Problems with mental health are one of the primary causes of the overall disease burden worldwide.1 According to the World Health Organization, over 300 million people are estimated to suffer from depression, which is equivalent to 4.4% of the world’s population.2
Serotonin reuptake inhibitors (SSRIs) have been the primary method of treatment for depression for many years; however they are not effective in all individuals, with success rates at about one in three.3 This has led researchers to investigate other potential factors which may be contributing to the growing body of mental dis-ease amongst the global population.
Enter: the gut. By now, it is unlikely to come as a surprise that there is a connection between the gut and the brain. However, what might be less familiar are the plethora of scientific studies which have been released over the past several years suggesting that inflammation (especially that which is generated within the gut) is a major driving factor of depression. Just like conditions such as obesity, heart disease and diabetes; the research is showing us that the origins of depression are inflammatory – with several neurological consequences.
And so, with this new understanding of the brain, scientists are looking at novel and alternative therapies for depression. One such therapy which has been yielding rather impressive results is the use of probiotics.
In this article, we will be looking at the new paradigm of depression, how the brain and gut communicate, as well as what the research is showing us regarding the use of probiotics as a novel therapy in cases of depression.
The old and the new: changing paradigms of depression
For a long time, it was believed that depression was caused by a deficiency of neurotransmitters such as serotonin, also known as the ‘happy’ chemical. This ‘serotonin model’ of depression led to the widespread use of selective serotonin reuptake inhibitors (SSRIs), which essentially increase levels of serotonin in the brain. However, how this neurotransmitter imbalance came to be was never fully understood and often assumed to be genetically driven. In recent years, a multitude of factors have come to be associated with the cascade of depression, including environmental, dietary, lifestyle and genetic; with chronic inflammation appearing as a central feature.
Several studies have implicated cytokines – chemical messengers released during the inflammatory process – in the pathology of depression. A variety of meta-analyses, cross-sectional and longitudinal studies have compared blood concentrations of pro-inflammatory and anti-inflammatory cytokines in patients with depression versus healthy controls. Across these studies, peripheral levels of IL-6, IL-10, IL-12, IL-13 and TNF-α were generally elevated, while IFN-γ levels tended to be lower in patients with depression.4–6 For instance, markers of inflammation such as CRP and IL-6 were found to be elevated by up to 50% in patients with clinical depression.7 In a study of over 1,000 women, increases in CRP triggered the onset of depression,8 while other studies show how symptoms of depression were resolved once these signs of inflammation returned to normal.9 Interestingly, even among healthy individuals, signs of depression would appear in tandem with increasing levels of inflammation.10
These cytokines appear to induce symptoms of depression through several mechanisms. When inflammation is high, the enzyme indoleamine 2,3-dioxygenase (IDO) is stimulated, which converts tryptophan into kynurenine. This does two things: (1) reduces the levels of tryptophan available to make serotonin and so levels of serotonin decline, (2) metabolites of the kynurenine pathway such as 3-hydroxy-kynurenine (3-OH-KYN) and quinolinic acid (QUIN) are released, which have toxic effects on brain function. 3-OH-KYN can produce oxidative stress by increasing the production of reactive oxygen species (ROS), while QUIN may overstimulate the hippocampal N-methyl-D-aspartate (NMDA) receptors, which leads to apoptosis and hippocampal atrophy – both of which have been associated with depression.11
Production of neopterin is also stimulated at the expense of tetrahydrobiopterin (BH4) under inflammatory conditions. This can impact the creation of neurotransmitters such as serotonin and dopamine, as BH4 plays a crucial role in their synthesis. From here a variety of symptoms of depression including a lack of enjoyment in the case of serotonin and a lack of motivation in the case of dopamine can be expressed.
As we can see, inflammation has very specific effects on brain behaviour, with multiple routes of creation including physical and psychological stress, pollution, infection, alcohol and poor diet.12–14 Gut dysfunction, too, appears to be a key factor – with systemic inflammation so radically able to alter the gut microbiome,12–14 it has led researchers to discover strong correlations between gut microbiome and brain health.15 In fact, differences in specific groups of gut bacteria present in those experiencing depression, anxiety and impaired brain function have been identified.16
Not-so-secret pals: how the gut and the brain communicate
The vagus nerve connects the brain with several parts of the gut, including the stomach, pancreas and intestines – making the gut a very influential path to the brain.17 This intricate, bidirectional network is a central means for communication between mind and body. It serves as a pathway for many things, including appetite regulation and ‘gut instincts’ – but also, when things go wrong, can be a channel for feelings of depression and anxiety.
Unlike the brain, the gut is designed to come into contact with intruders from the outside world. It is through the intestinal wall that the majority of nutrients, water and lipids are absorbed into the bloodstream. On the other hand, microbes, large food particles and other antigens cannot cross this barrier. Therefore, maintaining intestinal integrity is vital to ensuring that only what is deemed safe gets through to internal body systems. For this reason, the gut houses the bulk of our immune cells (the GALT – gut associated lymphoid tissue) which allow it to handle these interactions with foreign matter.18
Another central feature of the gut is the microbiome. The gut microbiome is made up of trillions of bacteria, viruses, fungi and other microscopic living things which are collectively referred to as ‘microbes.’ The balance of these microbes is central to our body’s ecosystem and when things get knocked out of balance, it can have a systemic effect on the global function of the body; impacting digestion, immunity and even brain health (to name a few). For example, when levels of inflammation are increased in the gut, inflammatory mediators such as cytokines can travel to the brain,19 particularly along the vagus nerve.
These alterations or ‘dysbiosis’ can damage the integrity of the intestinal wall and lead to increased intestinal permeability or ‘leaky gut’. When this happens, levels of LPS (lipopolysaccharides – endotoxins found in the outer membrane of Gram-negative bacteria like E. coli) can enter the bloodstream, cross the blood-brain barrier and bring about even more inflammation in the brain.
This is where probiotics come in…
With dysregulation of the microbiome and subsequent inflammation as a clear driving factor to depressive symptoms,20 researchers have been investigating the potential therapeutic role of probiotics in managing these symptoms.
In an eight week randomised controlled trial, patients with major depression were administered a combination of Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium bifidum or placebo. At the end of the trial, not only were significant differences noted in mood (assessed using the Beck Depression Inventory), but significant decreases in serum insulin, insulin resistance and serum C-reactive protein were recorded.21 Furthermore, a rise in plasma total glutathione (GSH) levels was noted in the intervention group when compared with placebo.21
Another study also found that oral probiotics, specifically of the Lactobacilli genera attenuated depressive and anxious behavioural symptoms in a chronic mild stress mouse model.22 In addition, a recent meta-analysis and systematic review of human controlled clinical trials on the use of probiotics showed significant effect on symptoms of depression, with an increased effect when results were restricted to psychiatric samples only.23
While further research is required to clarify dose and strain specific impacts on our brain chemistry, one thing that is very clear in the research so far is the low risk of using probiotics therapeutically due to their multimodal effects. Many researchers comment that probiotics appear to be very safe to use even while investigations continue in an effort to fully understand the precise mechanisms of impact.
- According to the World Health Organization, over 300 million people are estimated to suffer from depression, which is equivalent to 4.4% of the world’s population.
- Just like conditions such as obesity, heart disease and diabetes; the origins of depression are inflammatory rather than neurological. Increased inflammation can impact the body’s ability to produce important neurotransmitters such as serotonin and dopamine.
- The vagus nerve connects the brain and the gut; allowing for bidirectional communication and influence.
- Unlike the brain, the gut is designed to come into contact with intruders from the outside world. However, when levels of inflammation are increased in the gut this can result in increased inflammation in the brain.
- This kind of inflammatory cascade can be triggered by a variety of things. For example, consuming processed, nutrient-poor foods; experiencing real or perceived stress, infection and pollution, can all radically alter the gut microbiome and thus trigger an inflammatory response.
- Several studies demonstrate that a healthy gut microbiome is essential for maintaining brain health, and markers of inflammation are generally elevated in patients with depression.
- Studies have shown that Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium bifidum resulted in significant improvements in mood, insulin resistance and inflammation in patients with major depression.
If you have questions regarding the topics that have been raised, or any other health matters, please do contact me (Tracey) by phone or email at any time.
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Tracey Hanley and the Cytoplan Editorial Team
- Vos, T., et al (2015) ‘Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013.’ Lancet, 386(9995), pp. 743-800.
- (2017) ‘Depression and Other Common Mental Disorders Global Health Estimates.’ Retrieved from: http://apps.who.int/iris/bitstream/10665/254610/1/WHO-MSD-MER-2017.2-eng.pdf.
- John M (2005) ‘Eisenberg Center for Clinical Decisions and Communications Science JMEC for CD and C. Treatment Options When Your SSRI Antidepressant Is Not Working Well.’ Agency for Healthcare Research and Quality (US).
- Köhler, C. A., et al (2017) ‘Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies.’ Acta Psychiatr Scand, 135(5), pp. 373-387.
- Himmerich, H., et al (2019) ‘Cytokine Research in Depression: Principles, Challenges, and Open Questions.’ Front Psychiatry, 10, pp. 30.
- Kim J-M, et al (2018)’ Changes in pro-inflammatory cytokine levels and late-life depression: A two year population based longitudinal study.’ Psychoneuroendocrinology, 90, pp. 85-91.
- Kiecolt-Glaser, J, K., et al (2015) ‘Inflammation: Depression Fans the Flames and Feasts on the Heat. Am J Psychiatry, 172(11), pp. 1075-1091.
- Pasco, JA., et al (2010) ‘Association of high-sensitivity C-reactive protein with de novo major depression.’ Br J Psychiatry, 197(5), pp. 372-377.
- Dahl J, et al (2014) ‘The plasma levels of various cytokines are increased during ongoing depression and are reduced to normal levels after recovery.’ Psychoneuroendocrinology, 45, pp. 77-86.
- Haroon E, et al (2012) ‘Psychoneuroimmunology Meets Neuropsychopharmacology: Translational Implications of the Impact of Inflammation on Behavior’ Neuropsychopharmacology, 37(1), pp. 137-162.
- Mangoni A (1974) ‘kynurenine and depression.’ Adv Biochem Psychopharmacol, 11, pp. 293-298.
- Zinöcker MK and Lindseth IA (2018) ‘The Western Diet-Microbiome-Host Interaction and Its Role in Metabolic Disease.’ Nutrients, 10(3).
- Maier L, et al (2018) ‘Extensive impact of non-antibiotic drugs on human gut bacteria.’ Nature, 555(7698), pp. 623-628.
- Karl JP, et al (2018) ‘Effects of Psychological, Environmental and Physical Stressors on the Gut Microbiota.’ Front Microbiol, 9, pp. 2013.
- Dinan TG and Cryan JF (2017) ‘Microbes, Immunity, and Behavior: Psychoneuroimmunology Meets the Microbiome.’ Neuropsychopharmacology, 42(1), pp. 178-192.
- Bercik P, et al (2011) ‘The Intestinal Microbiota Affect Central Levels of Brain-Derived Neurotropic Factor and Behavior in Mice.’ Gastroenterology, 141(2), pp. 599-609.
- Dinan TG and Cryan JF (2017) ‘The Microbiome-Gut-Brain Axis in Health and Disease.’ Gastroenterol Clin North Am, 46(1), pp. 77-89.
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- Jacka FN (2017) ‘Nutritional Psychiatry: Where to Next?’ EBioMedicine, 17, pp. 24-29.
- Dinan TG and Cryan JF (2015) ‘The impact of gut microbiota on brain and behaviour.’ Curr Opin Clin Nutr Metab Care, 18(6), 552-558.
- Akkasheh G, et al (2016) ‘Clinical and metabolic response to probiotic administration in patients with major depressive disorder: A randomized, double-blind, placebo-controlled trial’ Nutrition, 32(3), pp. 315-320.
- Li N, et al (2018) ‘Oral Probiotics Ameliorate the Behavioral Deficits Induced by Chronic Mild Stress in Mice via the Gut Microbiota-Inflammation Axis.’ Front Behav Neurosci, 12, pp. 266.
- Liu RT, et al (2019) ‘Prebiotics and probiotics for depression and anxiety: A systematic review and meta-analysis of controlled clinical trials.’ Neurosci Biobehav Rev, 102, pp. 13-23.