The signaling that occurs between the microbiome and the brain is often mediated by compounds produced by the gut microbiome. This signaling could result in a more relaxed sleep cycle, or it could adversely affect it. Here’s a closer look at how the gut-brain axis impacts sleep quality.

What is the Gut Brain Axis?
The gut-brain axis refers to the two-way communication between the gastrointestinal tract and the brain which is a communication path between neurotransmitters produced by cells and metabolites produced by the microbiota in the gut. Having a “gut feeling” may be as much a chemical reaction as it is your intuition. 

Much of this two-way communication happens in what is called the autonomic nervous system (ANS). This part of the peripheral nervous system is like the central controller managing the function of your internal organs through the smooth muscles and glands. We are generally not conscious of the actions occurring in our autonomic nervous system but it handles our fight-or-flight response. This system regulates our respiration, dilation of pupils, heart rate, digestion, waste elimination and sexual arousal. There are three branches to the ANS: sympathetic “fight or flight”, parasympathetic “rest and digest” and enteric “second brain”. The sympathetic and parasympathetic systems often have opposite actions, meaning one may activate a response and the other then dampens the response. Generally speaking the sympathetic nervous system is more fast acting response oriented while the parasympathetic is a slow acting counterbalance. For example, you are awakened in the middle of the night by a loud thud: your heart pounds out of your chest and you jump to your feet in response.

 

That’s your fight-or-flight sympathetic nervous system. Then you pause for a moment to catch your breath and realize it's only your cat who knocked something off the counter in the kitchen and your body starts to relax. That’s your parasympathetic nervous system.

The enteric nervous system (ENS), also known as the second brain, is a mesh of neurons in the gut that can act independently of the sympathetic and parasympathetic nervous systems and is a primary source of the communication between the gut and the “first” brain. The neurons of the enteric nervous system control the motor functions of the gastrointestinal tract. That means gut motility, or the movement of food and liquids through the canal. Additionally, the ENS controls the secretion of enzymes in the gut and enzymes are essential to the proper digestion of fats, proteins and carbohydrates. The neurons in the ENS communicate through neurotransmitters just like the central nervous system and brain. These neurotransmitters include serotonin, dopamine and acetylcholine.

Intestinal metabolism is closely connected to brain function through our circulatory system and the vagus nerve. This network of communication is the gut-brain axis.

For a more detailed discussion of these topics you may be interested in The Mind Gut Connection by Dr. Emeran Mayer or Psychobiotic Revolution: Mood, Food and the New Science of the Gut-Brain Connection by Scott Anderson with John Cryan and Ted Dinan.

A new field of research called microbial endocrinology studies the interactions between microbes and their hosts, including human hosts and the effects these microbes have on our health and well-being. Research has shown that our microbiome influences metabolism, immunity, behavior and sleep. As it turns out, the microbes in our gut produce many of the neurotransmitters and hormones that are used by our endocrine system. For example, gut bacteria manufacture about 90-95% of the serotonin in our system. Serotonin is a chemical precursor to the production of melatonin, the main hormone involved in sleep and many other immune functions.

Melatonin Sleep and Innate Immunity
Melatonin is a hormone that is best known for its connection to the sleep wake cycle. Melatonin is produced in many cells in the body but is best known for the production and release from the pineal gland which regulates sleep through the cycles of light and dark. Melatonin is produced in the pineal gland in the morning from the signal of daylight and released in the evening by darkness. In the modern world we have many additional sources of light that can disrupt this natural cycle and interrupt the release of melatonin in the evening. Blue light inhibits the release of melatonin which is the basis for recommending to avoid electronics in the evening.

Melatonin is a major antioxidant. In fact, melatonin is a more powerful antioxidant than glutathione. To learn more you may be interested in this12 minute video by Dr. Berg. During sleep our body is working to restore our tissues and to take out “the trash."

Melatonin in the colon modulates intestinal microbiota in addition to our own sleep/wake cycles, in response to stress and sleep. In the study linked above, water stress (dehydration) and sleep deprivation shifted the microbiome to a profile with more Erysipelotrichaceae and Enterobacterailes.These bacteria are associated with inflammation. Treatment with melatonin restored the microbiome and increased Akkermansia and Lactobacillus species known for their anti-inflammatory health benefits. Some bacteria produce melatonin, including B.subtiliswhich is a key strain in many of our formulas.

There is less familiarity with other functions of melatonin in the body or the fact that melatonin is produced in many cells in the body. For many years, melatonin was considered exclusively a hormone of the pineal gland. In recent years, melatonin has been identified also in extrapineal tissues, such as retina, Harderian gland, gut mucosa, cerebellum, airway epithelium, liver, kidney, adrenals, thymus, thyroid, pancreas, ovary, carotid body, placenta, and endometrium, as well as in non-neuroendocrine cells like mast cells, NK cells, eosinophils, platelets, and endothelial cells. It acts as a master circadian clock regulator. Subcellular melatonin is produced by the mitochondria to handle the oxidative stress produced in the mitochondria.

Recent research is showing a relationship between the endocrine, nervous and immune systems based on molecular communication. That just means there is a common chemical language understood by all of these cells. And bacteria too! Melatonin is considered to be one of the major chemical messengers in this communication network.

The emerging role of the microbiome in gastrointestinal health and function has evolved to include research into the microbial signaling and the role of circadian rhythms. Studies suggest that this signaling from microbial metabolites plays an important role in maintaining homeostasis in the gut along with our own circadian mechanisms. Disruption of the circadian clock by nutritional deficiency and light/dark cycle disruption impacts the profile of the gut bacteria as noted above. The bacteria in our gut communicate with the tissues in our intestines but research is ongoing to determine how this delicate dance is working.

What is the microbiome?
The microbiome is the trillions of bacteria, fungi and viruses that live in and on our body. The number of cells in the microbiome is roughly equal to the number of human cells that we have. However, researchers have shown that the number of genes in the microbiome is between 150-300 times more than our human genes. These microbes function as our internal pharmacy to maintain our health. When the microbiome diversity is disrupted we can lose some of the important functions and metabolites that we need to be healthy. We are a superorganism made of microbes and human cells. Dr Rodney Dietert has an excellent book discussing the human superorganism and the rise of chronic disease if you want to learn more. As mentioned above, the microbiome is a primary driver for the production of serotonin and the production of important hormones involved in sleep.

The microbiome is a primary driver for the production of serotonin and the production of important hormones involved in sleep.

 

The Vagus Nerve and Sleep
Perhaps you have never heard of the vagus nerve. It is the longest nerve in the ANS and it is the super highway of communication between the gut and the brain. The ANS regulates breathing, heart rate, sweating, digestion and even social interaction. This important nerve has been associated with sleep quality. When things are in balance, your body and the microbiome are communicating well and the ANS will send signals to reduce your sympathetic nervous system signals before you fall asleep. This will lower your heart rate. A reduced heart produces a sense of relaxation and eventually sleep. If you are having trouble falling asleep or staying asleep your vagus nerve and microbial communication may be at play. Evidence has shown that stimulating the vagus nerve can produce effects on your overall health and contribute to improved sleep.

Deep breathing is a great way to send calming signals to the vagus nerve. It also provides better oxygenation and may even improve your microbiome. There are many good videos on breathing that you can find on YouTube. I like the work of Wim Hof and his beginner breathing technique. His technique has been shown to reduce stress and improve sleep quality. This is likely through some effects on the Vagus Nerve. Wim is also known as the Iceman. This nickname is derived from his technique of recommending cold showers and ice baths. Your body temperature lowers when you sleep. By taking a cool shower before bed, you are signaling your body that bedtime is near, beginning the process of lowering your body temperature. The cool water is a signal, picked up by your nervous system to help turn on sleep mode. Many people don’t like the idea of taking a cold shower. You can start with just 30 seconds and work your way up to two minutes. After a while you may grow to enjoy it. I do!

What else can we learn from the Vagus Nerve?
Many years ago conventional medicine would perform a vagotomy to treat stomach acid. This involved severing part or all of the vagus nerve. This treatment is no longer used, but data from patients with a severed vagus nerve showed a reduced risk of Parkinson’s disease. Disrupted sleep cycles are a well-documented symptom of PD.

Innate Immunity, Inflammation and Sleep
Many proinflammatory molecules are sleep-inducing. While many anti-inflammatory molecules can inhibit sleep. Sleep loss increases the production of these sleep regulatory molecules. The innate immune response is the primary signaling system for production of these molecules. Dr. Robert Naviaux of UCSD has published extensively on the disruption of the pro-inflammatory, anti-inflammatory cycle and its impact on many chronic illnesses and even aging. In this diagram from his paper Naviaux RK.

• Incomplete Healing as a Cause of Aging: The Role of Mitochondria and the Cell Danger Response. 
• Biology (Basel). 2019;8(2):27. Published 2019 May 11. doi:10.3390/biology8020027, you can see the central role of sleep in the healing cycle. 

The abbreviation CDR in this diagram stands for cell danger response. The CDR is a metabolic response that protects cells and hosts from harm. It is triggered by encounters with chemical, physical, or biological threats that exceed the cellular capacity for homeostasis. Imagine how our modern lives are constantly triggering this important response. Don’t worry too much about all of the technical terms in the diagram. If you want to know more you can read the paper. For now, you can see how important sleep is.

Inflammatory mechanisms are at play in the body on time scales from seconds to days. The mechanisms alter many functions in the body including blood flow, cell responses, and sleep. Sleep disorders like insomnia and sleep apnea have connections to the inflammatory mechanism. We have written a series of articles on inflammation and the connection with many chronic diseases like Type 2 diabetes, IBS, and cardiovascular disease. Pathogens including influenza, bacteria and HIV alter sleep, partly through these inflammatory mechanisms.

One of the key regulatory hormones involved in sleep is growth hormone-releasing hormone (GHRH) for non-REM sleep. Insulin resistance has also been shown to impact the release of this important hormone. Another key molecule involved in sleep in nitric oxide (NO) for REM sleep. NO is a critical inflammatory signaling molecule.

Glia, or glial cells, are non-nueronal cells of the central nervous system. Glia comprise about 90% of the cells in the brain. They are master regulators of neurotransmitters in the brain. Glia modulate inflammation.

Cytokines are molecules that signal inflammatory pathways during infection. Glia, neurons and many other cell types produce cytokines. More recently you may have heard of the cytokine storm that is an impact in acute Covid infections. Cytokines can produce both pro- and anti-inflammatory signals. Certain cytokines can alter expression of the circadian clock genes which control our sleep wake cycles. Cytokines are critical players in homeostatic sleep regulation.

We are familiar with how we feel tired and want to sleep when we have an acute infection of any kind. Cytokines are signaling the body to rest and allow the body to focus on fighting the infection to help us heal. But what happens when we stay in a state of low-grade chronic infection and our immune system is out of balance? Sleep disruption impacts our immune system’s ability to produce antibodies. Research has shown that sleep deprivation prior to taking an influenza vaccine will reduce the body’s ability to produce the critical antibodies designed to produce immunity.

Poor sleep quality can set up a vicious cycle of low grade inflammation. Research indicates that sleep loss induces a systemic low-grade inflammation characterized by the release of cytokines, chemokines, and acute-phase proteins; all of which may promote changes in the blood-brain barrier (BBB), particularly on brain endothelial cell. The blood-brain barrier is a key line of defense keeping aberrant molecules away from the brain.

Initial research showed that circulating cytokines were the messengers for immune-to-brain signaling. However, most of these molecules were considered to be too large to cross the BBB. Later research showed that these molecules can navigate through the BBB. Lipopolysaccharide, a major membrane component of most all gram negative bacteria, can disrupt the BBB in high doses under certain experimental conditions and has been used in animal models to induce Parkinson’s.

Nutritional Deficiency, the Microbiome and Sleep
Poor quality diet and nutritional deficiency can contribute to a whole host of health related issues including poor sleep. When it comes to sleep the B Vitamins are at the top of the list. B-12 is at the top of the list for nutrients that impact sleep. You can read more about the B vitamins here. Important electrolytes like magnesium and potassium are also critical for sleep. Magnesium is also critical in helping our bodies handle oxidative stress and most people do not get enough magnesium to address the stress. To learn more about the importance of trace minerals, magnesium and copper especially, check out the Root Cause Protocol or get the founder, Morley Robbins’ new book Cure Your Fatigue.



The food you eat affects the microbiome and impacts everything. Eating a healthy diet can improve your sleep. What and when you eat affects your sleep. Eating too close to bedtime can be a big driver of trouble falling asleep. This meta analysis papersummarizes the results of multiple papers on micronutrients and sleep. "In the 26 articles reviewed, researchers generally supported a potential role of micronutrients, particularly Fe and Mg, in the development of sleep stages among infants and in reversing age-related alterations in sleep architecture in older adults. Micronutrient status has also been linked to sleep duration, with sleep duration positively associated with Fe, Zn and Mg levels, and negatively associated with Cu, K and vitamin B12 levels.

The mechanisms underlying these relationships include the impact of micronutrients on excitatory/inhibitory neurotransmitters and the expression of circadian genes.” Ideally, you want to consume your last food at least two hours before bedtime. The earlier the better. At night your body and brain need to focus on rest and repair. If you are still digesting a heavy meal eaten before bedtime this critical process may not be optimized. Alcohol, sugar, spicy food and caffeine should also be avoided to improve sleep.

Prioritizing a good night’s sleep is one of the best things you can do for your health. If you’re looking for more information about how the microbiomeimpacts sleep,learn more here.This post provides an overview of how probiotics specifically can help. If you have any questions about the link between gut health and sleep quality, don’t hesitate to contact us!