
Is there a mediating role for gut microbiota and neurophysiological function?
How Do Gut Microbiota Impact the Brain?
So how might the gut microbiota influence outcomes luke mood, anxiety, and neurophyiosology more broadly?
The gut microbiota has been proposed to exert effects via a number of potential mediating factors:
- The vagus nerve
- Short chain fatty acids
- Tryptophan production
There is a discussion of each below. First, as a reminder, a mediating variable is a "variable that links the independent and the dependent variables, and whose existence explains the relationship between the other two variables".
The Vagus Nerve
The vagus nerve is the primary nerve of the parasympathetic system of the ANS. Anecdotal and experimental evidence for the involvement of vagus nerve in mental health and mood-related disorders has been reported following a surgical removal of all vagal fibers (called a subdiaphragmatic vagotomy) to treat peptic ulcers.
The gut microbial link has also been investigated. For example, mice with a severed vagus nerve, treated with a potential probiotic Lactobacillus rhamnose failed to show any anxiety related improvements. This would indicate that this bacterial strain is dependent on gut-brain communication via the vagus nerve. Similar has been reported for other bacterial strains, specifically Bifidobacterium logum. Advanced investigation of the vagus nerve has since resulted in a mounting body of evidence, in both humans and animals, for its role in appetite regulation, mood and inflammation.
The vagus nerve has an ability to express receptors for certain proinflammatory cytokines. This produces a neural signal that connects the PNS to the brain. In turn, this results in the activation of microglia cells, specialised macrophages responsible for maintaining the health of the CNS. In 2015, Erny et al., reported that germ-free mice (i.e. those bred to be completely free of bacteria) displayed impaired innate immune responses due to defective microglial. More interestingly they also showed that the activation of microglia cells could be modified by correcting the gut microbiota using dietary fibre.
Short-chain Fatty Acids
Enteroendocrine cells of the GI tract can produce and release specific molecules and hormones (such as the satiety peptide hormone, CCK) which transfer information to the brain. The fermentation of dietary fibres by bacteria in the colon produces metabolites called short-chain fatty acids (SCFAs). There are three main SCFAs produced in the colon:
These SCFAs are believed to play a key role in neuro-immunoendocrine regulation and to regulate physiological processes. For instance, butyrate produced by the microbiota provides energy to epithelial cells of the colon.
From: Dalile, B., Van Oudenhove, L., Vervliet, B. et al. Nat Rev Gastroenterol Hepatol 16, 461–478 (2019)
Copyright © 2019, Springer Nature Limited
Growing evidence supports the idea that these SCFAs also exert fundamental physiological effects on several organs, including the brain. Furthermore, Dinan and Cryan (2015) postulate that microbiota manipulation and SCFA administration are potential treatment targets for a range of psychiatric disorders.
The gut microbiota can produce a range of beneficial metabolites which can interact with the host’s immune, neural and endocrine systems and have a significant effect on health. Tryptophan (the precursor of serotonin) is increased in the plasma of animals treated with Bifidobacteria infantis. This may be significant given the brain has limited capacity to store tryptophan and needs a constant dietary supply to cross the blood brain barrier. Tryptophan comes from 2 main sources:
- Dietary sources - e.g., turkey
- Certain bacteria that can synthesize tryptophan - e.g., bifodobacteria
The gut microbiota can also synthesise neuroactive molecules such as:
- Gamma-aminobutyric acid (GABA)
Whether these microbial-derived neurotransmitters influence levels in the CNS has not been confirmed.
What are the dietary recommendations for optimal gut microbiota in promoting mental health?
Microbiota & Mental Health: What's the Role of Diet?
Diet is a key modifiable factor in the modulation of the gut microbiota and its ability to exert metabolic functions on the host. As such, our diet and gut microbiota work together to provide a certain level of resilience against disease or the rate at which disease may progress. There is a dearth of correlations between “unhealthy” dietary behaviour and mental health. And more recently, the emergence of evidence for certain foods or dietary behaviours in a microbiome-mediating role.
Many studies suggest an association between mood disorders and dysbiosis. Dysbiosis is characterised by:
- A reduction in microbial diversity
- A combination in the loss of beneficial bacteria and a rise in pathogenic bacteria
However, it’s too early to determine which bacterial strains play a role due to the lack of well-designed human interventions, standardised research methods and the current reliance on epidemiological or animal models for evidence.
To-date, intervention studies exploring specific nutrients and foods (e.g., fermented foods and certain dietary fibres), have been short in duration and have employed crude markers of disease, making it difficult to ascertain any firm conclusions.
A study published in Nature by Benton et al. in 2006, reported an improvement in mood as determined by a self-completed questionnaire (Profile Of Mood State - POMS), in those who consumed a probiotic drink and who reported ‘low mood’ at baseline. In this sample of 124 adults, only 20% were defined as having ‘low mood’ at baseline, making subgroup analysis statistically inappropriate. In addition, the cognitive and mood profile of the study population was reported overall as being generally very good at baseline; therefore leaving little room for significant improvements in mood. No faecal samples were obtained to measure the presence of Lactobacillus casei in the gut pre- or post-study, nor was dietary intakes assessed, therefore providing no confirmation of intervention efficacy or compliance. Finally, it is also important to acknowledge that the study was funded by Yakult, which may raise concern on investigator motives.
More recently, Rudzki et al. (2018) reported improved cognitive function in patients with major depressive disorder following intervention of probiotic Lactobacillus Plantarum 299v. However findings are based on the significantly reduced per-protocol sample, lowering the statistical power of the findings. Until further robust evidence is established, it is impossible to make dietary recommendations tailored to the microbiome and mental health. The European Food Safety Authority (EFSA) recognises the role of the gut microbiota in nutrition and health for few dietary considerations other than fibre fermentation, for gut transit time and regulating bowel habits. The beneficial effects of fibre are dependent on the amount, type, and characteristics of the consuming host, making controlled intervention studies extremely challenging.
Western diets high in saturated fat, sucrose and low in dietary fibre are known to have effects on the composition of the gut microbiota, such as reductions in Bifidobacteria and butyrate-producing bacteria. In contrast, diets of vegetarians or vegans, with high vegetable intake and excluding meat or any animal products, have shown a modulating effect on the composition of the gut microbiome. The Mediterranean diet, high in cereals, legumes, nuts, vegetables and fruits with low consumption of meat has been shown to increase levels of SCFAs. Adherence to a Mediterranean diet has also been linked to a reduced incidence of clinical depression in young adult populations. The mechanism is believed to be derived from the neurotransmitters (serotonin, noradrenaline and dopamine), who’s synthesis is supported by high levels of vitamin B and high polyphenol intakes increasing brain-derived neurotrophic factor.
Considering Western diets and impact on gut microbiota, Western lifestyles should also be added to the equation. The integration of multiple indicators, including microbiome data, anthropometry, biochemistry, lifestyle factors, psychosocial wellbeing, environmental factors and dietary intake should be modelled to better understand the interactions between the vast array of influencing factors and the individual, not group level, response. Integration of this extensive information, together with other person-specific factors appear to be essential to better understand the result of their complex interactions and predict microbiota effects on health.
There are many other well-studied nutrients with strong associations to gut microbiota composition and cognition and neuropsychiatric conditions including Omegas 3 and 6, vitamin D, numerous B-vitamins, and polyphenols. However, whilst diet may represent a means to target optimal gut microbiota to improve behaviour, clinical translation of these findings is required before diet can be proposed as a potential therapy.
Should probiotic supplements be used for the treatment of mood disorders?
Psychobiotics & Mood: What We Know
In short... it’s too soon to tell.
According to the International Scientific Association for Probiotics and Prebiotics (ISAPP):
- Probiotics = “live microorganisms which when administered in adequate amounts confer a health benefit on the host”
- Prebiotics = “selectively fermented dietary ingredients that result in specific changes, in the consumption and/or activity of the gastrointestinal microbiota, thus conferring benefit(s) upon host health”.
Research into the effects of pro- and prebiotic use in the treatment of mental disorders is far from conclusive and still in its infantile stage of exploration. Some specific probiotic strains have demonstrated promotion of the development of the intestinal barrier. Bifidobacterium infantis decreased pro-inflammatory cytokines in deprived rats, an animal model representation for IBS, and improved depressive behaviour. It is believed that the microbiota, as well as pro- and prebiotics, can have a significant impact on the gut- brain axis, but further research in this area is needed to reveal the magnitude, mechanisms and clinical relevance of these effects.
Few studies have investigated the effects of probiotics as primary clinical endpoints in clinical trials. In one study, positive effects of the probiotics Lactobacillus helveticus and Bifodobaterium longum in an animal model were confirmed in adult human volunteers in a randomised double blind trial. The active treatment reduced psychological distress, measured by the Hospital Anxiety and Depression Scale. In addition, a reduction of the stress hormone cortisol was also observed.
Prebiotics compounds that promote the abundance of microbes are also believed to be beneficial. Inulin, found in wheat and a number of fruit and vegetable sources (e.g., onions and bananas), is among the most studies prebiotics. Fermentation of inulin takes place entirely in the colon and has been observed to increase the Bifidobacteria longum strain, which has been shown in animal studies to influence stress-like behaviour. However, cause and effect cannot be inferred for any specific bacterial strains and well-designed studies in humans are necessary in order to evaluate their value as preventive and therapeutic strategies in psychiatric disorders.
The knowledge gained in recent years about the ability of gut microbes to influence and contribute to host health and well-being opens new windows of opportunity for nutritional and pharmacological tools to improve host-microbe symbiosis, potentially using probiotics and prebiotics. Translation of the effects of microbiota and probiotics on the brain-gut axis found in laboratory and animal studies and further understanding of how these effects might improve physiological (e.g., GI) and psychological (e.g., anxiety and depression) disturbances are certainly a major challenge for research.
Limited information is available on how the evidence in preclinical, animal studies may translate to humans involving the brain or the gut/brain axis. Most of the evidence reported relies on the germ-free model, this has several limitations and should be taken with caution when considering how it may translate to humans. Most notably, germ-free animals are born in conditions where their environment is controlled and sterile.
Scientists are just beginning to understand the means by which the gut-brain-microbiota axis functions. Various factors determine the means by which a single bacterial species, or the gut microbiota as a whole, can impact brain and behaviour, and a number of exciting questions still need to be addressed. Such as, the species type and the specific communication required. Researchers need to better understand how to assess and manipulate the potential microbial impact on the brain-gut axis amidst a large number of bacterial, host and environmental influences. An integrated approach must consider a number of parameters including extensive GI microbiome analysis, markers of immune and neural functions and responses to environmental conditions (e.g., stress and diet). Furthermore, it is not clear whether alterations observed in the microbiota of individuals with psychiatric disorders is from initial alterations at the gut microbial level (bottom-up effects) and/or changes in brain-to-gut signalling (top-down effects).
Interventions including gut microbial manipulation with antibiotics, fecal microbial transplantation and the potential of probiotics in mental health and mood disorders offer exciting opportunities for the clinicians therapeutic toolkit, particularly for experiencing mild-moderate symptoms where pharmaceutical interventions are often undesirable.
Summary: Key Points
- Numerous mechanisms have been identified for which our gut bacteria could play an important role in communication between the gut and the brain.
- This gut-brain-microbiota axis can exert a impact on the risk of the chronic disease.
- Studies also suggest there are a number of mechanisms by which the gut microbiota may impact aspects of neurophysiolgy, and thus mood, anxiety and depression.
- Diet has an impact on gut microbiota composition.
- It is believed that the microbiota, as well as pro- and prebiotics, can have a significant impact on the gut- brain axis, but further research in this area is needed to reveal the magnitude, mechanisms and clinical relevance of these effects.
- Most intervention trials looking at 'pyschobiotics' have been in vitro or animal studies. Of the human trials, there are currenlty significant limitations, that make conclusions difficult to make.
- Furthermore, it is not clear whether alterations observed in the microbiota of individuals with psychiatric disorders is from initial alterations at the gut microbial level (bottom-up effects) and/or changes in brain-to-gut signalling (top-down effects).