When all you see is black and gray


Today I want to talk about depression and the evidence implicating increased intestinal permeability and endotoxins in this psychological disorder. Having discussed how endotoxemia impacts your hormonal system, it’s now time to explore what this can mean for your mental state.

Wikipedia describes depression as:

“…a state of low mood and aversion to activity that can have a negative effect on a person’s thoughts, behavior, feelings, world view and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, worried, helpless, worthless, guilty, irritable, hurt, or restless. They may lose interest in activities that once were pleasurable; experience loss of appetite or overeating; have problems concentrating, remembering details, or making decisions; and may contemplate or attempt suicide. Insomnia, excessive sleeping, fatigue, loss of energy, or aches, pains or digestive problems that are resistant to treatment may be present.”

According to the Centers for Disease Control and Prevention, major depression afflicts 4.4% of the population at any one time with milder forms of depression affecting a little over 9% of the population. Among the population, those most likely to be afflicted are:

  • persons 45-64 years of age
  • women
  • blacks, Hispanics, non-Hispanic persons of other races or multiple races
  • persons with less than a high school education
  • those previously married
  • individuals unable to work or unemployed
  • persons without health insurance coverage

In the United States, rates of depression are more prevalent in the Southeast and correlate with rates of obesity and stroke.

Obviously, there are certain things on this list that would make anyone sad such as low educational attainment, not being able to find work or not having health insurance. Other life stressors like losing a loved-one, being ill or suffering from a traumatic event can set the stage for a period of intense sadness.

Nevertheless, many people also suffer from these life events but don’t enter the psychological abyss, or if they do, they don’t stay there. And as any psychiatrist or psychologist will tell you, there are plenty of very depressed people who would be considered successful by any measure yet still lose the will to carry on.

So let me present you with some findings that implicate endotoxemia and increased intestinal permeability as contributing causes of depression.

An interesting study was conducted in Belgium and published in the scientific literature in 2008 that examined the role of infection in the severely depressed. It found that chronic inflammation caused by gut-derived lipopolysaccharides (LPS) was behind the behavioral and mood disorders seen in the subjects studied.

A total of fifty-one persons participated: 23 controls (consisting mainly of staff and their family members) and 28 patients suffering from major depression. Excluded from the study were:

  • those diagnosed with other life-long disorders like anxiety disorders, schizophrenia, substance abuse and organic mental disorders
  • chronic fatigue sufferers or those suffering from inflammatory or autoimmune disorders
  • anyone taking antipsychotic drugs or anticonvulsants
  • patients with abnormal blood tests
  • patients with acute inflammatory or allergic reactions within the past month

A morning blood draw was collected from each participant and analyzed for the presence of IgA and IgM antibodies to six different gram-negative bacteria: Hafnia alvei, Pseudomonas aeruginosa, Morganella morganii, Pseudomonas putida, Citrobacter koseri and Klebsiella pneumoniae.


Courtesy of: The gut-brain barrier in major depression


As you can see in the above chart, both types of antibodies were elevated against all six gram-negative bacteria in the major depression group (MDD). IgM antibodies were significantly raised in 12 of the 28 suffering from MDD against none of the controls. IgA antibodies were elevated in 11 of the 28 MDD patients as opposed to only 2 in the control group.

In the following chart the symptoms highlighted in bold had the strongest correlation with higher IgM and IgA antibodies:



Fatigue, irritable bowel, the feeling of having an infection and disturbances in the autonomic nervous system (ANS) were the most common symptoms. The ANS controls things like sweating, intestinal peristalsis, heart rate, swallowing, breathing and sexual arousal. These symptoms, by the way, are also seen in those suffering from chronic fatigue syndrome.

The increase in both families of antibodies was accompanied by increased intestinal permeability. It was noted that those suffering from major depression had higher levels of the inflammatory cytokines interleukin 6 and interferon, the very same cytokines that were elevated in my previous post on endotoxemia and the HPA axis.

Systemic increases in LPS not only cause inflammation in the body, but also inflammation in the central nervous system. Increased levels of the cytokine tumor necrosis factor is elevated in brain tissue for ten months after an infection.

Through its effects on the HPA axis and liver, LPS induced inflammation can initiate what is known as the sickness behavior complex. This complex includes fatigue, disinterest in social interaction, anorexia, anxiety, failure to concentrate, weight loss and sleep disorders.

Let me remind everyone that inflammation caused by endotoxins from the gut lowers levels of tryptophan in the brain:


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


It does so by increasing the liver’s production of an enzyme called indoleamine 2,3 dioxygenase or IDO. This enzyme will convert tryptophan, the precursor of serotonin, to kynurenine instead. The more tryptophan shuttled to the kynurenine pathway, the less is available for the conversion of tryptophan to serotonin or 5-HT. However, altered serotonin levels are not the only reason these patients and the depressed experience what they do.

The kynurenine pathway produces two very harmful metabolites that have toxic effects on the brain: 3-hydroxy-kynurenine (3-OH-KYN) and quinolinic acid (QUIN). Both toxic byproducts can easily cross the blood-brain barrier and affect the central nervous system causing neurodegeneration.

Increased levels of both metabolites are found in people suffering from Parkinson’s disease, Huntington’s disease and AIDS-related dementia.

Both of these substances are also suspected of causing neuronal damage in the following conditions:

  • age-related dementia
  • infections of the central nervous system
  • malaria
  • ischemia or blood supply restriction
  • traumatic injury
  • hypoxia at birth
  • epilepsy
  • schizophrenia

These substances are also implicated in anxiety disorders.

In the following illustration, the role of cytokines on both the tryptophan to serotonin and tryptophan to kynurenine pathway is mapped out:


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


At the bottom, you can see how increases in the cytokines IFN-α, IFN-γ and TNF-α, but not IL-4 or IL-10, stimulates the production of indoleamine 2,3 dioxygenase or IDO leading to a decrease in tryptophan available for serotonin or 5-HT conversion. Instead, tryptophan is converted to kynurenine which increases the production of both 3-OH-KYN and QUIN.

Moreover, 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. Breaking this vicious cycle requires not only dealing with the traumatic event through therapy, but also healing and sealing the gut to prevent the chronic inflammation that keeps this all in motion.

The authors of the Belgium study also note that major depression is often accompanied by autoimmune disorders. This should shock no one. Increased translocation of bacteria and other contents of the gut lumen can set up the perfect scenario for molecular mimicry.

Molecular mimicry is the process whereby antibodies are formed against foreign intruders, but because these foreign substances resemble the tissue of the host, the antibodies formed to attack them also attack self-tissue. The example I gave of gluten ataxia in this post summarizes the process nicely.

Once again we see how endotoxemia or leaky-gut-fueled inflammation can affect every system in the body including the brain.

If someone suffers from severe depression, it’s imperative that increased intestinal permeability and endotoxemia be investigated. Otherwise the person risks an endless series of treatments that only address symptoms but leaves the source of inflammation untouched.

Speaking from experience, my mood was noticeably improved when I eliminated gluten from my life and resolved my small intestinal bacterial overgrowth through the use of garlic, probiotics and prebiotics. Things that in the past would send me into a prolonged funk or cause anxiety no longer bother me.

The key here is stopping whatever causes increased intestinal permeability and overgrowth of the small intestine with gram-negative bacteria. If you’re new to this blog, please read my series on small intestinal bacterial overgrowth (SIBO). This will help you understand how what happens in your gut affects your well-being and how beneficial bacteria are key to stopping gut inflammation.

While it is sadly the norm for psychologists and psychiatrists to study the brain in isolation from the body, the reality is that inflammation from the gut does impact every bodily system, including the brain. We pay a heavy price for ignoring that forgotten organ known as our gut flora. This is especially true for those who tragically take their own life to escape their psychological distress.



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

Maes M., Kubera M., Leunis J.-C. (2008) The gut-brain barrier in major depression: Intestinal mucosal dysfunction with an increased tranlocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuroendocrinology Letters, 29(1): 117-124.

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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