The Nexus of the Microbiome, ECS, Hormones, & Neurotransmitters

The human body is a sophisticated mechanism. Naturally, it took a long time to break down the functions behind the scenes that make us work.

Back when we identified ourselves as Homo sapiens in the phylogenetic tree, we used to think that all of the parts of the body are controlled by the brain and a lot of our metabolic processes are controlled largely by our genetics. This set the stage for the human genome project. The idea behind it was to sequence the entire human genes and look at the gene code with the assumption that there would be a dysfunctional gene for every non-communicable human disease like diabetes, cancer, heart disease, etc. But the finding was astounding.

Given the complexity of human functions, it was estimated that there would be somewhere around 200,000 - 250,000 functional genes. As it turned out, a human body has approximately 22,000 functional genes only which is about half of an earthworm’s. Imagine sitting at the top of the food chain with less genetic material than an earthworm!

A decade after that, The Human Microbiome project solved this riddle. Turns out, what we lack in functional human gene count, we make up for in microbial genes. An average human body has more than 4 million bacterial genes primarily residing in the gastrointestinal (GI) tract or the gut that control 90% of our metabolic activity and other everyday functions. It’s fascinating to think that bacteria is what makes us human! In addition to bacteria; fungi, viruses, archaea, and phages also colonize the intestine. All of this is collectively known as the gut microbiome.

The gut microbiome is an important part of the human body. It is interlinked with various organs and drives a lot of our physiological functions. The gut is like the jack of all trades. It produces hormones like our glands, neurotransmitters like the neurons, it also produces enzymes and metabolites, talks with the endocannabinoid system, and even controls our brains in some ways! In this blog, we are going to look at each of these functions in detail.

The Enteric Nervous System & Gut-Brain Connection

The GI tract is essential for food digestion, nutrient absorption, energy balance, and even protection from disease-causing microorganisms. The GI physiology is controlled by nerves that connect the gut tissues with the Central Nervous System (CNS). These nerves also connect the CNS with the network of neurons and cells present on the gut wall. This entire setup is also known as the Enteric Nervous System (ENS). The ENS is one of the systems that contribute to the sensory functions of the gut and enables it to build barriers that allow absorption of nutrients and exclusion of harmful chemicals and microorganisms.

It’s like a whole microscopic city in there with its own amenities, from roadways to sewage. But it also takes a long time to build a fully functioning city, which is why the colonization of the GI tract with microbes starts before birth. Maternal microbial factors contribute to the development of the ENS of a child during pregnancy. Immediately after birth, colonization of the GI tract begins to occur even more rapidly than in the womb with trillions of microbes that influence metabolism, circadian rhythm, immune response, etc.

The gut is connected directly to the brain via a bidirectional pathway of nerves. This connection is known as the gut-brain axis. The biggest nerve connecting the two is called the vagus nerve. These nerves carry information from the gut to the brain. Based on this information, the CNS generates appropriate behavioral responses. 

Neurotransmitters Produced in the Gut

The vagus nerve that connects the gut with the brain is the main component of the parasympathetic nervous system. Let’s back up a bit here. What exactly is the parasympathetic nervous system? 

The involuntary part of the nervous system contains two branches - sympathetic and parasympathetic. The sympathetic part is what regulates our fight or flight response while the parasympathetic helms the digestive system, among others. People who are easily stressed, highly anxious, or depressive tend to have a high level of activation of the sympathetic nervous system and a lower functioning of parasympathetic system.

The nervous system interacts with nerve cells or neurons through the usage of chemical messengers called neurotransmitters. In simpler words, neurotransmitters are signaling molecules that initiate an action. For example, when you eat food, neurotransmitters like dopamine, serotonin, GABA, etc. kick into action to increase the parasympathetic function of the body, thus facilitating digestion. This is why you digest and assimilate food the best in the parasympathetic state. 

All of these neurotransmitters are produced in the gut. In fact, 90% of the body’s supply of serotonin is produced in the gut. GABA or gamma-aminobutyric acid that regulates food intake and feelings of anxiety and fear is produced by certain bacterial strains in the gut. The gut produces stress-response neurotransmitters, norepinephrine and dopamine that influence mood and feelings of reward and motivation. Histamine, which is closely connected to our allergies, is also synthesized by bacteria in the gut.

That’s not all - the metabolic activity that goes on inside the gut releases gasses. Some of these gasses like Nitric Oxide (NO) and Hydrogen Sulfide (H2S) act as neurotransmitters that modify gut functions.

How the Microbiome Affects Neurotransmitters

Remember the direct highway between the gut and the brain? The neurotransmitters produced in the gut are sent directly to the brain via this path. These neurotransmitters along with the ones produced in the nerve cells work tirelessly to keep your brain functioning, manage your breathing, concentration levels, etc. and even control feelings like fear, joy, pleasure, and others. For this reason, the gut is considered your second brain. 

Let’s look at an example: histamine is a neurotransmitter produced by the gut. It hustles the allergens out of the body by triggering an allergic response. A high level of histamine release is one of the ways that your gut microbiome flags an ongoing viral infection. Stress levels go up with an infection. This triggers a rise in the epinephrine and norepinephrine hormone levels in the blood. The viruses in the body pick up this reading and become more virulent. In response, the microbiome starts to produce more histamine to trigger an immune response.

Given the close relationship between the gut and the brain, any disruption of the gut microbiome will affect the neurotransmitters being sent to the brain, thus affecting behavior and cognitive activity. This is the very reason why we get more anxious when we have a gut infection like diarrhea, etc.

A common dysfunction of the gut is intestinal permeability where bacteria can leak through the intestinal walls. This condition is also known as leaky gut. Leaky gut is a big driver of depression and anxiety because the endotoxins that leak through, travel past the blood-brain barrier in the human body and interfere with the binding of neurotransmitters to the brain. What happens as a result is, even if your body produces enough neurotransmitters, they won’t bind with the receptors in your brain effectively and therefore, will not show any effect. 

Addiction is one of the dangerous outcomes of a leaky gut. If the brain does not receive its daily share of the neurotransmitter, dopamine due to gut dysfunction, it begins to crave a dopamine kick from external sources. This leads to addiction. One of the things that help with such problems is gardening therapy. When patients get their hands into the soil, the bacteria in the soil makes it to the body and it helps improve the gut lining through the increase in microbiome diversity, leading to more dopamine and serotonin release.

Relationship Between the Gut Microbiome & Hormones

In addition to producing neurotransmitters, the gut microbiome acts as an endocrine organ by synthesizing several chemicals of hormonal nature that are released into the bloodstream.

Interestingly, the gut also plays a big part in metabolizing these hormones. For example, when the estrogen hormone is produced, it cycles through the body, performs its tasks, and is then dumped into the gut. The microbes in the gut metabolize the estrogen and get rid of it. If you have low levels of microbes responsible for this role, then the estrogen is reabsorbed in the gut and pushed back into the bloodstream. This builds estrogen dominance in the body, leading to conditions like polycystic ovary syndrome, a higher risk of cancer, etc. 

The microbiome also controls the release of certain hormones. For example, the gut regulates the release of the hunger hormone, ghrelin, satiety hormones, leptin and adiponectin, as well as the release of cyclic AMPs which are messengers that regulate food intake by signaling your cells to increase the utilization of fatty acids from the food for energy.

We all have that friend who can eat whatever they want and never gain weight. The general assumption is that they have a high metabolism rate. Turns out, that is not always the case. It has a lot more to do with their gut microbiome setting than metabolism. When you are full, your microbiome signals to your brain to dial down the production of ghrelin. For those with ghrelin and leptin dysfunction, a high-calorie meal can only barely reduce the ghrelin level from that of a fasting state and within two to three hours, it increases again. This is the foundation for metabolic syndrome and obesity.

The Gut Microbiome Also Produces Metabolites

The gut does not stop at neurotransmitters and hormones. Metabolites, which are organic compounds formed in the body as an outcome of metabolic activities, are also manufactured by the gut. The variety of metabolites produced by the gut depends on the different molecule components like carbohydrates, amino acids, etc. in the food that we take. Let’s take a closer look.

1. Carbohydrate-Derived Metabolites

Before we get into metabolites, let’s try to understand what happens in the GI tract when we consume food. The GI tract kicks into action to absorb all nutrients in the meal through the secretion of bile acids, fatty acids, etc. The upper GI tract digests and absorbs simple sugars and amino acids from the protein in the meal. Most of the fat content is also absorbed in the tract while a minor portion escapes and gets accumulated in the colon for excretion.

The human gut cannot digest dietary fibers present in carbohydrates. So they escape the upper gut, undigested, and are picked up by certain bacteria to be used as sources of energy. These bacteria metabolize the fibers into short chain fatty acids (SCFA) which are the main metabolites produced by the gut.

These short chain fatty acids have endocrine properties. They travel to different organs from the GI tract like the liver, brain, etc. and contribute to energy regulation, glucose and lipid metabolism, inflammation, immunity modulation, and so on. SCFAs also produce tight-junction proteins that serve as a paracellular barrier, locking the microbiome in the gut.

Intake of such non-digestible carbohydrates or dietary fibers triggers a healthy production of gut peptides. Gut peptides are chemical messengers that regulate GI functions like digestion, absorption, motility, etc. A healthy peptide production leads to decreased fat mass gain, reduction in insulin resistance, and improved glucose tolerance. This is one of the reasons behind the use of carbohydrate as a nutritional support to therapeutic care. Studies have also shown that these carbohydrates are responsible for the improvement in metabolic parameters of patients with Type-2 diabetes. 

2. Amino-Acid-Derived Metabolites

When it comes to amino acids, there’s good news and there’s bad news. Let’s do the good news first. The amino acid, tryptophan, is metabolized in the gut to produce molecules like indoles and their derivatives which have endocrine properties. Among these derivatives, indole-3 propionic acid (IPA) has anti-inflammatory effects, improves metabolism by reinforcing gut barrier functions, and increases immune response. IPA reduces the risk of developing Type-2 diabetes by protecting β cell function and increases the secretion of insulin.

Now the bad news. Branched chain amino acids (BCAA) contribute to the onset of metabolic disorders by triggering insulin resistance. Turns out, the gut microbiome of those with insulin resistance has a high amount of enzymes for BCAA production but a low amount of enzymes for BCAA utilization. Similar results have been found for the amino acid, histidine. Microbial metabolization of histidine produces a compound called imidazole propionate which directly contributes to glucose disorders and is therefore found in high levels in patients with Type-2 diabetes. 

Choline is a derivative of amino acid which is broken down into trimethylamine N-oxide (TMAO) by gut bacteria. TMAO is associated with cardiovascular risk and triggers platelet hyperresponsiveness and thrombosis.

Gut Bacteria & the Endocannabinoid System

The gut regulates the harvesting of energy from the food we consume through the production of metabolites. Another system that is deeply involved in the control of energy metabolism is the endocannabinoid system (ECS).

The ECS is a cell signaling network comprising endocannabinoids, cannabinoid receptors, enzymes, and lipids that regulate and balance key functions of the body like appetite, energy, blood pressure, memory and learning, immune response, etc. 

As it turns out, the gut and the ECS are interlinked in many ways. 

The ECS has two primary receptors, CB1 and CB2. The endocannabinoid molecules bind to these receptors to signal the ECS to take action. Turns out, the gut microbiota can also modulate the activation of CB1 and CB2 receptors of the ECS which in turn, generates an anti-inflammatory effect in response to gut diseases. 

The gut produces a substance called N-acyl amide which mimics the lipids of the endocannabinoid system (ECS). Just like the ECS, N-acyl amide has been found to regulate glucose and energy metabolism.

The gut microbiome goes beyond exhibiting functions analogous to the ECS. Apparently, the gut and ECS engage in cross-talk. Whenever there is a change in gut microbiome composition due to intake of probiotics or any changes in the body, it reflects as a variation in the ECS which causes gut permeability and release of endotoxin into the blood. On the other hand, the ECS plays a role in reducing gut permeability by enhancing the effect of tight-junction proteins that uphold the integrity of the blood-brain barrier and prevent gut permeability.

Interestingly, the cross-talk between the gut and the ECS is not restricted to the intestine alone. Interactions have also been observed between the gut microbiome and the ECS in the adipose tissues, more commonly known as body fat. Changes in gut composition induced by pro or antibiotics lead to altered levels of lipids and altered behavior of ECS receptors and enzymes in the adipose tissues, especially in endocrine activities.

The ECS & Gut Work in Conjunction With Hormones to Control Appetite

Out of the many responsibilities that endocannabinoid molecules have, one is informing the body about the changes in energy availability. These molecules are not stored in the body but are produced and released on demand. The levels of these molecules change with the energy status of a person, increasing during fasting and decreasing during food intake. 

Evidence suggests that the intake of palatable food increases the endocannabinoid level which in turn induces the increase of dopamine. These endocannabinoids act through the CB1 receptors to generate the following effects:

1. Hedonically positive sensations during food intake
2. Signaling of the olfactory circuits to increase odor detection

The gut microbiome plays a role in controlling the function of the ECS in appetite regulation. Studies have shown that the endocannabinoids produced in the gut regulate the intake of fat and preference of fat-rich food by engaging perceptions like taste, texture, etc. 

We have all had our episodes of binge eating. Turns out, the cross-talk between the gut and the ECS has a lot to do with that. When we eat food rich in lipids, what we generally refer to as “munchies”, endocannabinoid levels in the gut increase. This activates the CB1 receptors in the region of the brain that are associated with reward behavior. This drives the motivation to binge eat and enjoy food.

The signaling mechanism of the CB1 receptors is linked to the action of hormones like ghrelin, leptin, and glucocorticoids that play a role in energy balance. Ghrelin’s appetite-stimulating effect is mediated by the ECS. The CB1 receptor signaling mechanism during food intake recruits the protein kinase that influences the action of ghrelin in the hypothalamus. So, when you are consuming food for pleasure, you are likely to have an increased level of ghrelin in your system. 

Role of ECS in Hunger & Weight Changes

The ECS and the gut microbiome together control a large part of our metabolic processes. The ECS fuels appetite and the motivation to seek food by working at a cellular level. Food intake is regulated by cannabinoid levels in the hypothalamus. And this cannabinoid level is regulated by hormones like ghrelin, leptin, etc. which are released depending on the metabolic condition of the body.

As you consume food, certain bacterial strains in the gut produce gamma-aminobutyric acid (GABA) that regulates food intake. But changes in the microbiome, also known as dysbiosis, can affect hunger and satiety. If the GABA levels are low due to the presence of dysbiosis, the brain does not signal the stomach to stop eating. This causes overeating.

Dysbiosis among those with obesity increases the synthesis of CB1 receptors. In other words, the ECS becomes overactive among those with obesity issues. This promotes metabolic processes that lead to symptoms like weight gain, insulin resistance, lipogenesis, and dyslipidemia which is a condition characterized by an unhealthy level of fat in the blood.

Having said that, all is not clear as day with the ECS’s role in regulating appetite. There is a level of contradiction that does not quite fit the equation.

The endocannabinoids AEA and 2-AG contribute to metabolism. But these bind to receptors other than the cannabinoid receptors to influence metabolic responses. Simultaneously, certain lipids with structures similar to endocannabinoids are produced for metabolic processes that do not bind to the cannabinoid receptors. Strikingly, these lipids have opposite effects on metabolism than the endocannabinoids they mimic. For example, the lipid, oleoylethanolamide which is structurally similar to the endocannabinoid, AEA decreases appetite and promotes weight loss. This is completely opposite to the effect that AEA causes by binding with CB1 receptors.

Cardiometabolic Disorders & ECS

Interestingly, such contradictory behavior of the ECS extends to cardiometabolic disorders as well. Most metabolic and cardiometabolic disorders are characterized by inflammation. And in each of these scenarios, the ECS shows up through increased activity. As it turns out, the ECS with its complex signaling system plays a protective role in regulating this inflammation. However, there are two contradicting sides to this.

The endocannabinoid system mitigates inflammation through the activation of CB2 receptors. This starts a chain reaction to elevate the level of anti-inflammatory cytokines in the body, which are proteins secreted by the immune system. These cytokines bring down the inflammatory cell levels, thus reducing the inflammation.

What’s surprising is, contrary to their anti-inflammatory effects, endocannabinoids are also drivers of systemic inflammation. Systemic inflammation occurs when the immune system is continuously working to defend the body. For example, constant stress, prolonged infection, or chronic diseases can put the body in such a state. A series of actions take place in endocannabinoid-induced systemic inflammation. The endocannabinoid, AEA, nicknamed ‘gate openers’, induces gut permeability. This leads to increased cytokine production. As a result, inflammation starts to occur in the adipose tissue. Along with that, increase in endocannabinoid, 2-AG, causes an increase in the recruitment of leukocytes as well as pro-inflammatory cytokines and free radicals, thus adding fuel to the inflammation.

ECS, Gut, and Cardiovascular Functions

The contrasting behavior of the ECS has also been found in its cardiovascular functions. 

The ECS plays a beneficial role in the cardiovascular system in two ways:

1. By decreasing oxidative stress and inflammation
2. By stimulating protective pathways through the CB1 and CB2 receptors present in the blood vessels

CB2 is linked to a decrease in oxidative stress and overall well functioning of the blood vessels. Reduction in CB2 receptors causes atherosclerosis which is characterized by the deposition of fat in the inner walls of the arteries. 

Despite the beneficial effect of the ECS in cardiovascular health as pointed out above, it also triggers cardiovascular diseases. It has been found that the gut microbiota plays a role in modulating the ECS to catalyze the onset of atherosclerosis.

Role of the Microbiome in Diseases

Most of the chronic illnesses that we discussed here like cardiovascular disease, metabolic disorders and also diseases like Alzheimer’s, Parkinson’s, dementia, etc. are driven by chronic low-grade inflammation. The biggest source of this inflammation is the leakiness of the gut, which in more scientific terms is known as barrier dysfunction. 

Let’s take diabetes for example. The onset of diabetes comes from years of intestinal permeability that initiates the process of insulin resistance. It happens in two ways:

1. The leaky gut targets the pancreas and disrupts its cell function, rendering it unable to release insulin
2. Endotoxins released from the leaky gut make their way to the brain and cause inflammatory changes in the hypothalamus. This hampers its ability to read blood sugar levels, thus causing central insulin resistance. Central insulin resistance happens even if your pancreas is working fine and producing the insulin you need.

Therefore, a vast majority of our chronic diseases can be traced back to the ecological changes in the microbiome. But the good news is, it also means that modulating the microbiome to restore balance could save millions of lives.

How to Heal the Gut

The goal is to seal up the gut lining and keep it functioning optimally. But the problem is, the human body does not have the means to heal a leaky gut. Remember we have only 22,000 genes in our reserve? Most of that goes into coding for our features and determining things like eye color, hair, shape, etc. Thankfully, to make up for that, we have evolved to outsource a lot of our functions to the bacteria in the gut. But if we do not have an adequate amount of those, they can’t do the job for us. So we need to provide the gut with certain tools to put things into motion.

First, we need to increase the diversity of the microbiome. This can be done by expanding the diversity in your diet. Roots, tubers, and nuts contain different types of resistant starches that feed and increase the growth of microbes. Probiotics can also help to a great extent in healing leaky gut. It also helps to stay away from foods that negatively affect our bodies.

Secondly, we need to upregulate the presence of keystone strains of bacteria. Keystone strains are certain species of bacteria that attract other bacteria and microbes and bring them together by sending chemical signals to these cells. This mechanism is also known as quorum sensing. Think of them as the social butterflies in a group, they have a lot of friends, throw a lot of parties, and always seem to move around in a growing group. The introduction of keystone strains lays the foundation of a stable microbial ecosystem and provides protection against several chronic illnesses.

When the gut microbiome is improved and adjusted, it triggers the production of certain pulse biotics which are essential nutrients and metabolites produced by the microbiome itself that we cannot get an adequate amount from our diet.

Building Gut Resilience

There are instances when your body cannot tolerate certain food. But that’s not the fault of the food. It is the microbiome changing the outcome of the food in your body. The second part of intolerance comes from your immune response to the food. The T regulatory cells of your immune system are supposed to identify the dysfunctional response of your body to food and block it out so that you can have more resilience. But the upregulation of the T-reg system is dependent on the health of your microbiome. Sometimes, inflammation in the gut can also bring down the T-reg system. 

In such cases, what needs to be done first is to remove foods that are offensive to your body so that there is no stress on your gut. Repairing your gut can be done through fasting, intake of probiotics, immunoglobulins, green tea, etc. The goal is to have a good balance of all the species in your microbiome. The beauty of the gut is that it repairs relatively quickly. Results might show in around 6-8 weeks on intake of probiotics. 

Once your gut lining is rebuilt and the gut is healed through the intake of wholesome and diverse food that your body can tolerate, it’s time to build resilience by bringing in other wholesome foods which your body could not tolerate previously. 

An interesting fact is that the microbiome can adjust to the type of food you put into your system based on the environment you live in. For example, the human system is not built to break down seaweed in a diet. But those who have been consuming seaweed for generations have developed an inherent system in their microbiome to be able to disintegrate and digest it. Being omnivores, it has allowed humans the pliability and resilience within our microbiome to help us adapt to different situations. 

Conclusion

The human-microbiome relationship is essentially symbiotic. The human body provides a Goldilocks environment for the gut microbiota to thrive. In exchange, the microbiota fulfills certain functions that the body isn’t equipped to handle by itself. From manufacturing energy sources to protecting us against pathogenic toxins, the gut microbiome is crucial to our existence. It’s fascinating to think that at the end of the day, almost everything about us comes down to our bacterial signature.