The pathogenesis of major depressive disorder involves a complex interplay of social, psychological, and biological factors. Gut health, specifically, may play an important role in the disease and its treatment.
Increased intestinal permeability, a.k.a “leaky gut,” plays a role in a wide variety of chronic inflammatory diseases such as irritable bowel disease, asthma, diabetes type-1, obesity, autism spectrum disorder, and depression. The rates of chronic inflammatory diseases have risen steadily in industrialized nations since the 1950s. Given that depression is associated with both chronic low-grade inflammation and intestinal permeability, it is perhaps not surprising that major depressive disorder is currently the fourth-leading cause of premature death in the world and is expected to become the second-leading contributor to the overall disease burden by 2030.
Causes and Effects of Intestinal Permeability
There are a large number of factors that can increase intestinal permeability. Gluten, a protein found in wheat, barley, and rye that is indigestible to humans, temporarily increases intestinal permeability in all individuals, even those without celiac disease, wheat allergy, or non-celiac gluten sensitivity. Alcohol consumption, small intestinal bacterial overgrowth, and low stomach acid can also cause or contribute to “leaky gut.”
When the intestinal lining becomes permeable, toxins, bacterial pathogens, and dietary antigens can cross from the intestinal lumen, the hollow area of the gut, into the bloodstream. The immune system of susceptible individuals will respond to these foreign particles, regardless of whether or not they pose a threat. Research suggests that immune dysregulation, specifically activation of the inflammatory response system, accompanies depression.
Certain cytokines, molecules that direct the immune system to sites of trauma or injury, are elevated in individuals with depression (specifically interleukin-6 and TNF-alpha). In one study, researchers injected otherwise healthy volunteers with endotoxins and observed that an elevated level of cytokines correlated with the emergence of depressive symptoms.
Another observed a correlation between depressive symptoms, intestinal permeability, and cytokine levels in adolescent girls in the midst of a major depressive episode. Pro-inflammatory cytokines open paracellular pathways, increasing intestinal permeability even more in a vicious cycle. Cytokines also stimulate a reaction of the hypothalamic-pituitary-adrenal (HPA) axis that leads to the release of cortisol, a stress hormone. Hyperactivity or dysregulation of the HPA axis is one of the indicators of major depression and anxiety.
Beyond causing the release of cytokines and dysregulation of the HPA axis, intestinal permeability can create further problems in the functioning of the blood brain barrier. The disruption of this barrier can lead to depressive symptoms. Because the tight junctions of the lining of the intestine are structurally similar to those of the blood brain barrier, a disruption in one can cause a disruption in the other. When both barriers become permeable, microbial compounds from the gut can enter the bloodstream and flow into compartments of the brain, causing symptoms associated with depression, such as fatigue, inability to concentrate, and changes in weight or sleeping patterns.
Lipopolysaccharide (LPS), a powerful endotoxin, is particularly pernicious when the intestine has become too permeable. The presence of LPS in the gut is harmless. Individuals with healthy GI tracts can consume it orally without any negative effects. However, when it enters the bloodstream, it acts as an emergency signal causing a powerful inflammatory response. LPS levels in patients with major depressive disorder are chronically elevated.
This disease process plays a role, not only in depression but also a wide variety of other chronic inflammatory diseases, such as asthma, diabetes, and celiac disease, among many others.
Possible Interventions
Taking action to heal the gut can positively impact mental health.
Dietary changes might help individuals with increased intestinal permeability and related inflammation. A gluten-free diet has been shown to improve mood disorders and psychological well-being in patients with celiac disease, irritable bowel syndrome, and non-celiac gluten sensitivity. Since gluten causes intestinal permeability in all individuals, it is wise to limit the consumption of gluten.
The effects of probiotics in the gut are complex and their underlying mechanisms of action are often not well understood; however, certain strains have been shown to improve mood and cognition. In fact, some research has found that probiotics are as effective in reducing depressive symptoms as antidepressants.
It’s possible that the psychological effect of probiotics is related to their effect on the intestinal barrier. Research has shown that they can improve intestinal barrier integrity and suppress the release of inflammatory cytokines. Some strains can increase the secretion of IgA and the production of intestinal mucosa, which helps repair the intestines and buffers against bacteria and food antigens. Certain Lactobacillus species have been shown to improve HPA axis functionality. While it is too early to say for certain, it is possible that the gut-healing effects of probiotics are linked to the psychological benefits they offer.
It is important to choose a well-researched probiotic from a reputable company, as the effects of probiotics vary not only by species, but by strain.
Prebiotics, foods that feed the bacteria of the gut microbiome, have shown similar positive effects on both mood and the integrity of the intestinal lining. Many plant-based foods, such as garlic, onion, beans, and cooked and cooled rice and potatoes, are rich in prebiotics and can feed your microbiome.
Those with depression or an increased risk of depression are often low in zinc, magnesium, selenium, iron, and vitamins D, B-12, B-6, E, and folate. This is no surprise given that increased intestinal permeability can affect nutrient absorption. These micronutrient deficiencies may affect serotonin levels and contribute to inflammation. Vegetables and fruits are some of the best dietary sources of these micronutrients. One might also consider supplementing with a multivitamin.
If you’re suffering from gastrointestinal issues and mental health symptoms, you may be surprised how much positive impact you can have on your body and mind health through improving your diet.
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