Gut↔Brain Axis
Does the Microbiota Affect Brain Health?
Have you ever experienced that moment where your gut feels uneasy before a final exam, a date, or an important job interview? This physiological response is not entirely random and suggests that the brain and gut are connected.
There is constant bidirectional communication between the gut and the brain through physical connections and biochemical interactions to regulate specific aspects of homeostasis. The gut–brain axis comprises different routes of communication including endocrine, immune, and neural mechanism.1 An example is the use of chemicals called neurotransmitters. Neurotransmitters produced in the brain, such as serotonin, control feelings and emotions. Serotonin contributes to feelings of happiness and helps control the body clock. Interestingly, the cells lining the gut and the trillions of microbes living there produce a large proportion of serotonin.2
This collection of microbes – also known as the microbiota – protects us from infection and maintains intestinal homeostasis. It also stimulates the release of gut peptides and hormones to influence the central nervous system.
Aside from influencing the endocrine system, the gut microbiota also utilizes our nerve signaling.1 More than 500 neurons (cells that helps the brain to tell the body what to do) connect the gut and the brain and is the biggest nerve connection. The vagus nerve runs from the brain through the face and thorax to the abdomen.3 In addition to regulating internal organ function such as digestion, heart rate, and respiratory rate, the vagus nerve can also regulate certain reflex actions such as coughing, swallowing, and vomiting.
The involvement of gut vagal neurons in mental health and mood-related disorders traces back to the early 20th century when surgeons used gastrectomy to treat peptic ulcers. One of the side effects of the procedure is an ablation of vagus nerve activity from the stomach downward, disrupting the communication between the lower gastrointestinal tract and the brain.
Studies show that the gut microbiota influences the vagus nerve. For instance, the gut microbiota produces lots of short-chain fatty acids (SCFAs) such as butyrate, propionate, and acetate by digesting fibre in our food. SCFAs affect brain function in various ways. One study found that consuming propionate can reduce food intake and reduce activity in the brain related to reward from high-energy food.4 SCFA, butyrate, and the microbes that produce it, are also important for forming the barrier between the brain and the blood. Metabolites produced by the gut microbiota can:
- activate enteroendocrine cells to release gut hormones, or
- be absorbed across the epithelial cell layer to be taken up in the bloodstream, or
- activate the vagus nerve to influence the central nervous system.
Studies using germ-free mice (mice raised without any exposure to microbes) further demonstrate the involvement of the gut-brain connection. Germ-free mice show alterations in sociability, locomotor activity, and repetitive stereotyped behaviour depicting the vital role of the gut microbiota in normal stress responsivity, sociability, cognition, and maintenance of central nervous system homeostasis.5 Researchers found that giving mice wide-spectrum antibiotics to deplete their gut microbiota after weaning impacts anxiety, cognitive behaviour, and key neuromodulators (tryptophan, monoamines, and neuropeptides) of the gut-brain axis, suggesting that dysregulation of this axis might contribute to the pathogenesis of disorders associated with altered anxiety and cognition.6
In recent years, increasing evidence shows that a dysregulated microbiome impacts gastrointestinal health and affects brain-related disorders.7 There are many developments in the current knowledge about how the gut microbiota is related to conditions such as anxiety disorder, autism spectrum disorder, Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis.
Anxiety Disorders
Anxiety and depression are diverse and complex disorders that can have devastating effects on human function and quality of life.8,9 When the body experiences stress, it alters our normal physiological response to shut down non-essential activity (such as digestion) and directs its resources and energy to the brain and muscles. During a stress response, the vagus nerve might not function properly. This results in an elevated level of pro-inflammatory cytokines and alterations to the gut barrier, leading to increased inflammation, which can change the gut microbiota. The resulting dysbiosis might impact the production of neurotransmitters such as serotonin. Furthermore, a study in rodents found that the genera of Clostridiaceae and Clostridiales, were notably greater in high-anxiety mice than in low-anxiety mice.10
Autism Spectrum Disorder (ASD)
Autism is the fastest growing developmental disability in the world.11 It disrupts communication, social and interactive skills, and it involves repetitive behaviour. While the underlying etiology remains unclear, many with ASD also experience unusual gut inflammation. Some research shows that individuals with ASD often have an altered composition of gut microbes and disrupted mucosal homeostasis compared to individuals without ASD. Children with ASD have been consistently found to have lower levels of Veillonellaceae, Coprococcus, and Prevotella gut bacteria than those without the condition.12 In one study, germ-free mice avoided other mice, shunned new social situations, and groomed themselves excessively.5 In a different study, researchers gave germ-free mice gut microbes from people with ASD and at six weeks old, offspring of these mice socialized less, produced fewer vocal sounds, and engaged in more repetitive behaviour, compared with mice descended from animals that received gut microbes from donors who did not have ASD.13 Mice with ASD-like symptoms had lower levels of Bifidobacterium and Blautia, leading to lower production of tryptophan and bile acid which are compounds needed to produce serotonin. Hence, various studies clearly demonstrate that gut microbiota composition is linked to ASD.
Alzheimer’s Disease
Alzheimer’s disease is the most common form of dementia and by far the greatest factor causing disability and dependency among older people around the world.14 It is a degenerative disorder caused by an aggregation of amyloid plaque leading to progressive loss of neurons. Gut microbiota is a source of amyloid-related proteins. In a rodent model of Alzheimer’s disease, susceptible animals had a remarkable shift in the gut microbiota diversity compared to non-susceptible mice. Additionally, germ-free animals showed a decreased level of cerebral amyloid pathology compared to healthy mice with gut microbiota.15
Fecal microbiota transfer from healthy donor mice was able to reduce amyloid plaque formation and cognitive impairment in susceptible recipient mice.16 Further, a recent study demonstrated that gut microbiota from Alzheimer’s disease patients can promote intestinal inflammation in mice.17 While age remains the greatest risk factor, the gut microbiota also plays an important role in the pathogenesis of Alzheimer’s disease.
Parkinson’s Disease
Parkinson’s disease is the second most common neurodegenerative disease in the world after Alzheimer’s disease.18 Symptoms and signs are in large part due to the loss of neurons that control balance and movement. One of the signs that link Parkinson’s to the gut is that prior to onset of motor symptoms, these patients often have gastrointestinal symptoms, such as difficulty swallowing and constipation.
Research shows a significant reduction of several microorganism metabolic products in patients with Parkinson’s disease, which may contribute to constipation.19 Changes in the gut microbiota composition and reduced SCFA production has been consistently reported in Parkinson’s patients compared to healthy individuals. In particular, stool and tissue biopsies from these individuals contain less butyrate-producing bacteria such as from the taxonomic family Lachnospiraceae and species Faecalibacterium prausnitzii. It is intriguing, and probably significant, that one of the hallmarks of dysbiotic microbiota in Parkinson’s Disease is low abundance of SCFA producers, which correlates with increased neuroinflammation.
Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition characterised by progressive loss of motor neurons.20 The cause of ALS is largely unknown. ALS patients do not generally experience gastrointestinal complication during disease onset. However, some evidence linking the gastrointestinal tract and ALS came from a rodent study. While studying a genetic mutation by developing a mouse model, researchers found that mice only developed inflammatory characteristics in one facility but not another.21 Looking for environmental differences between the mice, they found that the gut microbiota was responsible for the difference. The diseased animals had reduced levels of the butyrate-producing bacteria Butyrivibrio fibrisolvens.22 In a subsequent study, mice receiving butyrate supplementation developed improved intestinal homeostasis and showed delayed weight loss and death compared to untreated controls. Yet, human studies of the gut microbiota in ALS have not yielded conclusive evidence.
Conclusion
It is clear that the gut-brain axis is important to our overall health. The gut microbiota influences function through neurotransmitters, hormonal production, and mucosal homeostasis. The resulting changes are associated with conditions such as autism spectrum disorder, Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Understanding the link between the gut microbiota and the brain through the gut-brain axis will allow for novel therapeutic interventions. Research has shown promising results in a variety of treatments including prebiotics, probiotics, dietary changes, and fecal microbiota transfer. However, more research, including randomized controlled trials, is needed to understand the causal effect of the gut microbiota and brain health.