Does the gut hold the key to brain development and health?

Through decades of research, scientists have established the strong connection between the gut and brain, modulated by neurons, neurotransmitters, hormones, and immune mediators. More recently, focus has been extended to the role of the gut microbiota (referring to the trillions of microorganisms and viruses residing in the gut), creating considerable excitement with findings that suggest specific intestinal microorganisms (the greatest amount of information comes from studies of bacteria) may be associated with memory, learning, stress, and mood and even neurodevelopmental and neurodegenerative disorders.

Today, the so-called microbiota–gut–brain axis is an area of multi-disciplinary research that has captured international attention. Scientists specialised in neurology, endocrinology, immunology, microbiology, and bioinformatics have all found a niche worthy of exploration. Interest is such that international journals publish as many as 30 new studies a day related to this field.

While there is now considerable evidence that the microbiota–gut–brain axis plays an important role in mental and cognitive health, human clinical studies have as yet provided few clear answers to one burning question. How?

How does the gut microbiota influence brain development and function? Are brain disorders potentially shaped by the gut microbiota? What role does diet play and what is its scope in influencing the microbiota-gut-brain axis? How do dietary supplements exert their apparent effect(s) on stress, mood, and cognition? What physiological mechanisms are at play? And do alterations in microbiota-gut-brain interactions through life reflect the cause or symptom of an underlying brain condition?

Answering these questions is critical to harnessing the intestinal microbiota as a tool for ameliorating or preventing brain disorders, determining potential links with metabolic and cardiovascular diseases and for developing nutritional and therapeutic strategies that support and strengthen the brain health of the individual.

This perspective paper offers a short introduction to the microbiota–gut–brain axis, the knowledge and research so far and the considerable remaining gaps in the understanding of causes and mechanisms. Finally, the paper proposes how future meaningful progress can be made, which should benefit researchers active in fundamental and clinical gut–brain research from a multi or transdisciplinary perspective (including doctors and possibly patients/care takers), professionals in the mental health care, as well as research funders, food industry and investors. Once the mechanisms of gut microbiota modulation of brain health are unravelled, the potential for improving human quality of life and well-being is vast.

 

The two-way street between gut and brain

Microbiota–gut–brain communication, research, and potential therapeutic strategies

A ‘gut feeling’ or the sensation of ‘butterflies’ in the stomach are common illustrations of how a response in the brain is felt in the gut. Beyond that, microbiota–gut–brain interactions are much more complex to describe—as is abundantly clear from the intense research efforts to document them and propose links with brain development, physiology, function, and health.

As a highly complex community, the gut microbiota has a myriad of functions including education of the immune system, protection against pathogens, energy homeostasis and metabolite production. Diet is a key determinant of composition of gut microbial populations and impacts on gut transit time and gut environmental conditions, and critically determines the supply of substrates for microbial growth.

The gut microbiota is modifiable by diet and specific dietary components, and it plays a key role in shaping the composition and activity of the microbiota from birth, which impacts lifelong health.

In relation to brain development and brain health, up until now, many of the studies examining the microbiota–gut–brain axis have been performed in animal models; far fewer clinical studies have investigated whether the interactions observed in rodents are also observed in humans. Due to a heavy reliance on association studies, there is still little evidence of the triggers and mechanisms linking the microbiota to gut–brain communication.

Pathways for communication

At a fundamental level, the gut–brain axis is a two way communication pathway composed of the central, enteric, and autonomic nervous systems and the hypothalamic–pituitary–adrenal (HPA) axis. The microbiota–gut–brain axis includes the gut microbes—comprising bacteria, viruses, fungi, and archaea—and their metabolites and by-products as factors in this two way communication.

The vagus nerve, the immune and neuroendocrine systems, the neurotransmitters and metabolites along with the gut microbiota are currently the key pathways of interest in microbiota–gut–brain axis research.

The vagus nerve—the physical connection between brain and gut.

The tenth cranial nerve that extends from the brain to the abdomen is responsible for regulating internal organ functions such as digestion, heart rate and respiratory rate. Comprising efferent and afferent neurons (neurons that receive information from our sensory organs (e.g. eye, skin) and transmit this input to the central nervous system are called afferent neurons. Neurons that send impulses from the central nervous system to your limbs and organs are called efferent neurons), the vagus nerve carries motor signals between the brain and organs, including the intestinal cells, which are also subject to the influence of the gut microbiota. The brain is, in this way, able to ‘sense’ the environment in the gut.

The immune system—firm roots in the gastrointestinal tract

Evidence of the immune system’s crucial role in gut–brain signalling is growing. Today, it is widely recognised that most neurological conditions, including autism spectrum disorders (ASD), epilepsy, Alzheimer’s disease, Parkinson’s disease and cerebrovascular diseases, have low-grade systemic inflammatory components. This low-grade inflammation is indicative of a malfunctioning immune response and dysbiotic microbiota.

From a brain health perspective, microbiota-immune interactions are of interest due to the systemic low-grade inflammation often seen in neurodegenerative, neuropsychiatric, and metabolic disorders. For example, there have been extensive studies of the causal role of the microbiota in inflammatory bowel disease (IBD), which is associated with an increased susceptibility to Parkinson’s disease.

The neuroendocrine system—gut hormones and the regulation of well-being

Recent studies suggest that gut hormones are involved in the physiological processes that lead to disorders such as anxiety and depression—with indications that mood disorders and obesity often co-exist. Scientists focus increasingly on the ability of the microbiota to modulate gut hormones and consequently, their potential to regulate mood.

Increasing evidence supports the concept of two way communication between the neuroendocrine system and gut microbiota. Disturbances in both systems have been associated with disorders such as depression and irritable bowel syndrome. Findings further indicate that the gut microbiota can activate the HPA axis—one of the body’s major neuroendocrine systems that controls responses to stress and is involved in regulating, for example, mood and emotions and the immune system.

A growing body of research suggests that a number of neurotransmitters function as hormones and vice versa. Dopamine and serotonin, for example, are known to have hormonal properties. Although these hormone-like neurotransmitters are not solely produced in the gut, the gut microbiota is thought to play a role in their modulation.

Neurotransmitters and metabolites

In the context of the microbiota–gut–brain axis, noteworthy neurotransmitters include dopamine, serotonin, noradrenaline, and gamma-aminobutyric acid (GABA). The neuroactive amino acids tyramine and tryptophan, short-chain fatty acids (SCFA), and bile acids are other molecules of interest.

GABA

GABA is believed to have a role in behaviour, cognition and the body’s response to stress, anxiety and fear, while low GABA levels are associated with psychiatric illnesses, including schizophrenia, autism and depression. Although the regulatory importance of the microbiota is not yet fully mapped, studies of germ-free animals suggest that the microbiota influences circulating GABA levels. GABA is also produced by some Lactobacilli and specific strains of Bifidobacterium.

Serotonin and tryptophan

Much research has linked the microbiota with serotonin regulation in the gut. Serotonin is involved in mood, cognition, sleep, and appetite control. Today, selective serotonin reuptake inhibitors (SSRI) are commonly prescribed treatments for depression as they increase the level of available serotonin in the brain. Neurobalance also does this in a more natural way. Studies also focus on the amino acid tryptophan as the sole precursor of serotonin. It has been proposed that gut microbiota may influence tryptophan uptake and, in that way, serotonin synthesis.

Dopamine

Dopamine is a major neurotransmitter associated with the brain’s reward system and is a precursor for epinephrine, also known as adrenaline, and norepinephrine, which contributes to arousal and alertness as well as behaviour and cognition. Disorders associated with dopamine deficiency include addiction, schizophrenia, and Parkinson’s disease. Research suggests that certain bacteria produce or metabolise dopamine.

SCFAs

The SCFAs propionate, butyrate and acetate are metabolites mainly produced and regulated by the bacterial fermentation of complex plant-based polysaccharides in the gut. In recent years, research has explored the potential role of SCFAs in gut–brain communication with and across the blood–brain barrier (BBB) and in supporting BBB integrity—a progressively leaky BBB being seen in Alzheimer’s disease.

Studies have led to a wide range of findings that connect butyrate, for example, with memory, cognition, mood, and metabolism. Acetate has been associated with appetite regulation, and propionate may be involved in protecting against type 2 diabetes and obesity and reducing stress behaviours.

Gut microbiota—the omnipresent factor, modulated by diet

Research has repeatedly revealed new aspects of the microbiota’s contribution to gut–brain crosstalk, beginning with maternal nutrition and the colonisation of the infant gut at birth. It is also known that age, gender, genetics, environmental factors, geography, disease, exercise, fasting and diet influence the microbiota’s composition—diet and nutritional status being among the most influential factors. Recent reviews give a comprehensive overview of the role of diet in shaping the gut microbiota. The gut microbiota itself can influence dietary preferences via the mesocorticolimbic system, responsible for the hedonic response to food intake.

Greater knowledge of the gut microbiota represents exciting possibilities to track changes in microbiota composition, activity, and behaviour in relation to the development and progression of brain disorders. Another promising avenue of exploration is the modulation of the gut microbiota by specific dietary components such as probiotics, prebiotics, postbiotics, synbiotics, and parabiotics. Such work could lead to novel therapeutic strategies.

The potential for nutritional and therapeutic strategies

Research has established many links, associations, and hypotheses about the lifelong influence of the gut microbiota on brain health. Underlining this critical role, one review ranks the gut microbiota as the fourth key factor in early-life programming of brain health and disease, alongside prenatal and postnatal environment, and host genetics. The scientific challenge is to identify opportunities to alter and fine-tune the microbiota and, through that, enhance human health and wellbeing.

To this end, clinical trials have explored dietary supplementation with pro-, pre-, syn- and postbiotics, omega-3 polyunsaturated fatty acids and phytochemicals, such as polyphenols, which may act as prebiotics. High-fibre diets—promoting SCFA production by the gut microbiota—are a promising intervention to overcome maternal-obesity-induced impairment of cognitive and social functions. Faecal microbiota transplants are another potential therapeutic opportunity. Here, important regulatory differences apply whether developing strategies for clinical therapies or foods.

Regulation of stress, mood, and anxiety

Research has associated the gut microbiota with a range of stress- and mood-related conditions. In relation to stress, several clinical studies have linked probiotic and prebiotic supplementation with a positive outcome. The majority of mood and anxiety studies, on the other hand, have relied on pre-clinical animal models. Healthy mice that received a probiotic formulation with Lactobacillus rhamnosus, for example, were seen to perform best in tests designed to provoke anxiety, depression, and stress [70].

Some clinical trials have observed a significant reduction in stress and anxiety following probiotic intervention with Lactobacillus and Bifidobacterium strains. Reviews of clinical trials found probiotics had a limited effect on psychological outcomes—although this could be partly explained by an incomplete evidence base along with a large heterogeneity in the population, cognitive tests, and interventions. Another study reported a positive probiotic effect on mood and anxiety in patients with IBD.

Implications for autism spectrum disorder

The microbiota has been demonstrated to have a clear role in autism spectrum disorder (ASD). One study has observed how the transplantation of microbes from a human diagnosed with ASD induced-like behaviour in mice. Conversely, several clinical studies of ASD have found that microbiota modulation through antibiotic, prebiotic and probiotic and faecal transplantation treatments can improve social behaviour. Researchers have further reported a reduction in anxiety behaviour, hyperactivity and defiance behaviours. The most beneficial probiotics for ASD are D-lactate free probiotics. Some strains of bacteria produce d-lactate acidosis, which increases neurological and behavioural issues found with ASD. D-lactate free probiotics enhance the microbiota without increasing this deleterious lactate acidosis, thus avoiding compounding neurological symptoms.

Other findings show that children diagnosed with ASD are four times more likely to have GI symptoms, including inflammation and abdominal pain and that faecal transplantation may have long-term beneficial effects on intestinal and behavioural symptoms.

Learning and memory

A number of studies have explored the relationship between the gut microbiota and the development of learning and memory systems in childhood. This has led to a growing appreciation that sensitive periods of development occur across the microbiota–gut–brain axis.

A new approach to cognitive development research is required, including the microbiota–gut–brain axis as a peripheral force among the complex biological systems that act on behaviour. By improving understanding, this may lay the foundation for innovative therapies for learning and memory disorders.

Cognitive performance and age-related disorders

Many scientists now believe in the close relationship between microbial diversity and healthy ageing. Studies in mice have shown that faecal microbiota transplantation can correct age-related defects in immune function – and that a similar transplant from aged to young mice has a detrimental impact on key functions of the CNS. These and other findings highlight the importance of the microbiota-gut-brain axis during ageing and raise the possibility that a ‘young’ microbiota may maintain or improve cognitive functions in life’s later years.

Neurological research suggests the microbiota also play a role in neurodegenerative diseases. This supports the idea that an ageing gut microbiota could be linked to immune and neuronal dysfunction in Parkinson’s and Alzheimer’s disease. Indeed, studies of faecal microbiota transplants in transgenic mouse models point to a causal relationship between intestinal microbiota, protein aggregation and cognitive problems. More studies are necessary to confirm this.

Knowledge with potential

Whether changes in the microbiota are key to detecting and understanding the physiological processes that lead to brain disorders is still unknown. But the possibilities are undeniable. Research has uncovered positive indications that therapeutic interventions may have a beneficial impact, for example in neurodevelopmental disorders, such as ASD, and age-related neurodegenerative disorders. And there is every reason to be optimistic about the potential to reduce stress and anxiety. The task now is to overcome the barriers to further discovery.