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The Brain and the Microbiome: Development and Regulation

A deep evolutionary relationship.

by Malay Nanavaty

How do the Brain and the Microbiome Interact?

When you look at the human genome, you will notice that the number of genes we have is incredibly low. Our entire genome has approximately 20,000 genes. This is mostly explained by the process of gene splicing, which enables one genetic code to serve many functions. However, this lack of raw diversity also opens up the possibility of symbiotic relationships between organisms in and on our bodies with our cellular systems. Following this logic, it is possible that at least some critical molecules our bodies need to produce come from our microbiome.

This hypothesis is indeed borne out by the science; many microbiome gene products have a distinct impact on mammalian cell function. This suggests that the microbiome as a whole may be acting as a type of “bioreactor” for our bodies. These bacteria appear to be making molecules that direct our immune systems, regulate our metabolisms, and modulate our epigenome. In fact, our bodies have evolutionary mechanisms for converting bacterial molecules into more useful versions of the chemical, solidifying the claim that our microbiomes have co-evolved with our species.

The Microbiome and Brain Development

Another interesting finding about the microbiome is its importance in early brain development. Microbiome transplantation is much more effective if it is done in the early years of life. A poor microbiome in early childhood has been found to be correlated with many neurological defects. This suggests that the microbiome produces chemicals that help maintain and adapt our brains to whatever situation we are born into.

Character Traits and the Microbiome

Lab studies on mice have shown the effect of the microbiome on personality traits in mice and rats. For example, mice that have been denied a microbiome tend to be more timid than the average mouse. Similarly, rats denied a microbiome tend to show increased aggression compared to their normal counterparts. This suggests that the microbiome plays an important role in regulating the basic behavior of these species.

Such a finding has a large evolutionary impact, since risk taking behavior and aggression levels must be optimized in order to survive in the wild. It appears that the microbiome helps these lab animals retain the appropriate character traits to thrive. Since the early microbiome is dependent on diet for colonization, it would be reasonable to assume that animals with different food sources (and thus different microbiota) may have different types of modulation in the brain. These changes, personality shifts or otherwise, may actually be an attempt of the microbiome to prepare their host for life in the environment depicted by their early diet.

The Role of the Immune System

Generally, the microbiome is a source of constant stimulation for the innate immune system. This is because the presence of bacteria in the body requires the immune system to stay alert for opportunistic pathogens. Chemically, this alertness translates to elevated levels of the class of chemicals known as cytokines. This stimulation by cytokines, in turn, induces the immune cells in your body to release various molecules, some of which are essential for the promotion of non-REM sleep. During the day, these molecules are inhibited by naturally elevated cortisol levels. As these levels fall at night, the sleep molecules produced by these immune cells begin to take effect.

However, there is a downside to cytokine release. While a moderate level of cytokines is beneficial, pushing levels too high begins to generate problems. In people with microbiome dysbiosis, cytokine levels remain much higher than in healthy people. This elevation in cytokines overstimulates the immune system and the nervous system. This generates hypersensitivity to stressful stimuli, making these people more prone to anxiety and lowering their pain threshold. Over time, this constant state of alertness leads to physiological fatigue which manifests as depression. Thus, it is no surprise that a poor microbiome is associated with diseases such as depression, restless leg syndrome (anxiety induced), and fibromyalgia (pain threshold).

Probiotics and Their Effect

Probiotics can play a role in helping manage these issues in the microbiome. We know that bacteria ingested through food can help stimulate the immune system. One way the body responds to this bacterial load is by reducing the permeability of the gut to bacterial molecules. Reduced gut permeability means that less of the ‘stuff’ in the gut is able to interact with the body tissue. Thus, hostile bacteria in the gut are unable to penetrate the mucus lining of the gut and trigger the immune system. When this happens, these bacteria are not able to stress our bodies as much, lowering baseline cytokine levels.

Adaptive Immunity: Celiac’s Disease and the Brain

Very little research has been done on the effect of the microbiome on the adaptive immune system. This is the part of the immune system that attacks foreign invaders with antibodies and can trigger autoimmune responses. The only well studied link between the two had been done regarding Celiac’s Disease (CD). This autoimmune condition is triggered by ingestion of gluten and often results in neurological dysfunction as well. A contributing factor in this condition is the level of Bifidobacterium in the host. People with CD typically have lower levels of these bacteria, which play a critical role in detoxifying gluten breakdown products. Additionally, these bacteria generate anti-inflammatory molecules that may help ward off/mitigate unproductive immune responses.

Bacterial Metabolites and Their impact on the Brain

While a healthy microbiome generates many beneficial molecules that help us thrive, they also create some unfortunate byproducts. Fortunately, our bodies have developed mechanisms to efficiently break down these byproducts and excrete them. One of the most common toxic byproducts produced by the microbiome is ammonia.

Ammonia and a Healthy Liver

Ammonia is produced in the breakdown process of proteins. When our microbiomes begin to ferment the proteins we eat, they release ammonia which is then absorbed into our bloodstream. In healthy people, this ammonia is captured by the liver and excreted before it can do anything malicious. However, if the liver has been damaged by poor drinking and eating habits, the story changes quite drastically.

As the damaged liver becomes overwhelmed with ammonia, the excess toxin begins to spill into general circulation. Ammonia is special because it is able to cross the blood brain barrier and interact with your central nervous system. Once in the brain, ammonia inhibits the production of normal neurotransmitters such as dopamine and serotonin. Instead, ammonia facilitates production of the less effective neurotransmitter octopamine. This results in learning and motor deficits in people with damaged livers, symptoms commonly found in alcoholics.

Short Chain Fatty Acids: A Double-Edged Sword

One of the most common byproducts of bacterial activity in the gut is the production of SCFAs. These molecules are produced as bacteria break down fibers and have beneficial properties. For example, SCFAs are anti-inflammatory and help maintain the tissue integrity of the gut by serving as a food source for our cells.

Recently, it has been discovered that SCFAs play an important role in the epigenetic regulation of our genome. Specifically, SCFAs stop our body from unwinding our DNA and exposing them to damage. The excess unwinding (deacetylation) of DNA has been linked to neurological disorders such as schizophrenia, dementia, and dementia.

However, SCFAs do not always produce the beneficial qualities we associate with them.

SCFAs, Autism, Pregnancy, and Microbiomes

Autism is one of the most studied neurological conditions when it comes to microbiome research. There is a growing body of evidence suggesting that these two factors are significantly linked. Surprisingly, SCFAs have become implicated in the development of such neurological diseases. Laboratory studies in animal models have shown that excess SCFAs too early in life may actually alter the composition of the microbiome and contribute to the poor development of the host’s brain. This is another good example of how time is an important dimension to look at when determining the utility of individual molecules; something beneficial in adulthood can be exactly the opposite when you are a child.

Another interesting finding shows that the brain structures characteristic of people diagnosed with autism begins to develop in the womb. This suggests that perhaps the maternal microbiome also plays a role in proper infant brain development. Once born, however, the infant microbiome becomes essential for brain development.

The Microbiome and Signalling Molecules

The bacteria that live in our guts are also special because of the molecules they use to signal to each other. Interestingly, many hormones that are used by our brains for daily functioning are also used by bacteria for different purposes. Neuroendocrine molecules such as serotonin, GABA, acetylcholine, epinephrine, and dopamine are commonplace in the microbiome and may even be imported to our brains for use.

Since these molecules serve different purposes in bacteria, we can see very interesting patterns in the microbiomes of people with different dispositions. For example, people that are easily stressed tend to have elevated epinephrine levels at baseline. However, E. coli and Actinobacteria recognize epinephrine as a growth signal. Thus, stressed individuals are observed to have higher levels of these bacteria living in their guts. Such patterns of bacterial adaptation highlight the many different ways we communicate and modulate our microbiome (and vice versa).

Conclusion

The brain and the microbiome appear to have an incredibly strong link to one another. Intuitively, this makes sense; the brain needs constant information on the state of the outside world, and diet is a reliable indicator of prosperity. Because of this dependence, the bacteria in our gut and our brains have grown deeply interconnected, sharing molecules, negotiating metabolism, and even collaborating on the management of both our DNA and our conscious mood. On top of all that, the microbiome has become an indispensable tool in early life, guiding the development of the complex structures in the brain. The current research only scratches the surface of this evolutionary relationship. With more, perhaps we will finally come to understand exactly how deep this connection truly is.

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The Brain and the Microbiome: Development and Regulation

A deep evolutionary relationship.

by Malay Nanavaty

Stress and the Microbiome: A Notable Relationship

Gut reactions and brain health

by Malay Nanavaty
 

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