Intestinal Permeability, Inflammation, and Depression
“Leaky gut” is a term thrown around quite often nowadays, taking the blame for and/or being commonly associated with an array of pesky symptoms and conditions (often rightfully so, however, usually indirectly) - such as mood disorders, skin problems, digestive trouble, etc. But what even is leaky gut? Leaky gut refers to an increased permeability of the intestinal epithelial lining, often resulting from increased expression of zonulin and the resulting degradation of epithelial tight junctions. When the intestinal lining is more permeable, molecules such as bacteria, toxins, and food particles can escape from the digestive tract and enter into the bloodstream, throwing the immune system into a frenzy when it identifies these foreign molecules. This activation of the immune system triggers the production and release of a variety of pro-inflammatory cytokines, such as TNFalpha, IL-6, and CRP. If the gut is constantly “leaky”, the immune system remains in a heightened state, leading to immune over-reactivity and systemic inflammation (which are both thought to underly autoimmunity).¹ Although it is common knowledge that chronic systemic inflammation is incredibly detrimental, can these inflammatory cytokines actually cause depression?
Elevated levels of pro-inflammatory cytokines are strongly associated with the risk and development of depression.² This positive association has been shown to be not only correlative, but causal. When LPS (endotoxin) and IFN-gamma were administered (which trigger pro-inflammatory cytokine release), they induced depressive symptoms when compared to a placebo containing saline.³ Cytokines can cross the blood-brain-barrier (BBB), especially if there is increased permeability of the BBB (“leaky BBB”). Once in the brain, they can inhibit neurotransmitter release, increase neurotransmitter (i.e. serotonin) re-uptake (the opposite of what SSRIs do), lower serotonin production by shunting tryptophan to kynurenine pathways, and decrease BDNF, amongst other things.⁴ Hence, why leaky gut may be so correlated with depression: the ensuing inflammation that then affects the brain.
Other things that lead to chronically high levels of inflammation include obesity (adipose tissue releases adipokines that can lead to meta-inflammation), diet, nutritional deficiencies, exposure to toxins & pollutants, and stress.⁶ When we are stressed, we release corticotropin-releasing hormone (CRH), which travels to the gut to increase pro-inflammatory cytokines, which negatively impact the intestinal lining by damaging tight junction proteins and increasing intestinal permeability.³ This can create a vicious cycle as the increased permeability leads to even more inflammation. CRH also activates ACTH synthesis, which goes on to activate cortisol synthesis. The well-known cortisol hormone affects the expressions of many genes involved in metabolism, brain health, and more. Long-term elevation of cortisol can lead to hippocampal shrinkage and amygdala growth, and this is another way stress may play an important role in the development of depression and anxiety.³
The good news is that there are many effective ways to lower inflammation. For instance, depressive symptoms induced by inflammatory cytokines can be mitigated by the administration of anti-inflammatory EPA, an omega-3 fatty acid. Omega-3 fatty acids have been recently touted as a potential treatment for depression, and studies have found it to be clinically beneficial compared to a placebo.⁵
Other ways include…
prioritizing sleep
cutting out refined sugar (i.e. sugar-sweetened beverages)
Sugar consumption is associated with increases in CRP and inflammation, as well as mood dysregulation in a multitude of studies.⁷
exercising
Exercise can lower quinolinic acid, a neurotoxin associated with depression, by reducing kynurenine.⁸
consuming adequate b vitamins to lower homocysteine (which is positively associated with depression and cardiovascular disease).
consuming adequate zinc.
Zinc may be beneficial in treating depression. Zinc deficiency is positively correlated with depression, and zinc supplementation has been shown to reduce depressive symptoms in some individuals.
References
Paray BA, Albeshr MF, Jan AT, Rather IA. Leaky gut and autoimmunity: An intricate balance in individuals health and the diseased state. Int J Mol Sci [Internet]. 2020 [cited 2023 Aug 15];21(24):9770. Available from: http://dx.doi.org/10.3390/ijms21249770
Jeon SW, Kim YK. Neuroinflammation and cytokine abnormality in major depression: Cause or consequence in that illness? World J Psychiatry [Internet]. 2016 [cited 2023 Aug 15];6(3):283. Available from: https://www.wjgnet.com/2220-3206/full/v6/i3/283.htm
Patrick R. The Underlying Mechanisms of Depression. Found My Fitness; 2017.
Miller AH, Haroon E, Raison CL, Felger JC. Cytokine targets in the brain: Impact on neurotransmitters and neurocircuits: Review: Cytokine targets in the brain. Depress Anxiety [Internet]. 2013 [cited 2023 Aug 15];30(4):297–306. Available from: http://dx.doi.org/10.1002/da.22084
Liao Y, Xie B, Zhang H, He Q, Guo L, Subramanieapillai M, et al. Efficacy of omega-3 PUFAs in depression: A meta-analysis. Transl Psychiatry [Internet]. 2019 [cited 2023 Aug 15];9(1):1–9. Available from: https://www.nature.com/articles/s41398-019-0515-5
Coppack SW. Pro-inflammatory cytokines and adipose tissue. Proc Nutr Soc [Internet]. 2001 [cited 2023 Aug 15];60(3):349–56. Available from: https://pubmed.ncbi.nlm.nih.gov/11681809/
Ma X, Nan F, Liang H, Shu P, Fan X, Song X, et al. Excessive intake of sugar: An accomplice of inflammation. Front Immunol [Internet]. 2022 [cited 2023 Aug 15];13. Available from: http://dx.doi.org/10.3389/fimmu.2022.988481
Schlittler M, Goiny M, Agudelo LZ, Venckunas T, Brazaitis M, Skurvydas A, et al. Endurance exercise increases skeletal muscle kynurenine aminotransferases and plasma kynurenic acid in humans. Am J Physiol Cell Physiol [Internet]. 2016;310(10):C836–40. Available from: http://dx.doi.org/10.1152/ajpcell.00053.2016