Gut feelings: moods, microbes and our microbiome

All disease begins in the gut, according to Hippocrates. Seems he may well have been onto something, writes Dr Linda Thomas

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The total mass of bacteria within the intestine is approximately the same as the human brain.³  

This “hidden kingdom”, as it has been referred to, is estimated to be in excess of 1000 species and 700 strains. However, what constitutes a healthy microbiome is still being elucidated. Just how microbes interact with the brain and behaviour will provide us with a more complete understanding of human psychology and who we really “are”.

Although the realisation of the contribution of microbes to neural processes is less than a decade old, the emergence of a gut-brain relationship has been heralded as a paradigm shift.  

Researchers have identified gut microbiota that interact with brain regions associated with mood and behaviour.¹⁰ These brain-gut interactions may play an important role in human health and health-related behaviours. Research suggests that your gut microbiota can influence your emotion. This, in turn, changes the decisions we make and the behaviours in which we engage.  

The gastrointestinal tract contains the enteric nervous system. This system of interconnected network of neurons is similar in number to that of the spinal cord.⁸

The concept of a “gut-brain-microbiota” communication channel has been established in both animal models and healthy humans, but we do not yet know the full implications of this. 

Many mechanisms have been shown to be involved in this cross talk, including neuroepithelial circuits involving sensory neurons, the vagus nerve, immune activation and metabolites such as short chain fatty acids, neurotransmitters and even vitamins. 

We recognise the bi-directional nature of this communication between our gut and our brain, via neuroendocrine and neuroimmune pathways but we are yet to understand the influence that, for example, strong negative emotion may have on our microbiome, or conversely, how a change in the ratio or taxa of our microbiome impacts our mood.  

It has been postulated that the brain-gut-microbiota axis plays a role in stress-related mental illness, but just how fundamental is our microbiome for our brain function? ^1,2

Animal studies suggest that essential neurodevelopmental functions, such myelination, neurogenesis and microglia activation, do not occur normally in laboratory animals raised in germ-free conditions.^5,1 More recently, microbial contributions to adult neurogenesis has been recognised in the hippocampus and the development of the blood-brain barrier.⁷ 

Additionally, it has been possible to both alter brain chemistry and transfer behavioural traits, such as anxiety and depression, from human patients to laboratory animals through the process of faecal transplant. These studies provide the possibility of a future therapeutic option for the use of microbiota transplantation in the treatment of such commonly occurring disorders.  

Major depression is recognised by the World Health Organisation as one of the major causes of morbidity worldwide. This stress-related disorder is associated with dysregulation of the hypothalamic-pituitary-adrenal axis (HPA axis) with accompanying increases of cortisol and pro-inflammatory cytokines.

It is known that our microbiome influences both our HPA axis and our immune system. Studies have shown that the effects of hyperresponsive HPA axis in animals raised in sterile environments, can be reversed with the introduction of a single strain of the bacterium, Bifidobacterium infantis.

 It has also been shown that Lactobacillus rhamnosus lowers behavioural measures of anxiety in mice, associated with increased expression of GABA receptors.³ This therapeutic effect appears to be mediated via the vagus nerve and is eliminated by vagotomy.  

However, as humans, can taking these bacterial strains improve our brain health and behaviour? 

Large human studies have demonstrated that patients with major depression can be stratified according to their microbiome into acute and less severe disease groups, suggesting promise for diagnostic and potentially therapeutic benefits.  

Our microbiome is also known to interact with host cognition in animal models. Germ-free animals have impaired working memory as well as altered social behaviour.  

Additionally, both animal and human studies have demonstrated altered cognition associated with Bifidobacterium longum supplementation.  

Research indicates that our microbiome is associated with health in the elderly and those in care have less “diversity” than those living in the community.  Ageing is accompanied by a myriad of clinical issues, including a basal pro-inflammatory state known as “inflamm-aging”. 

Manipulation of the microbiome of older adults to reduce this pro-inflammatory state may hold promise as an innovative strategy to affect comorbidities associated with ageing. 

A link has also been established between the microbiome and neuropsychiatric diseases such as Parkinson’s disease, multiple sclerosis and even autism spectrum disorders.  

While research on the association between schizophrenia and the microbiome is still in its early stages, the evidence of its relationship to antipsychotic-induced obesity is more supported.  

So how can we influence our microbiome? 

Probiotics are living microorganisms that when ingested in sufficient quantities can ameliorate the health of the host. 

The term “psychobiotics”, as coined by the researchers Dinan and Cryan, refers to probiotics with mental health benefits.

Trials of psychobiotics have aimed to demonstrate an impact of supplementation on stress, mood and cognition. Pre-clinical studies suggest the efficacy of various bacterial strains in attenuating stress and enhancing cognition in healthy subjects, however randomised, placebo controlled trials remain to be conducted.⁹ 

Conversely, rather than providing additional good bacteria through psychobiotics, there is also evidence of the antidepressant effect of antibiotics such as minocycline.⁴ 

While there is much interest in manipulating the microbiome through diet, probiotics and antibiotics, the most controversial method so far is faecal microbiome transplantation (FMT). There is strong evidence that this procedure is beneficial in the treatment of gut disorders such as Clostridium difficile infection and ulcerative colitis. 

Because such a method has produced therapeutic effects in these disorders, it is postulated that it may similarly affect the gut-brain-microbiome axis; indeed symptoms of irritable bowel syndrome (IBS) may be ameliorated by FMT. 

In animal models, FMT from depressed or anxious human donors are able to transfer these phenotypic behaviours to rodents.⁶ FMT is not currently adopted for therapeutic use, however. 

Findings appear to indicate that psychological or behavioural therapies may in turn impact on gut physiology and the gut microbiota, in a “top-down” processing way. Currently cognitive behavioural therapy has been successfully employed as an intervention to reduce IBS symptoms.⁷  It remains to be fully elucidated the types of psychological interventions that most positively impact the gut and reverse any dysbiosis. 

Furthermore, focusing on lifestyle factors in addition to psychological interventions may also ameliorate any dysfunction within the gut-brain-microbiome-axis. Future research will further develop knowledge of how the axis affects our emotions, our thinking and our social and cultural behaviour. 

It is well known that there is a high level of co-morbidity between psychological distress and gastrointestinal disorders. There is much promise for the resolution of both psychological and gastrointestinal issues through dietary modification, probiotic supplementation and pharmacological intervention. Therefore it may seem that psychology and microbiology are unlikely associates, the future may demand a new way of “looking within”.   

Dr Linda Thomas, PhD (Mucosal Immunology), is a clinical psychologist and visiting fellow of ANU in gut-brain-microbiome research. She directs a specialist gut health clinic, targeting diet, exercise and lifestyle factors along with cognitive behavioural therapy to improve cognition, behaviour and psychological wellbeing.

References: 

1. Burokas, A, Arboleya, S, Moloney, RD, Peterson, VL, Murphy, K, Clarke, G, Stanton, C, Dinan, TG & Cryan, JF 2017, ‘Targeting the microbiota-gut-brain axis: prebiotics have anxiolytic and antidepressant-like effects and reverse the impact of chronic stress in mice’, Biological Psychiatry , vol. 82, no. 7, pp.472-487 

2. Dash, S, Clarke, G, Berk, M & Jacka, FN 2015, ‘The gut microbiome and diet in psychiatry: focus on depression’, Current Opinion in Psychiatry , vol. 28, no. 1, pp. 1-6 

3. Dinan, TG & Cryan, JF 2016, ‘Mood by microbe: towards clinical translation’, Genome Medicine , Vol. 8, no. 36.  

4. Miyaoka, T, Wake, R, Furuya, M, Liaury, K, Ieda, M, Kawakami, K, Tsuchie, K, Taki, M, Ishihara, K, Araki, T & Horiguchi, J 2012, ‘Minocycline as adjunctive therapy for patients with unipolar psychotic depression: an open-label study’, Progress in Neuro-Psychopharmacology & Biological Psychiatry , vol. 37, no. 2, pp. 222-226 

5. Rieder, R, Wisniewski, PJ, Alderman, BL & Campbell, SC 2017, ‘Microbes and mental health: a review’, Brain, Behavior and Immunity , vol. 66, pp. 9-17 

6. Sakar, A, Lehto, SM, Harty, S, Dinan, TG, Cryan, JF & Burnet, PWJ 2016, ‘Psychobiotics and the manipulation of bacteria-gut-brain signals’, Trends in Neurosciences , vol. 39, no. 11, 763-781 

7. Sakar, A, Harty, S, Lehto, SM, Moeller, AH, Dinan, TG, Dunbar, RIM, Cryan, JF & Burnet, PWJ 2018, ‘The microbiome in psychology and cognitive neuroscience’, Trends in Cognitive Sciences, vol. 22, no. 7, pp. 611-636 

8. Sasselli, V, Pachnis, V & Burns, AJ 2012, ‘The enteric nervous system’, Developmental Biology , vol. 366, no. 1, pp. 64-73 

9. Smith, PA 2015, ‘The tantalizing links between gut microbes and the brain’, Nature , vol. 526, no. 7573, pp. 312-314 

10. Tillisch, K, Mayer, EA, Gupta, A, Gill, Z, Brazeilles, R, Le Nevé, B, van Hylckama Vlieg, JET, Guyonnet, D, Derrien, M & Labus, JS 2017, ‘Brain structure and response to emotional stimuli as related to gut microbial profiles in healthy women’, Psychosomatic Medicine