Probiotics: an integrative approach for depression and anxiety

Our microbiota is a complex community of organisms working together to maintain dynamic ecological balance. Of the trillions of bacteria that inhabit the human body, 80% live in the gut.[1] These bacteria are not only essential for normal GI function, but also for systemic processes, brain development and function, behaviour, and cognitive and emotional processing. 

This one kilogram mass of bacteria may weigh the same as the brain, yet the gut microbiota is far superior in genomic and biochemical complexity.[2] Its ability to communicate with the brain and nervous system through a network called the gut-brain axis is not yet fully understood, but with a large research focus in this area new insights are rapidly developing.[1]

‘The emerging links between our gut microbiome and the central nervous system (CNS) are regarded as a paradigm shift in neuroscience with possible implications for not only understanding the pathophysiology of stress related psychiatric disorders, but also their treatment.’[3]

The gut-brain axis: a bidirectional pathway

The gut-brain axis was first discovered in an animal study in 2004, when, during an increased hypothalamic-pituitary-adrenal (HPA) stress response, the levels of brain-derived neurotrophic factor (BDNF) in the hippocampus decreased.[4] BDNF influences survival and differentiation of neurons, formation of functional synapses and brain neuroplasticity.[5] Since then, both experimental and human clinical trials have shown the gut-brain axis to be a bidirectional network involving complex signalling pathways.[2,4,6] This network is comprised of:[1,6]

• gut microbiota and its metabolites
• CNS
• enteric nervous system (ENS)
• the parasympathetic and sympathetic branches of the autonomic nervous system (ANS)
• neuroendocrine and neuroimmune pathways.

Communication between the gut microbiota and the nervous system occurs through afferent and efferent nerve pathways with five recognised routes, all of which may be involved in the regulation of emotion and behaviour:[1,6]            
1.     neuroanatomical network of the gut brain axis (though the vagus nerve, ANS and gut ENS)
2.    neuroendocrine-HPA axis pathway
3.    gut immune system (involving toll-like receptors [TLRs] and cytokines)
4.    neurotransmitters and neural regulators, such as short chain fatty acids (SCFAs), made by gut bacteria
5.    intestinal mucosal barrier and blood-brain barrier.

It is important to remember that this complex axis works bidirectionally and mutually. Studies show that an altered emotional state and chronic stress can adversely affect gut microbiota composition and function. In turn, this may lead to increased intestinal permeability, allowing greater access of bacteria, metabolic products, such as lipopolysaccharides (LPS) and neuroactive peptides to enter the circulation and affect areas of the nervous system that regulate cognition, mood and behaviour.[7] Additionally, an imbalance of bacteria in the gut can alter immune and inflammatory responses leading to vagal nerve activation and changes to brain and neural functions, as well as further damage to the intestinal barrier.[7] A dysfunction in either gut or brain has potential health effects on the body as a whole.[8]

The importance of probiotics

During adult life the core composition of the gut microbiota remains fairly stable; however, lifestyle, stress, drugs, infection and genetic influences may change the microbiota and its genome (collectively called the microbiome), leading to wide ranging health effects.[1,6] Therefore, the use of probiotics may be necessary, with studies showing they can beneficially alter the gut environment and microbiota composition, reduce inflammation, strengthen the intestinal barrier, modulate the HPA axis, produce key neurotransmitters, such as GABA and serotonin, and generate SCFAs and a biologically active form of catecholamines. They also have the ability to regulate circulating levels of the precursor to serotonin – tryptophan, directly influencing serotonin’s production.[2,4,6,8] All of these actions have an impact on gut and brain functionality.

Targeted probiotic strains in stress, anxiety and depression

Preclinical and clinical research shows two specific strains of probiotics, Lactobacillus helveticus R0052 and Bifidobacterium longum R0175, may be used beneficially for improving the physical and psychological symptoms and development of stress and mood disorders, such as anxiety and depression.

In a 2008 double-blind placebo-controlled trial, this probiotic combination significantly improved the stress induced gastrointestinal symptoms of nausea, vomiting and abdominal pain in healthy but chronically stressed individuals. The total dose given was 3 billion colony-forming units (CFU) per day for three weeks.[9]    

Following on from this positive result the same researchers tested this probiotic combination and dose in a longer trial of 30 days, and included a range of psychological questionnaires and urinary free cortisol testing. Compared to placebo, there was a statistically significant reduction in anxiety and depression, with reduced markers of psychological distress, including somatisation, anger and hostility.

Additionally, median free cortisol levels decreased in those taking the probiotics. This is significant as cortisol regulation is often impaired in chronic stress and suggests that these probiotics moderated the HPA axis response to stress.[10] To test how this combination would work in those with low stress levels, the researchers performed a secondary analysis only looking at the subjects who had low cortisol levels at the start of the study. They found the results were the same except there was a greater benefit for those with obsessive compulsiveness, anxiety, paranoid ideation and heightened perceived stress.[11]

In these clinical trials the probiotic combination was found to be safe, well-tolerated, no reported adverse reactions, and did not demonstrate any addictive or rewarding properties or cause any learning or memory deficits, often seen with pharmaceuticals used in these conditions.[9,11] Preclinical studies have also supported the use of these probiotics, indicating they may protect neural networks, restore negative HPA axis feedback, modulate ANS responses to stress, reduce proinflammatory cytokines, and benefit intestinal barrier stability and brain plasticity, all of which can assist in alleviating stress and mood disorders.[12,13]

Supportive probiotics

A recent study has shown the benefits of the probiotic species L. acidophilus, L. casei and B. bifidum, to significantly reduce depression scores in major depressive disorder (MDD), while increasing levels of the antioxidant glutathione and decreasing serum insulin levels.[14] Even in non-depressed individuals, B. bifidum, B. lactis, L. acidophilus, L. brevis, L. casei, L. salivarius and Lactococcus lactis reduced overall cognitive reactivity and negative thoughts associated with sad mood in another study.[15] Other probiotic strains, without specific studies on their beneficial use for brain health, can be used to restore and maintain gut health and thereby support the gut-brain axis. B. lactis HN019 has shown significant improvement in gut transit time and supports microbiota levels.[16,17] This strain, along with L. rhamnosus HN001, has also had positive effects on cellular immunity.[18] Immune health, and therefore appropriate inflammatory response, is important for the gut-brain axis communication and function of both systems.

Psychobiotics for the gut-brain axis

A healthy and diverse gut microbiota is crucial. Dysbiosis, especially at the early and late stages in life, can have a profound impact on brain function from a neurological and mental health perspective.[2,7] Emerging evidence continues to examine the role of the gut-brain axis, with studies revealing probiotics may work as potential psychobiotics, due to their ability to be beneficial for mental health.[2] This increases our understanding of the brain and its relationship with the gut, and provides more integrative and potentially effective treatment options for neuropsychiatric conditions, such as depression and anxiety.[1]

References

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