How Gut Microbes Change your Brain

The mechanical and chemical changes gut microbes make that influence dementia, Parkinson's disease, chronic pain, and mental illness

Earlier, we discussed how the bacteria in our intestines are key to our ability to digest food and to how our immune system functions. We talked a little bit about how the gut microbiome influences our nervous system and our mental health. Today, I want to explore that concept in more detail. The microbes in our gut influence our enteric nervous system (the nervous system of the intestines) and therefore the central nervous system (brain and spinal cord) by the following mechanisms:

1. Production, expression and turnover of neurotransmitters and neurotrophic (nerve growth) factors. In fact, the gut microbiome is known to produce at least 60 neurotransmitters. Neurotransmitters are chemicals that cause nerves to fire and send an impulse to another nerve, muscle, or other structure.

2. Maintaining the intestinal barrier and keeping cells close enough together to form an effective barrier and separate things that enter the digestive system from our bodies

3. Modulating the enteric sensory nerves that carry information back to the brain

4. Production of bacterial metabolites (like short-chain fatty acids, which I discussed in more detail here.)

5. The regulation of the immune system of our mucous membranes, recognizing what is part of us and what is not, and what is harmful and what is not

The Enteric Nervous System

The enteric nervous system can sense more than 30 neurotransmitters most of which are found in the brain. More than 90% of serotonin and 50% of dopamine originate in the gut which are mainly produced by the gut microbiota. In fact, a study on mice showed that mice never exposed to bacteria produced three times less serotonin than normal mice. Serotonin and dopamine are vital to coordinating messages to activate the sympathetic nervous system (the “fight or flight” part). They are also intimately involved in controlling mood, happiness, and pleasure.

The vagus nerve is tremendously important to how your gut communicates with your brain. In addition, there is strong evidence that the communication between the gut and brain via the vagus nerve depends upon molecules released by gut microbes.Surprisingly, there are 9 times as many nerves sending messages back to your brain as nerves sending messages from your brain to your intestines. The nerves from your intestines are communicating about:

• Hunger

• Fullness

• Inflammation

• Energy Metabolism

The nerves from your brain are communicating about:

• Secreting digestive enzymes

• The stomach’s capacity

The vagus nerve also communicates about imbalances in bacterial populations. The brain uses this information to determine whether an inflammatory response is needed.

The vagus nerve, however, does not go through into the intestine to communicate directly with the gut microbiome. Instead, humans have between 100 million and 500 million nerves as part of the Enteric Nervous System, a network of nerves that works from the esophagus all the way through the intestines to the anus. This network controls:

• Intestinal muscle activity

• How the gut walls move

• Secretion of fluids

• Blood flow to the surface layers (mucosa) of the intestine

• How tight or leaky the surface layers (mucosa) of the intestine are

This enteric nervous system is dynamic and ever-changing, with a continuous process of nerve cell death and regeneration. A study in mice found that gut microbes secrete serotonin, then the serotonin is key to the maturation of the nerves of the enteric nervous system. When serotonin receptors were blocked or serotonin levels were low, those nerves were not able to complete the maturation process. In fact, rodents raised in a germ-free environment (in other words, with no microbes colonizing their guts), have increased release of a hormone called ACTH in the brain, which is a hormone which triggers the release of the stress hormone, cortisol. They also had less brain-derived neurotrophic factor (neurotrophic means nerve growth), which stimulates brain nerve growth and health, and also helps the gut maintain a tight barrier. Treating those mice with Bifidobacterium restored the brain-derived neurotrophic factor to normal levels.

How Does Your Microbiome Communicate With Your Brain?

One of the main ways that the microbiome “talks” to your brain is through metabolites (the chemicals made when bacteria digest their food). There are dozens of them, and they are depicted well in the chart below, which comes from a great review article about microbiome research. In the graphic, they use some medical jargon, so I wanted to translate:

• Neurotransmission=how nerves signals are sent between nerves

• BBB integrity management=keeping the barrier between the bloodstream and the brain strong/knowing what to let through

• Brain/neurons energy metabolism=providing energy that the brain and neurons can use

• Neurodevelopment=Regulating the development of the nervous system and which nerve connections form

• Neuroprotection=Protecting nerves and the brain from damage

• Bile acid synthesis=Making bile acids, which are important for digestion, absorbing nutrients, and converting food into energy

I had planned to dig into quite a few neurotransmitters, but to be honest they are a bit dry, so I am going to focus on:

• Serotonin, which is what we are trying to impact with SSRI antidepressant medications and is discussed a lot in the popular media

• Dopamine, which is involved in Parkinson’s disease and schizophrenia. It is also discussed often and sometimes misrepresented in the popular media

• Norepinephrine, which is used in antidepressant medications like Cymbalta and Effexor

• Short-chain fatty acids, which I did not know about before researching the gut microbiome, but are tremendously important

If you wish I said more or love geeking out about GABA and glutamate, leave a comment, we can dig deeper (though much of my GABA and glutamate knowledge has leaked out of my brain since second year of medical school 20 years ago).

Dopamine

Dopamine is known as the reward neurotransmitter, but it has a role in many other important activities too, including:

• Modifying behavior and thinking

• Voluntary movement

• Motivation

• Decreasing a hormone associated with breastfeeding

• Sleep

• Dreaming

• Mood

• Attention

• Working memory and learning

Dopamine is mainly produced in several different areas in the brain, but there are at least two types of bacteria that produce dopamine in the intestines as well. Studies on people who have Parkinson’s disease have shown that gut microbes can change the function of neurotransmitters. The authors of the paper suspect that mapping the gut microbiome may become a key part of choosing medications to treat Parkinson’s disease, and mental illness, specifically schizophrenia in the future.

Norepinephrine

In Emergency Medicine, we mostly know norepinephrine for its blood pressure raising properties. It is the pressor (medicine to bring blood pressure up into the normal range when it is dangerously low) that we use most. However, it is involved in some other crucial functions:

• Behavior and thinking (like memory, learning, and attention)

• Inflammation

• Modifies responses to the sympathetic and parasympathetic nervous system

Norepinephrine stimulates growth of multiple species of bacteria in the gut. Several other species produce norepinephrine directly

Serotonin

Serotonin is the neurotransmitter that is impacted by the common group of antidepressants called SSRIs. SSRI stands for Selective Serotonin Reuptake Inhibitors. That means the medication interferes with how the body normally removes serotonin, thus increasing serotonin levels in the brain. Serotonin is responsible for regulation of:

• Appetite

• Movement of intestines

• Mood

• Thinking

• Sleep patterns

Serotonin can be made by neurons in the gut and much of it is made by cells called enterochromaffin cells, but some authors think that 80% of the serotonin is produced by gut microbes. Several studies have shown that production of serotonin is regulated by gut microbes. Short-chain fatty acids are the messengers the microbes use to communicate with intestinal cells to make serotonin. Low levels of serotonin may lead to the development of a leaky gut, which is associated with irritable bowel syndrome.

Short-chain Fatty Acids

Short-chain fatty acids are a group of chemicals including lactate, butyrate, acetate, and propionate. They are mostly produced by bacteria in the colon. They are involved in communication about energy expenditure in the muscles and liver. We discussed their effects on the body as a whole here.

Patients with Parkinson’s disease had fewer butyrate-producing bacteria in the gut and higher numbers of bacteria that increase inflammation. Patients with fibromyalgia also had a change in the balance of butyrate producing bacteria.

Butyrate, propionate, and acetate all are key to the maturation of the brain’s immune cells (also known as microglia). Short chain fatty acids also regulate the production of dopamine and the conversion of dopamine to norepinephrine. Diets that increase the production of short chain fatty acids were found to relieve immune and metabolic problems in patients with schizophrenia.

Neurologic Disease, Pain, Mental Health and the Gut Microbiome

Specific gut microbes are associated with the development of Alzheimer’s, anxiety, autism, and depression. Human studies have shown decreased levels of Firmicutes and Bifidobacterium in the stool of people who have Alzheimer’s dementia. The decrease in these bacteria increases the risk of dementia. Some autopsy studies of brain tissue of people who had Alzheimer’s dementia shows that E. coli was located very near the amyloid plaques (the brain structure change we believe causes dementia). This suggests that imbalance in the gut microbes and increased permeability of the intestines may be involved in the development of amyloid plaques. Some animal research also suggests that dietary changes or probiotic supplements may improve behavioral and psychological symptoms of dementia. A couple weeks ago, we also discussed the microbiome’s role in the experience of pain.

The microbiome doesn’t only play a role in physical pain, but also emotional pain. Increasingly, research is showing that depression is an inflammatory disease. This changes our long held perception of it deriving from psychological sadness and/or fatigue. Dopamine, serotonin, and norepinephrine are all intimately involved in the depression disease process. They are all produced or converted into a usable form in the gut, by the microbes. Additionally, people who have major depressive disorder have increased levels of Actinobacteria, Proteobacteria, and Bacteroidetes, but decreased levels of Firmicutes. In human and animal studies, probiotic use reduces depression and anxiety symptoms, in some cases as much as antidepressant medications.

Here, I must pause to offer a clarification. As I began my initial research on the microbiome and probiotics, the evidence I was finding did not show that supplementation was beneficial. However, as I am diving into the benefits of probiotics on mental health specifically, there are multiple studies showing benefits, even for anxiety, depression, and insomnia due to test anxiety. Like most things, I still think the greatest benefits will come from whole food sources, but if you just can’t get to enjoying the funk of a good kimchi, a probiotic supplement is reasonable to consider.

There is also evidence that many antidepressant, mood stabilizer, and antipsychotic medications inhibit the growth of various types of bacteria. This may further worsen the imbalance between helpful and harmful bacteria in the gut. SSRI antidepressants are associated with antimicrobial activity against a wide variety of bacteria. Sertraline (Zoloft), in particular, is powerfully antimicrobial. Other antidepressants in the monoamine oxidase inhibitor and tricyclic antidepressant drug classes also have antimicrobial properties. Propranolol, lithium, valproate, and antipsychotic medications also possess antimicrobial activity.

We don’t yet know much about the impact of this activity, but research suggests that treatment with antipsychotic medications like risperidone and olanzapine are associated with decreased diversity of gut microbes, especially for female patients. If you are interested in the mechanism of action of these effects, you can read more in this review article. To be clear, I am not suggesting that you should not take these medications. They can be life-saving for people who need them. However, they may have impacts we don’t fully understand and taking them with a diet rich in probiotic foods or with a probiotic supplement is likely to be beneficial.

There have not been studies that looked directly at how herbal medicines impact the gut-brain, microbiome interactions. However, there are studies that suggest a positive relationship between herbal medicines and the gut microbiome in the following ways:

• Improving the balance of “good” bacteria and “bad” bacteria when they are out of balance

• Increasing the abundance of bacteria that benefit health

• Increasing the abundance of bacteria that produce short-chain fatty acids

• Anti-inflammatory effects

• Compounds in plants break down into compounds that influence how the gut, brain, and/or microbiome function (ginseng is an example of this)

• Some have prebiotic effects (make it easier for good bacteria to grow)

• Plant parts are metabolized into pharmacologically active compounds or short-chain fatty acids that act on the gut or brain

• Perhaps most fascinating, researchers hypothesize that a class of chemicals called polyphenols, which are frequently found in plants act as antibiotics, killing certain types of bacteria, while acting as prebiotics for others, helping them grow.

Studies in mice suggest that infections that disturb the gut microbiome may increase the likelihood of developing anxiety. Human studies that look at the link between intestinal infection and the development of anxiety followed people over 5 two year intervals. People who experienced an intestinal infection in the first interval, were 34% more likely to develop anxiety disorder in future rounds. Patients with anxiety also had changes in their microbiomes and fewer bacteria that produce short-chain fatty acids.

Animal studies found that mice under chronic stress had a decrease in Bacteroides genus bacteria and an increase in Clostridium bacteria (for context, Clostridium is the genus of bacteria that causes the diarrheal illness C. diff). In bipolar disorder, researchers have found increased levels of Flavonifractor and decreased levels of Faecalibacterium. Low levels of Faecalibacterium have also been found in people who have major depressive disorder and irritable bowel syndrome.

Researchers are just starting to investigate the role of the gut microbiome in obsessive-compulsive disorder (OCD), but the limited information that is available suggests that animals treated with both probiotic and prebiotic supplements (each was studied in its own separate study), had decreased OCD symptoms. Similarly, the role of the microbiome has not been studied much yet in PTSD. Researchers have found decreased levels of specific families of bacteria in people with more severe PTSD symptoms. Decreased exposure to those bacteria increases the risk of developing PTSD.

Patients with schizophrenia also have significant alterations in their gut microbiomes:

• Decreased microbial diversity in the gut

• Increased levels of IgA (an antibody that is especially found in the respiratory and digestive systems as well as secretions like saliva and tears), which changes how glutamate is made

• An abundance of certain types of harmful bacteria

These lead to increased inflammation and cognitive and behavioral changes. Using probiotics in addition to the standard treatment for schizophrenia, has been found to decrease weight gain, which is a common side effect with many antipsychotic medications and reduce symptoms of psychosis. When mice received a fecal transplant from a person with schizophrenia, they developed schizophrenia-related behaviors.

Researchers studied the impact of a probiotic supplement of Bifidobacterium on healthy volunteers. Those who received the probiotics had different brain activity both at rest and under social stress, and they endorsed higher vitality and less mental fatigue than those who received placebo. Another study, using a multispecies probiotic supplement, found that people who received the supplement reported better mood and had different brain activity in response to emotional decision-making and emotional recognition memory. Other studies show that higher diversity of bacterial species in the gut are correlated with higher levels of connectivity in the resting state of the brain. This connectivity is considered important in the development or prevention of depression.

Conclusion

Understanding the gut microbiome in this way makes me so curious about patterns that I notice in people when I care for them, how so many farmers get Parkinson’s disease, how patients with many diseases have similar personality and demeanor patterns to other people with the same disease. Now I wonder how much of these patterns are related to the microbes in their guts. It’s amazing to think that these tiny microbes shift so much in our bodies and they power they have to communicate within our bodies and to other bodies. Though there are systemic barriers to caring for our bodies and our microbiomes, there is also a lot that we can do to improve their and our health. Now, when you encounter someone who tells you your chronic pain, chronic disease, or mental illness is “all in your head”, you know that that is utter bull (or in this case human) shit!

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