Probiotics, Depression, and the Role of Inflammation

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Researchers examined evidence suggesting that probiotics may exert antidepressant effects via anti-inflammatory mechanisms.
Researchers examined evidence suggesting that probiotics may exert antidepressant effects via anti-inflammatory mechanisms.

As evidence continues to accumulate regarding associations between psychiatric disorders and alterations in gut microbiota, researchers are increasingly exploring the potential role of probiotics as a treatment for major depressive disorder (MDD). Various findings indicate that probiotics may reduce depressive symptoms in both clinical and subclinical depression, and results of animal and human studies have linked probiotics to significant reductions in circulating concentrations of proinflammatory cytokines, which may be mediated by changes in the gut microbiome.1

"It is widely recognized that MDD is associated with persistent low-grade inflammatory activation," researchers at the University of Toronto wrote in a narrative review published in July 2018 in Brain, Behavior, and Immunity.1 For example, a 2017 meta-analysis of 82 studies found that MDD was associated with increased levels of circulating pro-inflammatory cytokines.2 Patients with depression have also been shown to have high rates of comorbid inflammatory conditions, including coronary heart disease and rheumatoid arthritis, and other results have demonstrated antidepressant effects of anti-inflammatory agents, such as cytokine inhibitors and nonsteroidal anti-inflammatory drugs, compared with placebo.1,3

In addition, alterations in gut microbiota have been observed in patients with MDD vs healthy control patients, and numerous "studies indicate that the restoration of dysfunctional microbial populations in the gut may be associated with reductions in peripheral inflammation," as stated in the review.1 "Probiotics are known to influence the composition of intestinal microbiota in both humans and animal models; therefore, it is postulated that the anti-inflammatory effects of probiotics may be mediated by probiotic-induced changes in microbiota composition."

The authors examined evidence suggesting that probiotics may exert antidepressant effects via anti-inflammatory mechanisms. Selected findings are highlighted here:

  • Probiotics have been shown to normalize inflammation resulting from stress-induced impairments of the sympathetic nervous system and hypothalamic-pituitary-adrenal axis. In a 2004 study, an aberrant hypothalamic-pituitary-adrenal-mediated inflammatory stress response was completely normalized after administration of the probiotic Bifidobacterium infantis.4
  • In another study using the rat maternal separation model of stress, those treated with B infantis showed normalized immune response, reduced behavioral deficits, and restored brain concentrations of noradrenaline.5
  • Intestinal permeability has been linked to stress and inflammation, and probiotics have been associated with decreased intestinal permeability. Studies of stress-induced rats have reported that a variety of probiotics led to improvements in intestinal barrier function and microbial translocation.1
  • In patients with MDD, an 8-week randomized, double-blind, placebo-controlled trial (n=40) demonstrated that treatment with a capsule containing 3 different probiotic strains was associated with significant reductions in Beck Depression Inventory scores and multiple inflammatory markers compared with placebo.6
  • Similar results were found in a 2018 randomized trial of patients with MDD,7 and in studies of patients with postpartum depression and those with comorbid and/or secondary depression.1
  • Findings from human studies have been mixed, however. Another double-blind, randomized, placebo-controlled trial observed no effect of probiotic formulations on low mood, and a 2018 meta-analysis concluded that the overall effect of probiotic supplementation on mood was insignificant.8,9

"The foregoing discrepancy in the literature may be related to inter-study differences in methodology...and the fact that the majority of [randomized controlled trials] have been conducted in populations without clinically-diagnosed depression," wrote the review authors.1 "Alternatively, it is possible that probiotic treatment may help reduce symptoms of depression, but only in specific subpopulations with depression such as those with elevated inflammatory status." Much more research is needed to elucidate these and other issues related to the potential role of probiotics as an intervention for depression.

Psychiatry Advisor interviewed Caroline Wallace, a PhD candidate in clinical neuroscience at Queen's University in Ontario, Canada, who has studied10 the connection between probiotics and depression, to learn more about the potential mechanisms, treatment implications, and next steps in this area.

Psychiatry Advisor: What is known thus far about the potential effects of probiotics on depression?

Wallace: At present, the research is simply not there to say probiotics have definitive effects on depression. However, preclinical and clinical research on healthy humans has shown promising findings and continues to encourage further research.

Several animal studies have shown that consumption of probiotics by rodents reduced stress-induced increases of adrenocorticotrophic hormone, corticosterone, adrenaline, and noradrenaline; reduced levels of inflammatory markers; increased expression of brain-derived neurotrophic factor and tryptophan; and improved memory and anxiety- and depression-like behaviors.

On the human side, most of the research performed to date has been on humans not presenting with any mood disorder or symptoms. However, there have been 3 studies examining the effects of probiotic supplements on individuals diagnosed with depression. Two of the 3 studies6,7 both found significant improvements on the Beck Depression Inventory; although the third study8 included more measures of symptoms of depression, it did not find significant improvements on any of them.

Psychiatry Advisor: What are the proposed mechanisms underlying these effects?

Wallace: There are several proposed mechanisms of action. Communication between the gut and the brain occurs via multiple systems: the neuroendocrine system, the autonomic nervous system (the vagus nerve is a very important gut-brain connection), the enteric nervous system, and the immune system. Our group is particularly interested in how the immune system may be mediating these effects. When the tight junctions of the gastrointestinal lining become compromised, which can occur as a result of chronic stress, permeability increases, allowing bacteria and toxins similar to the endotoxin lipopolysaccharide to flow into the bloodstream.

Lipopolysaccharide is an innate immune activator, so once in the bloodstream, it causes the body to mount an elevated immune response, including a release of proinflammatory cytokines. These cytokines can travel to the brain and cause disruptions in neurotransmission of key neurotransmitters involved in mood regulation, such as dopamine, serotonin, and norepinephrine, which cause changes in reward circuitry in the prefrontal cortex and anterior cingulate cortex, and fear/arousal circuitry in the amygdala and insula. These changes manifest as core clinical features we see in depression, such as anhedonia and anxiety.

So, it is hypothesized that probiotics may alleviate symptoms of depression by improving the integrity of the gastrointestinal lining, thus reducing leakage of lipopolysaccharide into the bloodstream and reducing inflammation that may be causing neurotransmission alterations that cause depressive symptoms.

Psychiatry Advisor: What are the current and future treatment implications for clinicians?

Wallace: Although we are not there yet in terms of having guidelines for prescribing specific probiotics and/or diets to patients suffering from mental illness, in the future it may be an enticing option for patients for whom antidepressant medication is not recommended, such as those younger than 18 years, pregnant or breastfeeding women, or those who feel stigmatized or uncomfortable taking antidepressant medication.

Psychiatry Advisor: What should be next steps in terms of research in this area?

Wallace: More rigorous blinded randomized controlled trials are warranted, especially in clinical populations of individuals with depression. Further research on the dosing, time frame, and specific strain and species of probiotic is also necessary. Not all species and strains of probiotics have the same function; thus, not all of them will have the same effects, if any, on mental health. Of course, continued research on what may be mediating these effects, if any, is also important going forward. In addition, studying the use of probiotics as an adjunct alongside traditional antidepressant treatment may also be useful.

References

  1. Park C, Brietzke E, Rosenblat JD, et al. Probiotics for the treatment of depressive symptoms: An anti-inflammatory mechanism? Brain Behav Immun. 2018;73:115-124.
  2. Köhler O, Benros ME, Nordentoft M, et al. Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiatry. 2014;71(12):1381-1391.
  3. Köhler CA, Freitas TH, Maes M, et al. Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies. Acta Psychiatr Scand. 2017;135(5):373-387.
  4. Sudo N, Chida Y, Aiba Y, et al. Postnatal microbial colonization programsthe hypothalamic-pituitary-adrenal systemfor stress response in mice. J Physiol. 2004;558(Pt 1):263-275.
  5. Desbonnet L, Garrett L, Clarke G, Kiely B, Cryan JF, Dinan TG. Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression. Neuroscience. 2010;170(4):1179-1188.
  6. Akkasheh G, Kashani-Poor Z, Tajabadi-Ebrahimi M, et al. Clinical and metabolic response to probiotic administration in patients with major depressive disorder: a randomized, double-blind, placebo-controlled trial. Nutrition. 2016;32(3):315-320.
  7. Kazemi A, Noorbala AA, Azam K, Eskandari MH, Djafarian K. Effect of probiotic and prebiotic vs placebo on psychological outcomes in patients with major depressive disorder: a randomized clinical trial [published online April 24, 2018]. Clin Nutr. doi: 10.1016/j.clnu.2018.04.010
  8. Romijn AR, Rucklidge JJ, Kuijer RG, Frampton C. A double-blind, randomized, placebo-controlled trial of Lactobacillus helveticus and Bifidobacterium longum for the symptoms of depression. Aust NZ J Psychiatry. 2017;51(8):810-821.
  9. Ng QX, Peters C, Ho CYX, Lim DY, Yeo WS. A meta-analysis of the use of probiotics to alleviate depressive symptoms. J Affect Disord. 2018;228:13-19.
  10. Wallace, CJK, Milev R. The effects of probiotics on depressive symptoms in humans: a systematic review. Ann Gen Psychiatry. 2017;16:14.
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