The Simplified Guide to the Gut-Brain Axis – How the Gut and The Brain Talk to Each Other
The gut-brain axis (GBA) is a bidirectional link between the central nervous system (CNS) and the enteric nervous system (ENS) of the body. It involves direct and indirect pathways between cognitive and emotional centres in the brain with peripheral intestinal functions. In addition, the GBA involves complex crosstalk between the endocrine (hypothalamic-pituitary-adrenal axis), immune (cytokine and chemokines) and the autonomic nervous system (ANS).
The GBA primarily combines the sympathetic and parasympathetic arms of the autonomic nervous system (ANS), which drives both afferent and efferent neural signals between the gut and the brain, respectively. The HPA axis meanwhile coordinates adaptive responses against stress, including activation of memory and emotional centres in the brain’s limbic system.
The neuro-immuno-endocrine mediators of the GBA allow the brain to influence intestinal function (immune cells, epithelial cells, enteric neurons, and smooth muscle cells). Moreover, the gastrointestinal (GI) tract cells are also under the influence of the gut microbiota. Recent evidence suggests an emerging concept whereby the microbiome plays an important role in the GBA structure. 
THE GUT MICROBIOME
The microbiome refers to all microorganisms in or on their host as well as their genetic material. On the other hand, the microbiota defines the microbe population in a specific ecosystem, such as those populations found in the gut microbiota or skin microbiota.
There are approximately 1014 microorganisms within the gut, which is around 10 fold more cells than there are cells in the human body.
Collectively, the genetic material of the microbiome is approximately 150 times greater than the human genome, which has led some scientists to label the microbiome as a ‘superorganism’.
In recognition of this superorganism and the mutualistic co-evolution of humans and microbes, the Human Microbiome Project was set up to analyse this unique relationship to determine its role in health and disease.
This is particularly important given the rise in modern antimicrobial treatments, disinfectant use and harsh cleaning products that are frequently marketed and sold as necessary for good human health.
Within the gut, the bacterial phyla Firmicutes and Bacteroidetes are approximately 75% of the gut microbiota, and both of these phyla are very sensitive to change. 
Disruptions to the microbiome are increasingly becoming associated with the prevalence of allergies, autoimmune diseases, metabolic disorders and neuropsychiatric disorders that affect today’s society.
THE GUT-BRAIN LINK
A newborn is first exposed to the mother’s vaginal microbiota which influences the offsprings microbial signature. Studies show that the gut microbiota is central to the development and maturation of the human CNS and ENS in these early postnatal weeks. 
The interaction between the GI mucosal lining and the gut microbiome also helps to fine-tune the developing immune system.
Much of the research into the brain-gut-microbiota axis has involved germ-free animals and studying the effect of antibiotics, probiotics and faecal transplants to determine their effects of the gut microbiota on brain activity.
Many of these studies suggest that the gut microbiota produces relevant levels of neurotransmitters and are, in part, responsible for many facets of health and disease.
The microbes of the gut microbiota interact with the GBA through the following pathways.
1. The Vagus Nerve :
- Afferent Spinal and vagal sensory neurons carry feedback from the intestinal end to the brain stem which in turn engages the hypothalamus and limbic system (responsible for the regulation of emotions).
- Descending projections from the limbic system (activated via stress) influence the autonomic activity of the gut.
2. Neuroendocrine (gut hormone) signalling :
- Bacterial products are known to stimulate enteroendocrine cells (EECs) to produce several neuropeptides such as peptide YY, neuropeptide Y (NPY), cholecystokinin, glucagon-like peptide-1 and -2, and substance P.
- These neuropeptides then enter the bloodstream and/or directly influence the enteric nervous system.
3. Interference with Tryptophan metabolism :
- Approximately 95% of Serotonin (5-HT) is produced by gut mucosal enterochromaffin cells.
- Peripherally, 5-HT is involved in the regulation of GI secretion, motility (smooth muscle contraction and relaxation), and pain perception, whereas in the brain 5-HT is implicated in regulating mood and cognition.
- Gut microbiota also plays an important role in tryptophan metabolism which is the precursor to the production of Serotonin. (See point 4)
4. The Immune System :
- The gut-associated lymphoid tissue (GALT) comprises 70% of the body’s immune system and can be conceptualised as the largest immune organ in the body.
5. Altered Intestinal Permeability :
- Chronic stress has been shown to alter intestinal permeability (leaky gut syndrome), which is associated with a low-grade inflammation that can be functionally linked to psychiatric disorders such as depression . [Read more on the Gut-Microbiome and Depression]
- In many of these cases, it is the increased presence of circulating bacterial endotoxins, known as lipopolysaccharides (LPS), which are fundamental risk factors for disease.
- Alternatively, other studies have suggested that the gut microbiota can produce neuroactive substances that may influence the core symptoms of neuropsychiatric disorders.
- This alternative hypothesis could signify a critical and relevant role of gut microbiota in the pathophysiology of many disorders, including schizophrenia, autism, anxiety and depression.
6. Production of Microbial Metabolites :
- Many species of Lactobacillus and Bifidobacterium produce gamma-aminobutyric acid (GABA), which is the main inhibitory neurotransmitter in the brain.
- In addition, Candida, Escherichia, and Enterococcus produce the neurotransmitter serotonin, while some Bacillus species have been shown to produce dopamine.
- Bacteria also produce short-chain fatty acid (SCFAs), such as butyric acid, propionic acid and acetic acid, that are able to stimulate the sympathetic nervous system, mucosal serotonin release and thus influence the memory and learning process in the brain.
7. HPA Axis Involvement:
Acute stress has a limited effect on the gut microbiota however chronic stress may cause a clinically meaningful imbalance in the microbial community. [Ref]
- With increased levels of cortisol, there is an increase in the permeability of the gut wall (leaky gut), which then facilitates a systemic inflammatory response.
- A leaky gut drives a proinflammatory state as evidenced by increased levels of circulating TNF-α, interferon-γ, and IL-6.
- IL-6 is known to activate the HPA axis and over time it also down-regulates glucocorticoid receptors. These receptors are a feedback mechanism that suppresses the HPA axis, however, their downregulation results in a hyperactive and overly sensitive HPA axis.
- Evidence also suggests that these changes cause a reduction in hippocampal serotonin as well as a reduction in BDNF expression.
GIF summarising the Gut-Brain Axis :
GUT MICROBIOTA AND NEUROPSYCHIATRIC DISORDERS
There is mounting interest in determining how the gut microbiota can influence and contribute to the pathogenesis of neuropsychiatric disorders.
Research supports GI microbe-brain interactions most notably with anxiety and depressive-like behaviours with accumulating evidence pointing to specific microbial genes that can regulate neurotransmitter activity.
You can read the full nature article here.
In one study, Asano and colleagues showed that Clostridium produced biologically active dopamine in the gut lumen of mice. 
Given that dopamine is the key neurotransmitter associated with schizophrenia, it is possible that these bacterial metabolites can interact and stimulate the central and peripheral nervous systems.
In another study, there was a strong correlation found between functional GI disorders caused by dysbiosis and the subsequent presence of mood disorders. 
Dysbiosis is a microbial disturbance or imbalance that can cause functional GI disorders such as inflammatory bowel disease (IBD) and ulcerative colitis.
Interestingly, it is also well established that the response of the CNS to psychological and physical stressors can affect gut homoeostasis and result in diseases such as ulcerative colitis and irritable bowel syndrome (IBS).
GUT BRAIN AXIS AND MAJOR DEPRESSIVE DISORDER
Much research into intestinal microbial composition has been carried out using animal models, either by adding pathogenic bacteria and monitoring behaviour or by inducing depression-like symptoms and rescuing these animals through treatment.
A study by Desbonnet and colleagues showed that rats that had undergone maternal separation (model of induced depression-like behaviour) could be rescued by treatment with the probiotic Bifidobacterium infantis in conjunction with 30-mg/kg citalopram. 
Maternal separation causes reduced mobility, increased peripheral proinflammatory interleukin (IL)-6 secretion, and reduced levels of norepinephrine in these rats.
Treatment with both the probiotic and citalopram reversed these symptoms but not when they were administered separately.
Functional MRI analysis has previously shown there is a chronic low-level inflammatory condition in many cases of depression.
In these cases, depression is reliably associated with inflammatory biomarkers such as tumour necrosis factor (TNF)-α, IL-6, and C-reactive protein.
Several lines of evidence suggest that these inflammatory markers point to gut permeability issues and the presence of inflammatory inducers such as LPS.
View the video by Prof Berk on The Role of the Gut Microbiome and Diet in Depression.
Comprehensive article on the Gut Microbiome in Depression.
GUT BRAIN AXIS AND AUTISM SPECTRUM DISORDER (ASD)
Autism-spectrum disorder (ASD) is a group of neurodevelopmental disorders characterised by deficits in social interactions, including verbal and nonverbal behaviours.
Researchers believe that these ASD-like behaviours are a result of a complex interplay between genetic defects and environmental risk factors causing abnormal neurodevelopment during maturation in utero and in early childhood.
Analysis of genetic material in faecal matter from children with ASD showed a correlation between bacteria such as Clostridium and Desulfovibrio and altered neuro-behavioural development as observed in ASD.
Anecdotally, there have been observations of improved symptoms in ASD children who experience changes in gut microflora populations caused by ingestion of either antibiotics against these bacteria or probiotics that provide the gut with more synergistic bacteria.
Furthermore, analysis of faecal samples from ASD children has shown an imbalance in certain microbiota species with overall less diverse gut microbiota species.
The compositional differences included a lower abundance of Prevotella and Coprococcus species. The differences in microbial diversity and composition will result in changes in many neuroactive microbial metabolites.
Therefore, GI dysbiosis is a possible factor in ASD etiopathogenesis, just as it has been suggested to be a causative factor in psychiatric disorders such as depression.
The differences in microbial diversity and composition result in changes in many neuroactive microbial metabolites. Therefore, GI dysbiosis is a possible factor in ASD etiopathogenesis.
GUT BRAIN AXIS AND SCHIZOPHRENIA
Many studies on gut microbiota and schizophrenia have been preclinical studies and carried out in a schizophrenia-like behaviour rat model.
Experiments show that treatment with the human commensal bacteria Bacteroides fragilis can improve microbiota composition, correct gut permeability, and improve anxiety-like symptoms in this model. 
Furthermore, clinical studies on subjects with schizophrenia showed increased levels of lactic acid bacteria in the gut lumen, including Lactobacillus casei, Lactobacillus lactis, and Streptococci species such as Streptococcus mutans and Streptococcus thermophilius. 
The increased presence of these bacteria species is associated with alterations in adaptive Th2 immune responses, which is present in schizophrenia. [Learn more about the immune system in our video on Neuroinflammation]
Administration of probiotics to these individuals altered the microbiome and appeared to normalise some behavioural symptoms.
In addition, the pathogenic bacteria Clostridium is known to produce 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA) and p-cresol, which are microbial metabolites that can inhibit an enzyme called dopamine beta-hydroxylase.
This enzyme converts dopamine to norepinephrine, causing a concurrent rise in dopamine levels in the brain.
This can lead to behavioural problems and has been associated with exacerbating psychotic episodes in schizophrenia.
A 2019 paper compared the gut microbial communities of patients with schizophrenia and healthy controls to evaluate whether microbial dysbiosis was linked with episodes of illness or the severity of symptoms. The study showed the following findings:
- Microbial compositions of patients with schizophrenia were characterised by lower within-sample diversity.
- Bacterial taxonomic families Veillonellaceae, Prevotellaceae, Bacteroidaceae, and Coriobacteriaceae were increased in patients with schizophrenia.
- Lachnospiraceae, Ruminococcaceae, Norank, and Enterobacteriaceae were decreased in patients with schizophrenia.
- Altered gut microbial composition observed in SCZ is specific relative to the gut microbiome changes in depression.
- Veillonellaceae was negatively correlated with PANSS, whereas Bacteroidaceae, Streptococcaceae, Lachnospiraceae were positively correlated with PANSS.
- The combination of Aerococcaceae, Bifidobacteriaceae, Brucellaceae, Pasteurellaceae, and Rikenellaceae can distinguish patients with schizophrenia from healthy controls. Thus, this combination of gut microbiota may have potential diagnostic value in schizophrenia.
- The researchers also carried out faecal microbiota transplantation (FMT) experiments in mice. They found that mice transplanted with schizophrenia microbiota displayed locomotor hyperactivity, decreased anxiety and depressive-like behaviours, and increased startle responses, suggesting that the disturbed microbial composition of schizophrenia microbiota recipient mice was associated with several endophenotypes characteristic of mouse models of schizophrenia.
IRRITABLE BOWEL SYNDROME
Irritable bowel syndrome (IBS) is a gastrointestinal disorder characterised by altered bowel habits associated with abdominal discomfort or pain in the absence of detectable structural and biochemical abnormalities.
Psychiatric co-morbidity, e.g. depression and anxiety, are overrepresented in individuals with IBS.
Besides altered gastrointestinal motility, visceral hypersensitivity, post-infectious reactivity, alteration in faecal microflora, bacterial overgrowth, food sensitivity, carbohydrate malabsorption, and intestinal inflammation, the gut-brain alteration is known to be a major factor in the pathogenesis of IBS. 
Modulation of the gut-brain axis in IBS offers a promising therapeutic target for the future.
MANIPULATING THE GUT MICROBIOTA
The gut microbiota can be intentionally manipulated to help maintain health and prevent or treat disease.
Recent experimental evidence would appear to suggest that alterations to the gut microbiota composition through probiotic treatment could attenuate neuropsychiatric symptoms or even reduce the risk of developing future psychiatric symptoms.
For example, treatment with Lactobacillus rhamnosus induced region-dependent changes in GABA expression in the cortical cingulate, hippocampus, amygdala and prelimbic regions. 
This treatment thereby reduced the stress-induced release of cortisol, which in turn reduced anxiety and depression-related behaviour.
Read more on the evidence for the role of pre and probiotics in depression.
Antibiotics reduce the numbers and diversity of commensal bacteria, which can allow pathogenic or parasitic microbes an opportunity to thrive.
Wholesale microbiota changes caused by antibiotics have been shown to influence adult behaviour by modulation of hormone expression levels and tryptophan metabolic pathways associated with serotonin secretion.
In a previous article on the Hub, the study we covered showed that mice treated with antibiotics performed worse on memory tests due to impairments in hippocampal neurogenesis.
However, if mice were given probiotics or an exercise wheel, they showed profound improvements.
The researchers showed that a specific subset of monocytes acts as communicating cells between the brain, the immune system, and the gut.
3. Diet and Lifestyle
Diet is known to be one of the most important factors that influence gut microbiota. Prof Jacka has a series of talks on the role of diet in mental health, which you can view here.
Diet manipulation can influence gut microbiota by affecting the composition and function of the microbial community. These alterations, in turn, can modulate the innate and adaptive immune systems and influence behaviour and mood.
Read more on the role of Diet In Depression.
A recent study showed that a gluten-free diet improved schizophrenia symptoms in a single case where the individual also had a complex autoimmune disorder. 
Although remission from psychotic symptoms was attributed to maintaining a gluten-free diet, further studies are needed to determine the impact of dietary gluten in patients with schizophrenia and who are also gluten-sensitive.
4. Faecal Microbiota Transplantation (FMT)
There is increasing evidence that FMT may be a promising microbiota-modulating treatment for Major depressive disorder (MDD). [Green et al, 2023]
Gut Microbiome (Gut-Brain Axis) and Depression – Pathophysiology | Role of Pre and Probiotics
The mutualistic synergy between microbes and humans is a relationship that is essential for growth, development, health and the prevention of disease.
The past 5 years have seen an amazing increase in our knowledge of how bacteria signal to the brain and the implications this has for psychiatry. There are still many open questions, however.
Firstly, the mechanisms of how the microbiota signals to the brain are only slowly being unraveled. We are at the very early stages of research, which will need to employ experimental rigor that must be employed to unequivocally demonstrate that it is the actual production of a neurochemical in vivo by a specific microorganism, and not a non-neurochemical aspect of the microorganism, such as a cell wall component interacting with immune cells in the gut, that is responsible for a specific change in behavior.
Secondly, the individual components of bacteria that are mediating their effects need to be disentangled. The evolving field of metabolomics is advancing and assisting in our ability to better understand the signaling cascades and roles of bacterial products.
Thirdly, as most of the studies to date have been in rodents, further human studies are needed to determine if bacteria-based interventions can indeed have a positive effect on mental health, a so-called psychobiotic effect.
Although some preliminary studies have focused on the altered composition of the microbiota in depression and autism, the time is now ripe for a comprehensive analysis of the microbiota in other disorders, including schizophrenia, anxiety, drug addiction, and eating disorders followed by mechanistic studies that will determine if such changes have any causal relationship to psychiatric symptomatology.  [Foster et al., 2016]
- View the video by Prof Berk on The Role of the Gut Microbiome and Diet in Depression.
- Comprehensive article on the Gut Microbiome in Depression.