I wonder if that would fit in my snoring husband’s mouth?


This is part two of my three-part series on insomnia. Today I want to cover how disease and inflammation cause sleep problems.

In part one, I discussed some habits that help you get a good night’s sleep. And for a number of you who have occasional sleeplessness, improving your sleep hygiene is all that’s needed.

However, for those suffering from chronic, long-lasting insomnia proper sleep hygiene is rarely enough. The reason is that like those suffering from severe depression and anxiety, the problem goes much deeper.

Disease is an often overlooked cause of sleep problems, nevertheless, we all know that it can cause a sleepless night. All of us have had a bad cold or flu that made sleeping all but impossible. Stuffy nose, sore throat, hacking cough, fever–all of this can make getting restful sleep a challenge.

And many of you reading this suffer or have suffered from chronic pain that can also make sleep difficult.

However, there’s another disease that is often overlooked because it’s not well-known or understood: endotoxemia. As I’ve hopefully made clear from earlier posts, low-grade intestinal inflammation affects every system throughout the body manifesting in a whole host of symptoms, including sleep disturbance.

But before I talk about this, let me briefly explain how the body regulates sleep.

Circadian Rhythm

A circadian rhythm (from the Latin “circa diem” or “about a day”) is any biological process that occurs in a 24-hour period in response to external stimuli. Circadian cycles are self-sustaining, however, even in the absence of the stimuli that originally influenced them. A wide range of biological functions are regulated by the circadian clock including energy metabolism, cell cycles and repair, body temperature, hormone secretion and of interest to us today, sleep.

This rhythm is under the control of a “master” biological clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus.

But the SCN is not the only biological clock in the body, although it is the most important. In fact, most tissues within the body express peripheral or “slave” clocks that also regulate sleep. Whether these peripheral clocks respond to light is still unknown, but they do respond to feeding, temperature, activity, hormones and neuronal signals. It would not surprise me that beneficial gut bacteria also influence these secondary clocks. Interestingly, while the SCN usually coordinates these “slave” clocks, they are capable of functioning independently of the “master” clock.

In the hypothalamus, the SCN receives information about light from the ganglion cells in the retina via the retino-hypothalamic tract. Synchronization with actual day-night light cycles occurs through a process called entrainment. SCN rhythms can be shifted by exposing a person to a new light/dark schedule although this takes time as anyone who has experienced jet-lag or shift-work can tell you.

Light information is conveyed to the pineal gland, a tiny cone-like structure in the brain where melatonin is secreted in response to low light. Melatonin is a hormone produced from serotonin that induces drowsiness and lowers body temperature thus preparing the body for slumber. The less light sensed by the hypothalamus, the more melatonin produced, assuming serotonin levels are adequate to serve as a precursor, a point I’ll return to in a minute. Conversely, the more light sensed, the less melatonin produced as I mentioned in part one of this series.

So anything that negatively impacts the hypothalamus and the production of both serotonin and melatonin will cause sleep problems.

Inflammation and Cortisol Production

But there is another important hormone that shows variations during our daily sleep-wake cycle: cortisol.

In a healthy person experiencing normal levels of plasma cortisol and adjusted to a typical daytime schedule, cortisol levels are lowest at around midnight or about two to three hours after falling asleep. At this point, levels gradually begin to rise into early morning and dramatically increase after waking. In most people, plasma cortisol jumps about 50% thirty or so minutes after getting up from bed. This is called the Cortisol Awakening Response.

Cortisol levels peak around 9 a.m. and as the day continues, begin to decline until again reaching their lowest levels two to three hours after sleep commences.

What this means is that not only are the daily fluctuations in the level of melatonin important, so too the variations in cortisol production. So we can also say that anything that alters cortisol production during the evening and night will negatively impact sleep every bit as much as changes in melatonin, serotonin and hypothalamic function.

As you recall from my post, The Gut-Brain Axis: How Endotoxemia and “Leaky Gut” Impact the Hypothalamic-Pituitary-Adrenal Axis, cortisol is produced in response to immune activation.

I once again want to point your attention to this graph:


Courtesy: Regulation of the stress response by the gut microbiota: Implications for psychoneuroendocrinology.


For a step-by-step explanation of what’s going on here, please review the aforementioned post.

For today’s topic, it’s enough to emphasize that gut pathogens will provoke an immune response that will increase levels of cortisol; both via cytokine stimulation of the hypothalamus and direct stimulation of the adrenals by the prostaglandin pathway.

Cortisol directly impacts the central nervous system. As I wrote then:

“It decreases REM sleep but increases shallow sleep or time spent awake which makes sense if there is an external threat. In the stone-age, your distant ancestors avoided being eaten by marauding beasts because they could stay awake to defend themselves. However, chronically elevated cortisol is not great if you want to get some sleep.”

In a nutshell, increase levels of cortisol during the evening and night, and your chances of getting to sleep or staying asleep are about as likely as meeting a unicorn.

Very low blood-glucose levels can also cause sleep problems. If blood sugar drops too low at night to adequately supply brain and other cells, you may be jarred awake by a rise in cortisol to raise blood glucose and initiate feeding behavior. This is what happens during starvation or glucose deficiency. I’ll have more to say about glucose deficiency in the next post.

Those of you who have followed this blog for a while know that inflammation emanating from the gut is a running theme here. Many of you have been introduced to the disease concept of endotoxemia and know that it can affect all bodily systems. Sleep is one such system, and it is one of the first negatively affected.

I consider insomnia the proverbial canary in the coal mine. It is highly associated with cardiovascular disease, diabetes, obesity, cancer, skin diseases, gastrointestinal disorders, depression, anxiety, mood swings and dementia. It often predates these diseases by years, if not decades. And the reason this is so is because these disorders have a common cause—gut-derived inflammation.

I want to emphasize that translocation of gram-negative bacteria and their cell-wall remnants, lipopolysaccharides (LPS), are not the only sources of inflammation from the gut. Overgrowth of yeast, antigens from various foods, viral infections and intestinal parasites can all cause inflammation due to compromised gut barrier function.

And in extreme breaches of the intestinal gut wall, even normally friendly gram-positive gut flora can threaten our very existence.

One other point. This chronic inflammation has the potential to damage cells, including the cells in the suprachiasmatic nucleus of the hypothalamus, site of your biological clock. How long it takes for this to happen is anyone’s guess.

Tryptophan Metabolism

But the story doesn’t end here. Recall that melatonin is also involved in regulating our sleep-wake cycle. And recall that the pineal gland requires serotonin to produce melatonin.

Allow me to reproduce two graphs from my post on depression to illustrate what this means for sleep:


Courtesy: Regulation of the stress response by the gut microbiota


Gut-derived inflammation not only affects the hypothalamic-pituitary-adrenal(HPA) axis as seen on the right-hand side of this illustration, it also directly increases the production of an enzyme called indoleamine 2,3 dioxygenase or IDO in the liver.

IDO suppresses T-cell production, an immensely important set of immune cells. One subset of T-cells, natural killer cells, are your first line of defense against cancer. The more IDO produced, the more compromised your immune system becomes. This is a major reason why increased cortisol levels depress immune function and why inflammation is associated with cancer and autoimmune disorders.

But IDO is also important because it degrades tryptophan, the precursor of serotonin and serotonin’s metabolite melatonin, to kynurenine. The more tryptophan shuttled to the kynurenine pathway, the less is available for the production of serotonin or melatonin. And the less melatonin produced, the less likely you are to feel drowsy when it’s time to go to bed. Hence my comment in the last post that while melatonin is inhibited by light, it isn’t the only thing affecting melatonin for the worse.


Courtesy: The role of indoleamine 2,3-dioxygenase (IDO) in the pathophysiology of interferon-α-induced depression.


At the bottom of this chart, you can see how increases in the inflammatory cytokines IFN-α, IFN-γ and TNF-α, but not IL-4 or IL-10, stimulates the production of IDO leading to a decrease in tryptophan available for later melatonin production. Instead, tryptophan is converted to kynurenine, which increases the production of both 3-hydroxy-kynurenine (3-OH-KYN) and quinolinic acid (QUIN), both of which easily cross the blood-brain barrier.

These metabolites are implicated in the following disorders:

  • Parkinson’s disease
  • Huntington’s disease
  • AIDS-related dementia
  • Alzheimer’s disease
  • infections of the central nervous system
  • malaria
  • ischemia or blood supply restriction
  • traumatic injury
  • hypoxia at birth
  • epilepsy
  • schizophrenia

3-OH-KYN generates lots of free radicals that damage cell components in the brain, including DNA, and causes increased cell death or apoptosis.

QUINN also causes oxidative stress, depletes cellular energy and is an excitotoxin. Excitotoxins cause an excessive release of excitatory neurotransmitters that damage nerve and glial cells eventually resulting in cell death. It would not surprise me that the obsessive thoughts that rack the brain of many an insomniac in the middle of the night are due not only to increased cortisol levels, but also increased concentrations of quinolinic acid.

Nor would it be shocking that the hypothalamus itself, including the cells of the “master” biological clock, are similarly damaged by these toxic metabolites.

Melatonin is also a powerful antioxidant. By reducing its production, IDO not only impacts sleep, it inhibits the synthesis of a very powerful free radical scavenger.

Finally, recall that:

“…communication between the gut and brain is not one way. Traumatic events can trigger intense stress that can impair gut barrier function by initiating an inflammatory response after cortisol release from the adrenals, especially in the presence of already disordered gut flora.

This increased intestinal permeability can in turn cause a translocation of pathogens or other antigens from the gut into systemic circulation that then sets up a positive-feedback loop: chronic inflammation leading to increased IDO and cortisol production, leading to increased oxidative damage in the brain and leaky gut, leading to more inflammation, etc.”

The stress involved by repeatedly failing to get a good night’s sleep will also contribute to this vicious feed-back loop.

When Getting to Sleep is the Least of Your Problems

Not all inflammation results in sleeplessness. On the contrary, intense immune responses can result in the opposite: inability to stay awake or remain conscious.

Why would this be?

Cortisol is always released in stressful situations and illness is a stressful as it gets. As I wrote in my post on the HPA axis,

“…when cortisol production is increased glucose output in the liver goes up and glucose uptake by muscle, fat and other tissue goes down resulting in a rise in blood-glucose levels. In order to increase glucose production in the liver, it breaks down protein and fat in so the liver can produce glucose from these building blocks. Doing so mobilizes energy for the brain and the heart which makes sense in an emergency…”

If this breakdown of tissue, also known as catabolism, exceeds the buildup of tissue or anabolism, intense tiredness will result, overwhelming the waking signals from cortisol.

Let’s say you come down with a very bad flu. Cortisol levels will increase as a result of your immune system’s response to the virus. However, a number of other things happen as well.

Your body will produce loads of white blood cells to fight the infection, and this requires a lot of energy. Your vitamin and mineral stores will be depleted. Whatever glucose stores you had will be broken down to feed the brain and other cells. Thyroid function will be impacted for the worse, especially if you already have low function to begin with. IDO production in the liver will increase the production of QUINN which depletes cellular energy. And chances are, you’ll lose your appetite, or if you do eat, you’ll throw it up or it goes right through you further depriving your body of the nutrients it needs.

Is it any wonder so many people lose a lot of weight after a serious infection?

Gut Flora and Insomnia

If you have chronic insomnia and there are no obvious illnesses, external stressors, glucose deficiencies or sleep hygiene issues to explain why, I can confidently say your answer lies here.

As long as this gut inflammation exists, you will have a very hard time getting a restful night’s sleep. Your body is telling you something is seriously wrong and masking these symptoms with sleeping pills or other sleep aids is a recipe for health disasters further down the line.

Disordered gut flora or dysbiosis is the source of this inflammation. This dysbiosis can be from either the small intestine or colon or both. Once your beneficial gut flora is disturbed for whatever reason—diet, drugs (legal or not), external stress, environmental pollutants, etc–the chances are high that pathogenic bacteria and yeast will colonize the gut wall, compromise gut barrier function, translocate to systemic circulation, provoke a chronic immune response and result in sleep disorders along with much else.

Determining where in your digestive tract the inflammation is coming from can be difficult. Small intestinal bacterial overgrowth (SIBO) will also cause dysbiosis in the colon. Since small intestinal dysbiosis ALWAYS results in inability to properly digest food, that undigested food will reach your colon to be fermented by both friendly gut flora and pathogens that use it to fuel their growth. If you suspect SIBO, consider reading my series if you haven’t done so already. You can find part one here.

Friendly gut flora is crucial to maintaining the integrity of the intestinal wall and keeping pathogens from colonizing it. For more on this see my post The Many Vital Functions of Healthy Gut Flora. I can honestly tell you that if your friendly gut flora is disordered, your sleep and health are essentially screwed regardless of how “wholesome” or “Paleo” or “nutrient-dense” or “plant-based” your diet.

It will be impossible to tackle chronic insomnia caused by the hormonal and chemical imbalances wrought by gut dysbiosis without correcting gut flora. Doing so requires prebiotics, probiotics, an antiparasitic medication if you have parasites and perhaps an antibacterial if you have SIBO.

Eating fermented foods won’t cut it, not if you’re expecting rapid results. A healthy level of stomach acid will kill 99% of ingested bacteria within five minutes and that holds true for friendly bacteria in kefir or yogurt. I recommend fermented foods as part of a long-term diet strategy to support gut flora populations but not as a short-term corrective.

I recommend that prebiotics be taken in the morning or during the day to avoid any unwanted gas or bloating from interfering with sleep. Probiotics, on the other hand, should be taken before bedtime. In fact, a good way to know if the probiotic you’ve chosen is doing you any good is if your sleep improves while taking it.

Alcohol should also be minimized or avoided entirely during treatment. It will be very hard for your liver to detoxify alcohol and gut pathogens at the same time. And alcohol is well known to cause sleep disturbances among many other things as explained here.

In the next and last post in this series, I’ll discuss how diet can influence sleep.



Ait-Belgnaouri A., Durand H., Cartier C., Chaumaz G., Eutamene H., Ferrier L., Houdeau E., Fioramonti J., Bueno L., Theodorou V. (2012). Prevention of gut leakiness by a probiotic treatment leads to attenuated HPA response to an acute psychological stress in rats. Psychoneuroendocrinology, http://dx.doi.org/10.1016/j.bbr.2011.03.031.

Dinan T. G. and Cryan J. F. (2012). Regulation of the stress response by the gut microbiota: Implications for psychoneuroendocrinology. Psychoneuroendocrinology, 37: 1369-1378.

Hudson, T. and Bush B. (2010). The Role of Cortisol in Sleep. Natural Medicine Journal, 2(6): 26-29.

Mitrovic, I. Introduction to the Hypothalamo-Pituitary-Adrenal (HPA) Axis (Lecture). https://docs.google.com

Perez-De La Cruz V., Carrillo-Mora P., Santamaria A. (2012). Quinolinic Acid, an endogenous Molecule combining excitotoxicity, Oxidative stress and Other Toxic Mechanisms. International Journal of Tryptophan Research, 5: 1–8.

Wichers M. C. and Maes M. (2004). The role of indoleamine 2,3-dioxygenase (IDO) in the pathophysiology of interferon-α-induced depression. Journal of Psychiatry and Neuroscience, 29(1):11-7.

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