Key Takeaways
- MGB Axis Studies: Research on the Microbiota-Gut-Brain (MGB) axis primarily involves cross-sectional studies linking gut microbes to brain structure, but a deeper understanding of gut-brain communication is needed.
- ENS Similarities with CNS: The Enteric Nervous System (ENS), known as the “second brain,” shares traits with the central nervous system (CNS), prompting investigations into how CNS mechanisms affect ENS and vice versa.
- Serotonin’s Dual Role: Serotonin, crucial in both CNS and gut, influences the development and function of both systems.
- Interactions of ENS, CNS, and Microbiome: These systems play vital roles in brain and gut development, offering potential therapeutic targets for various medical conditions.
- Remaining Research Questions: Despite impressive progress, critical unanswered questions require further exploration for effective therapies.
- Advancements in Microbiome Study: Recent technology advances and cohort studies have expanded knowledge of the microbiome’s impact on health.
- Microbial Variation: Considerable differences exist in microbial composition among individuals, with factors influencing these variations still under study.
- Gut Microbiome and Mental Health: Changes in the gut microbiome are linked to neurological and mental conditions, though causation remains unclear.
- Maternal Influence on Microbiome: Maternal diet and stress during pregnancy can significantly shape an infant’s microbiome, affecting development.
- Microbial Influence on Neurodevelopment and ENS: Microbes impact neurodevelopment, including the ENS, with implications for gut motility and neural coding.
Introduction
The gut-brain axis is a complex bidirectional communication system between the gastrointestinal tract and the central nervous system.
Recent research has shown that this connection is not limited to the nervous system, but also involves the immune system and the gut microbiome.
The immune system plays a vital role in maintaining the balance between the gut and brain, and disruptions in this balance have been linked to a range of health issues, including autoimmune disorders, mood disorders, and neurodegenerative diseases.
Understanding the interplay between the immune system and the gut-brain axis is crucial for developing effective prevention and treatment strategies for these conditions.
In this article, we will explore the relationship between the immune system and the gut-brain axis, and how they work together to keep us healthy.
In This Article
The Gut-Brain Axis: How Our Second Brain Keeps Us in Balance
The gut-brain axis is a vital component in maintaining homeostasis within the body.
There are many intrinsic and extrinsic factors that influence signaling along this axis, which in turn modulates the function of both the enteric and central nervous systems.
Recent studies have identified the microbiome as a significant factor in modulating gut-brain signaling, leading to the establishment of the concept of a microbiota-gut-brain axis.
The idea that the brain and gut are linked was known by some of the greatest modern biologists like Darwin, Pavlov, James, Bernard, and Cannon before the 20th century1, but it wasn’t until then that scientists began studying how changes in gut physiology can affect emotions.
Initially, these studies were limited because of the lack of advanced technology, but recent research has shown that there are actually very close links between mental and gastrointestinal health.2
Unraveling the Gut-Brain Axis: From Ancient Beliefs to Modern Science
Pioneering Insights in the 19th Century
This research has also revealed some of the mechanisms behind the connection.
The Role of Nerves and Beyond
The nerves in our gut play a big role in how it works.
The Enteric Nervous System (ENS) is made up of lots of neurons and glia and it goes all through the intestine.
This system can work without help from the brain, but the brain [6] and other parts of the Autonomic Nervous System (ANS) can also affect how our gut works.
This system can work without help from the brain, but the brain 3and other parts of the Autonomic Nervous System (ANS) can also affect how our gut works.
Other things like the immune system and the bacteria living in our gut can also play a role.
Disorders and the Gut-Brain Axis
Studies have shown that there is a link between the brain and the gut, and the way they work together.
For some illnesses, like Parkinson’s disease, problems with the gut might start happening before issues with the brain show up.
Other disorders of the brain-gut connection, like irritable bowel syndrome (IBS), can include psychological symptoms and mental health issues. 4
Historical Perspective on Holistic Medicine
As far back as Ancient Greece, philosophers like Hippocrates, Plato, and Aristotle believed that the brain and the rest of the body are connected.
This idea eventually led to the realization that when studying diseases, looking at the whole person is more important than just looking at a single organ system 5
It wasn’t until the 1840s that William Beaumont proved that emotions can have an effect on digestion, showing that the brain and gut are connected and that there is something called a gut-brain axis.
Signs and symptoms in the gut are an important part of illnesses that involve the brain and the digestive system, such as Irritable Bowel Syndrome (IBS).
These are usually connected to emotional issues and mental health diagnoses.
Modern Tools for Understanding
Thanks to brain scans, it is now possible to see how the brain and the gut are linked.
This means that we can see how feelings in the gut can activate areas of the brain that control how we feel emotionally. 6
The gastrointestinal (GI) system is controlled by a complex network of nerves and muscles 7, 8
This network includes the enteric nervous system (ENS) which is inside the intestines, as well as signals from the brain 9 and other parts of the autonomic nervous system.
The immune system and the microbiome also have an influence on GI physiology.
It’s not just the brain that’s in charge- the gut can also send signals to the brain, and changes in how the two systems communicate can lead to health problems.
The Microbiome’s Impact
In recent years, scientists have begun to realize how important our microbiome (the trillions of tiny living organisms found in our gut) is in how it affects our brain.
Studies are still relatively new but have already discovered how the microbiome can influence a person’s emotions, thinking, and learning.
This has made the microbiome a possible target for therapies in the future. 10, 11
The Gut Connectome
Gut microorganisms communicate with the central nervous system (CNS) through various channels, including neural, endocrine, and immune signaling.
Similarly, the CNS can influence the gut microbiota both directly, by inducing the expression of virulence genes through stress mediators, and indirectly, by controlling gut function through the autonomic nervous system (ANS) which regulates factors like motility, immune response, and secretion.
Additionally, the enteric nervous system (ENS) plays a role in modulating microbial composition by affecting secretion, motility, permeability, and immune defense 12
These interconnected pathways are now being recognized as a complex communication network, often referred to as the gut connectome 13
Studies have shown that some gastrointestinal problems in neurological conditions can be caused by genetic defects and environmental factors that affect both gut and brain development.
The enteric nervous system (ENS), also known as the “second brain,” has many similarities with the central nervous system (CNS).
These similarities have led researchers to investigate how the mechanisms that cause CNS disorders can also lead to ENS dysfunction and vice versa.
For instance, serotonin, a key transmitter in both the CNS and gut, can affect the development and long-term functions of both systems.
Future Therapeutic Targets
The critical involvement of the enteric nervous system (ENS), central nervous system (CNS), and the microbiome in brain and gut development and function suggests that understanding their relationships can lead to new therapeutic targets for common yet poorly understood medical conditions.
While current research is impressive, there are still important unanswered questions that need to be addressed to facilitate the development of effective therapies.
This review focuses on the current evidence supporting the interactions between the brain, gut, and gut microbiota, and their contribution to human disease.
The Microbiota-Gut-Brain (MGB) Axis
Unraveling the Microbiome: Advances in the Past Decade
The past decade has seen a huge jump in our comprehension of the microbiome and its connection to a variety of aspects of health and disease, thanks to the improvement of next-generation sequencing technologies and large cohort studies 14
Microbial Diversity in the Gut: Key Insights and Challenges
In humans, the greatest number of microbes is found in the gut, where an estimated 3×1013 microbes from over 60 genera can be found 15
There is a huge amount of difference between people when it comes to their microbial makeup and we are still learning about the factors that affect it in both healthy and sick people.
Research studies have also shown that changes in the diversity and proportion of bacteria and their by-products in the gut are linked to many neurological and mental health issues like Parkinson’s disease, Alzheimer’s disease, autism, and depression 16
These studies do not yet offer proof that the gut microbiome is the cause of these conditions.
In the field of clinical research, the exploration of the MGB axis has been primarily limited to cross-sectional studies that establish connections between gut microbes and brain structure in both healthy individuals and those with various medical conditions 17
There is a big difference in what we know about how the gut and the brain communicate with each other.
Scientists have studied how the immune system, signals from the gut to the brain, and the vagus nerve (which links the gut and the brain) help the gut and the brain to send messages to each other 18
However, more research is needed to really understand the communication between the gut and the brain.
HIGHLIGHT
Advancements in sequencing technology have shown connections between the gut microbiome and neurological/mental health conditions, though causation remains unconfirmed. More research is needed.
MGB Axis in Early Life
Maternal Influence on Infant Microbes
It is still uncertain whether microbial colonization takes place in the womb 19
Yet, maternal diet 20 and stress during pregnancy 21 have been found to influence an infant’s microbiome.
The maternal microbiome can thus significantly affect an infant’s development and physiology 22
Interestingly, the times of greatest changes in the developing microbiota partially match with the periods of development of the brain and digestive system. 23
This suggests that the microbiome may be important for these important bodily systems.
Microbial Transformations from Birth to Adulthood
Changes in the microbiota occur continuously during adolescence24 , but these modifications become more gradual and move towards an adult-like profile.25
In adults, what you consume has the biggest effect on the composition of the microbiota 26 , although antibiotic use can also disrupt the microbiota at any age. 27
After a few days of being born, a shift occurs in the microbiota population in order to provide the nutrients necessary to support a baby’s brain and body development .28
This change in gut microbiota may depend on if the baby is breast or formula-fed.
At weaning, a major change takes place, when an infant transitions from breastmilk or formula to a solid diet, which is observed in various species including humans and rodents .29,30
Although there are continuous modifications until adolescence, these changes are more gradual and directed towards an adult-like profile .31
Differences in gut microbiota may be related to how an infant is fed, either through breast milk or formula.
Most studies suggest that when compared to formula-fed babies, breastfed babies have a less diverse and less rich microbiome, with higher levels of Proteobacteria and Bifidobacteria, and lower levels of Bacteroidetes and Firmicutes.
However, these differences don’t seem to be connected to differences in the behavior of the babies, such as colic 32, 33
The postnatal microbiota is not very stable in the first few months of a baby’s life, but it gets more stable and varied as the baby grows older.
How the baby’s gut gets colonized when they are born depends on lots of things, like how they were born, if they are breastfed, if they were born prematurely, what the environment is like, their genetics if they have had antibiotics, and things about their mother like if she is ill, stressed or overweight.
However, these differences do not seem to be related to infant behavior like colic.
HIGHLIGHT
Maternal diet and stress affect infant microbiome, impacting brain and digestive system development. Microbiota changes from birth to adulthood, influenced by diet and antibiotics.
Microbiota and CNS Development
Impact of Microbiota Composition on Neural Processes
Research in germ-free (GF) mice has provided the strongest evidence for the role of the microbiota in neurodevelopment.
Studies, where GF rodents have been re-colonized with “normal” microbiota (from specific pathogen-free animals) at different ages, have demonstrated that post-weaning re-colonization is more effective at restoring GF deficits than recolonization later in life in certain aspects of brain or immune function and behavior 34,35
However, some functions in GF animals, such as those affecting CNS serotonergic neurotransmission, cannot be recovered by re-colonization by the time of weaning, indicating that the window for microbial influence on these functions has already closed.
Research has shown that the composition of the microbiota has a major impact on fundamental central neural processes such as development, myelination, neurogenesis and microglia activation 36
Germ-free (GF) mice studies have provided the strongest evidence for the role of the microbiota in neurodevelopment 37
Microbiota Influence on Cognitive Development
Post-weaning re-colonization of GF rodents with “normal” microbiota has been found to be more effective than recolonization later in life at restoring deficits seen in the GF mice when it comes to specific features of brain or immune function and behavior.38
Studies that have followed up to two years of age have repeatedly found a connection between early antibiotic exposure and cognitive development 39
Another study found a link between cognitive ability at two years old and the composition of the microbiota a year earlier 40
Recently, scientists have discovered that the different types of bacteria in infants’ bodies can influence their cognitive abilities when they are two years old.
What’s more, they found a connection between those bacteria and the way different parts of the brain are connected.
This connection is linked to cognitive abilities at two years old 41
HIGHLIGHT
Germ-free mouse research highlights microbiota’s role in neurodevelopment, impacting brain functions and cognitive development, with early antibiotic exposure implications.
ENS Development
ENS Development Beyond Birth: A Lifelong Journey
Research has shown that the development of the enteric nervous system does not end after birth. In fact, it continues throughout life in animal models 42
Glial cells, which are a type of nerve cell, remain at low levels, and neurons may even be replaced more quickly than glial cells 43, 44
Additionally, the connections between nerve cells in the enteric nervous system may change even after adolescence 45, 46
Gut Microbiota’s Impact on the Enteric Nervous System
Research into the development of the ENS has mostly looked at its molecular and genetic origins 47
In recent years, however, there has been more focus on factors such as the gut microbiota and the immune system in the postnatal gut environment, which can help form the ENS 48
Studies on GF mice (mice with a reduced number of enteric neurons and altered gut-brain neural pathways show that these mice have deficits in gut motility as well as reduced excitability of intrinsic primary afferent neurons.
However, by conventionalizing adult GF mice (giving them exposure to bacteria) the deficit in intestinal transit time can be reduced 49, neuronal excitability can be restored 50, enteric neuron coding can be altered and enteric glial cell density and gut physiology can be normalized
This demonstrates that the microbiota plays an important role in ENS plasticity (the ability of the enteric nervous system to change according to the environment).
Similar effects have been noted after bacterial exposure through probiotics or specific bacterial strains 51
Research has shown that certain microorganisms can affect the activity of the intestines’ nerves 52
This includes things like G-protein-coupled receptor signals, serotonin, short-chain fatty acids, interactions between microbes and the intestinal wall, and aryl hydrocarbon receptor (Ahr) , which is a type of transcription factor. 53
Aryl hydrocarbon receptor (Ahr) is a type of biosensor found in the gut that helps to maintain balance between intestinal epithelial cells and immune cells.
Recently, researchers discovered that when Ahr is not present in the neurons of the gut or when its regulator (CYP1A1) is overactive, the colon muscles don’t move as much as they should, similar to what happens when the gut has no bacteria 54
Preclinical studies have explored the possibility of reverse regulation where the enteric nervous system influences the microbiome.
Changes in the composition of colonic and/or fecal microbiota have been observed in cases of congenital aganglionosis in animal models.
However, further research is needed to fully understand the relationship between the ENS and the microbiome 55
HIGHLIGHT
While initial research hints at changes in microbiota composition in congenital aganglionosis animal models, further investigation is imperative to fully comprehend the complex interactions between the ENS and the microbiome.
Discussion
The gut-brain axis, a critical component in maintaining bodily homeostasis, has gained significant attention in recent years.
This axis encompasses the intricate interplay between the gut, the enteric nervous system (ENS), the central nervous system (CNS), the immune system, and the microbiome.
- Historical Context: The brain-gut connection has been recognized since ancient times, but it wasn’t until the 20th century that scientists delved into how gut physiology can impact emotions and mental health.
- The Role of the Enteric Nervous System (ENS): The ENS, also known as the “second brain,” is a complex neural network in the intestines. It works independently but is influenced by the CNS and autonomic nervous system. This network regulates gut function and communicates with the brain.
- Microbiota-Gut-Brain Axis: The microbiome plays a crucial role in regulating gut-brain signaling. Communication between the gut microbiota and the CNS occurs through neural, endocrine, and immune pathways, while the CNS impacts factors such as motility, immune response, and secretion. The ENS is also involved in this relationship.
- Implications for Health: The gut-brain axis is vital for our health. Disruptions in this axis can cause conditions like Parkinson’s disease, and irritable bowel syndrome, and may also be linked to neurological disorders such as Alzheimer’s disease, autism, and depression.
- Developmental Aspects: The gut-brain axis development is ongoing and can have long-term health implications. Factors such as antibiotic exposure, diet, stress during pregnancy, and breastfeeding can shape an individual’s microbiome and impact their cognitive development.
- ENS Plasticity: The ENS is highly adaptable to environmental changes and is influenced by microbial exposure. Studies on germ-free mice have shown the crucial role of microbiota in ENS function and gut physiology.
- Mechanisms of Communication: Gut microorganisms can affect intestinal nerves through various mechanisms, including G-protein-coupled receptor signals, serotonin, short-chain fatty acids, interactions with the intestinal wall, and the aryl hydrocarbon receptor. Understanding these mechanisms is important for understanding the gut-brain connection.
- Future Therapeutic Avenues: The gut-brain axis offers new potential for therapeutic interventions. Targeting the microbiome to improve emotional well-being, cognitive function, and gastrointestinal health shows promise, but more research is required.
Conclusion
The gut-brain axis is a complex and dynamic system that plays a crucial role in maintaining overall health and well-being.
Recent research has shed light on the significant influence of the microbiome on this axis, highlighting the microbiota-gut-brain connection.
Understanding the intricacies of this communication network has the potential to revolutionize our approach to treating a range of conditions, from neurological disorders to mental health issues.
However, while current research is promising, there are still many unanswered questions, and further investigation is needed to fully harness the therapeutic potential of this axis.
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