Depression

Worldwide, 350 million people in different age groups are estimated to suffer from depression (WHO figures). Depression is more prevalent among women than among men. It is a mental state that strongly affects the social, psychological and physical aspects of someone’s life. People suffering from depression tend to feel washed-out and miserable, which frequently prevents them from participating in society in a normal way. Furthermore, depression can trigger other diseases, both mental and physical1, and can even lead people to commit suicide.

Worldwide, 8 to 12 percent of people are estimated to experience an episode of depression at some point in their lives2. There are drugs to treat depression, but existing treatments unfortunately do not always achieve adequate results. Moreover, drug treatments are often associated with unpleasant side effects. A survey among 1,829 users of antidepressants even showed that half of them developed new psychological issues caused by the drugs they were taking3. Although the exact figures are subject to debate, the fact that antidepressants have significant side effects is uncontested. Side effects may be acceptable if people are taking antidepressants for a severe, deep depression, but they can be harder to accept for people with mild depression.

A depression is the result of a complex interplay between various factors, which can be of a social, psychological or biological nature. Depression can, for instance, result from a chronic illness or from stressful situations at home (relationship trouble, a sudden bereavement) or at work (bullying, dismissal, high workload), or from hormone imbalances that can trigger postpartum depression or depression in adolescence. Depression can be the result of a physical illness, but depression can also lead to physical complaints. However, regardless of whether it is cause or effect, depression always affects the sufferer’s quality of life. In addition, the social and economic burden of sick leave from work due to depression is considerable. In short, this complex and frequently seen condition requires additional measures and, above all, a new prevention and treatment perspective.

The influence of microbiota on depression

The communication between the brain and the gut is bidirectional. Depression can lead to gut symptoms, but the microbiota can also affect someone’s susceptibility to depression. The barrier function of the intestinal wall has a key role in these processes. As described in the piece about the gut-brain axis (link), increased permeability of the intestinal wall can disrupt the dialogue between the microbiota and the brain. Therefore, as we know the composition of the microbiota plays an important part in keeping the intestinal wall healthy, seems increasingly likely that the intestinal microbiota plays an important role in the prevention of depression4.

A healthy intestinal microbiota typically has a high diversity of bacterial species with a certain balance in their respective population sizes. The ecological balance of the bacterial populations can be disrupted by a number of different causes. The resulting imbalance is also known as dysbiosis. Frequently seen causes for this include an inadequate or monotonous diet (e.g. high in fat or sugar, but also too low in carbohydrates or fibre), too little exercise, use of antibiotics or prolonged mental stress. The resulting dysbiosis inhibits the ability of the microbiota to produce nutrients (especially butyric acid) needed to keep the intestinal wall healthy and to maintain its barrier function. The result is a condition known as “leaky gut”. A leaky gut allows bacteria and particles to pass from the intestines into the underlying tissue. The cells of the body’s immune system identify these particles as foreign substances and will trigger an inflammatory response. If this situation persists, it is known as low-grade inflammation. This low-grade inflammation triggers the activation of neurons and the release of proinflammatory substances, known as cytokines, into the bloodstream. In the brain, these proinflammatory cytokines inhibit the production of serotonin and melatonin, which can lead to signs of depression, including lethargy, insomnia, reduced sex drive and eating disorders5. This, in turn, will affect the gut by perpetuating the dysbiosis. Breaking this feedback loop and restoring a balanced microbiota is therefore essential.

Probiotics and susceptibility to depression

Depression is one of the most extensively researched conditions associated with the gut-brain axis. Some time ago, the positive effect of probiotics in the treatment of depression was recognized6. Since then, a great deal of research has been done into the relationship between depression, microbiota and how probiotics can influence these processes.

Preclinical research with mice has shown that germ-free mice (i.e. mice without microbiota) do not go through the same emotional development as healthy mice, and that they display symptoms associated with depression7. These effects could be reduced by administering specific probiotic bacteria. A randomized, double-blind, placebo-controlled trial (RCT) by Steenbergen et al. with 40 healthy subjects showed that the group given a probiotic formula containing 8 specific strains was significantly less susceptible to depression than the control group8. The effectiveness of probiotics in people with depression has been demonstrated in another RCT, conducted by Akkasheh et al.9. This trial examined the effect of a probiotic formula consisting of 3 bacterial strains in patients with a depressive disorder. The degree of depression was measured using the “Beck Depression Inventory” (BDI), a multiple-choice questionnaire developed by Aaron Beck that has been validated in a great number of trials and is one of the most widely used psychometric tests to measure the severity of depression. In the group taking the probiotic, a significant reduction in the BDI score was seen, as well as a significant reduction in serum hs-CRP and insulin levels.

Perhaps the most significant evidence for the efficacy of probiotics in the treatment of depression was shown by a systematic meta-analysis of relevant clinical trials conducted in recent years, which focused on the effect of probiotics on depression10. Using statistical analysis allowed the effect of bias to be excluded as far as possible and allowed the different values resulting from the trials to be combined. Eventually, 5 trials were carried forward to the meta-analysis, which concluded that, for all trials together, there was a significant reduction in depression in subjects taking the probiotics when compared to subjects taking a placebo.

Depression is often accompanied by gastrointestinal symptoms, including abdominal pain, nausea and vomiting. These symptoms can be partially attributed to a deterioration of the intestinal mucosa caused by dysbiosis, resulting in a so-called“leaky gut”11. This allows bacteria and other substances to leak out of the intestines into the underlying tissues and causing an inflammatory response there. A trial conducted by Diop et al. showed that probiotics can reduce these stress-induced gastrointestinal symptoms12.

Strain selection for the Ecologic® Barrier formulation

Winclove developed the indication-specific probiotic formulation Ecologic® Barrier with the following strains: Bifidobacterium bifidum W23, Bifidobacterium lactis W52, Lactobacillus acidophilus W37, Lactobacillus brevis W63, Lactobacillus casei W56, Lactobacillus salivarius W24, Lactococcus lactis W19 and Lactococcus lactis W58.

Ecologic® Barrier formula for depression

A number of trials have been conducted to demonstrate that the selection of strains in Ecologic® Barrier has the desired effect. The Ecologic® Barrier formula was initially tested in an animal trial, conducted at Aarhus University in Denmark. In this trial, rats were given the multispecies probiotic or a placebo for a period of eight weeks, after which they were subjected to a forced swim test. This is a standard test to determine depression-like behaviour in rodents; the more depressed a rat is, the less it will move. It appeared that the rats given the indication-specific probiotic moved significantly more than the rats given the placebo13.

After that, the effect of the eight strains in Ecologic® Barrier (Bifidobacterium bifidum W23, Bifidobacterium lactis W52, Lactobacillus acidophilus W37, Lactobacillus brevis W63, Lactobacillus casei W56, Lactobacillus salivarius W24, Lactococcus lactis W19 and Lactococcus lactis W58) was trialled in healthy human subjects in a pilot RCT conducted in collaboration with Leiden University. In this four-week trial, one group of students was given the multispecies probiotic while the other group was given a placebo. Before and after the treatment, all subjects completed a validated questionnaire to measure their cognitive reactivity to low mood, seen as an indicator of susceptibility to depression. At baseline, no differences between the groups were found. After four weeks, however, susceptibility to depression had dropped significantly in the group using the indication-specific multispecies probiotic when compared to the placebo group. This trial showed that the probiotic group was significantly less susceptible to depression8. The most pronounced difference of cognitive reactivity was seen in the categories aggression and rumination. These results gave rise to a follow-up trial, to be conducted with an older population and with depression sufferers.

The research formulation Ecologic® Barrier is not sold as a consumer product. However our worldwide business partners offer the formulation Ecologic® Barrier as their own branded product. Thus the specific bacterial composition can be found in different products around the world.

References

  • 1. Goodwin, G. M. Depression and associated physical diseases and symptoms. Dialogues in clinical neuroscience 8, 259-265 (2006).
  • 2. Andrade, L. et al. The epidemiology of major depressive episodes: results from the International Consortium of Psychiatric Epidemiology (ICPE) Surveys. International journal of methods in psychiatric research 12, 3-21 (2003).
  • 3. Read, J., Cartwright, C. & Gibson, K. Adverse emotional and interpersonal effects reported by 1829 New Zealanders while taking antidepressants. Psychiatry research 216, 67-73, doi:10.1016/j.psychres.2014.01.042 (2014).
  • 4. Forsythe, P., Sudo, N., Dinan, T., Taylor, V. H. & Bienenstock, J. Mood and gut feelings. Brain, behavior, and immunity 24, 9-16, doi:10.1016/j.bbi.2009.05.058 (2010).
  • 5. Dinan, T. G. Inflammatory markers in depression. Current opinion in psychiatry 22, 32-36, doi:10.1097/YCO.0b013e328315a561 (2009).
  • 6. Logan, A. C. & Katzman, M. Major depressive disorder: probiotics may be an adjuvant therapy. Medical hypotheses 64, 533-538, doi:10.1016/j.mehy.2004.08.019 (2005).
  • 7. Foster, J. A. & McVey Neufeld, K. A. Gut-brain axis: how the microbiome influences anxiety and depression. Trends in neurosciences 36, 305-312, doi:10.1016/j.tins.2013.01.005 (2013).
  • 8. a. b. Steenbergen, L., Sellaro, R., van Hemert, S., Bosch, J. A. & Colzato, L. S. A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood. Brain, behavior, and immunity 48, 258-264, doi:10.1016/j.bbi.2015.04.003 (2015).
  • 9. Akkasheh, G. et al. Clinical and metabolic response to probiotic administration in patients with major depressive disorder: A randomized, double-blind, placebo-controlled trial. Nutrition (Burbank, Los Angeles County, Calif.) 32, 315-320, doi:10.1016/j.nut.2015.09.003 (2016).
  • 10. Huang, R., Wang, K. & Hu, J. Effect of Probiotics on Depression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Nutrients 8, doi:10.3390/nu8080483 (2016).
  • 11. Maes, M., Kubera, M. & Leunis, J. C. The gut-brain barrier in major depression: intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuro endocrinology letters 29, 117-124 (2008).
  • 12. Diop, L., Guillou, S. & Durand, H. Probiotic food supplement reduces stress-induced gastrointestinal symptoms in volunteers: a double-blind, placebo-controlled, randomized trial. Nutr Res 28, 1-5, doi:10.1016/j.nutres.2007.10.001 (2008).
  • 13. Abildgaard, A., Lund, S., Hokland, M. & Wegener, G. Probiotic treatment alters behavior in rats on standard and high-fat diet. Acta Neuropsychiatrica 26, 1 (2014).