Gut microbiota and stress-related disorders

STRESS-RELATED DISORDERS

Psychiatric disorders are chronic, debilitating disorders that significantly impair daily functioning, and are among the top ten leading causes of burden of disease worldwide [1]. Exposure to environmental stressors and trauma is associated with increased incidence of post-traumatic stress disorder (PTSD), major depressive disorder (MDD) and anxiety disorders [2, 3]. These stress-related disorders are associated with increased mortality, reduced life expectancy, are highly comorbid, and exhibit variable response to first line pharmacotherapy. There are no clinically actionable biomarkers for these disorders, further complicating their diagnosis and treatment. To facilitate the development of novel therapeutic strategies and potential interventions, it is imperative that we gain deeper insight into the biological mechanisms underlying these disorders.

THE MICROBIOME-GUT-BRAIN (MGB) AXIS

“Microbiota” is the term referring to the trillions of microorganisms that live in and on us. The complete catalogue of these microbes and their genes constitutes the human microbiome. The gut microbiome, crucial in maintaining numerous aspects of our physiological functioning, is a dynamic system, the composition of which is affected by numerous factors including host genetics, age, diet and ethnicity [4-6]. The microbiome-gut-brain (MGB) axis is a complex, bidirectional system of communication between the gut microbiome, the gut, and the central nervous system (CNS), facilitated by direct and indirect communication pathways (Figure 1).

The vagus nerve, the major parasympathetic nerve of the autonomic nervous system, represents a direct link between the gut and the brain, with vagal afferents and efferents facilitating reciprocal interaction between the enteric nervous system and the brain. Indirect communication within the MGB axis takes on many forms. Microbiota produce several microbial-derived molecules, including neurotransmitters and metabolites, which act at multiple locations in the body. Many of these molecules, including serotonin (5-HT) have been found to regulate behaviour, brain function and health. As much as 95% of the 5-HT in the body is produced in the enterochromaffin cells lining the intestine, and 5-HT levels in the gut are influenced by microbial metabolites including indole, bile acids and short-chain fatty acids (SCFAs). 5-HT produced in the gut cannot bypass the blood-brain barrier (BBB), and therefore cannot affect 5-HT levels in the brain. However, animal studies provide evidence to suggest that levels of the 5-HT precursor, tryptophan, modulated by certain gut bacteria, are associated the regulation of 5-HT neurotransmission in the brain [7].

Alterations in SCFAs, a product of bacterial fermentation of host-undigestible polysaccharides, have been found to be associated with exposure to chronic stress and depressive-like behaviour in animal studies. SCFAs are involved in a number of regulatory functions, including modulation of gut activity and intestinal integrity, and activation of microglia (innate immune cells in the brain, which play an important role in regulating neuronal survival and responses). SCFAs are capable of crossing the BBB, and in doing so, may affect brain function.

It is well established that the gut microbiome plays an important role in the development of both the peripheral and central immune systems, and accumulating evidence suggests that increased inflammation is associated with stress-related disorders. An imbalance in gut microbial composition can compromise the integrity of the intestinal epithelium [8], increasing intestinal permeability and facilitating translocation of bacteria, or bacterial components, across the epithelial barrier into systemic circulation. This promotes low-grade inflammation, which stimulates increased expression of pro-inflammatory cytokines. Proinflammatory cytokines can stimulate the hypothalamic-pituitary adrenal (HPA) axis to secrete cortisol, which may further increase intestinal permeability. Indeed, evidence of gut and brain barrier dysfunction has been reported in stress-related disorders.

INVESTIGATING THE GUT MICROBIOME IN STRESS-RELATED DISORDERS: PRECLINICAL AND CLINICAL FINDINGS

Several preclinical investigations support the idea that the gut microbiome composition is associated with stress-related disorders. Investigations using germ-free (GF, microbiologically sterile) animals have played a crucial role in our understanding of the MGB axis. In their seminal investigation, Sudo and colleagues [9] observed an exaggerated stress response, evidenced by increased levels of corticosterone, in GF mice compared to controls, following acute restraint stress. This exaggerated HPA axis response to stress was normalised upon mono-colonisation of the GF mice with Bifidobacterium infantum. Studies have also shown that it is possible to transfer anxiety- like behavioural phenotypes between two mouse strains, by means of fecal microbiota transplant (FMT) [10]. Similarly, several studies have reported on the development of depressive- and anxiety-like behaviour, and altered neuroendocrine-immune pathways, in microbiota-depleted rodents following FMT from humans diagnosed with MDD, suggesting a causal role for gut microbiota in depressive-like behaviour [11-13]. Animal studies have also shown that exposure to stress can cause long-lasting alterations in the gut microbiome – two recent studies reported on decreased relative abundance of Akkermansia muciniphila in the gut microbiome of stressed animals over time, compared to control animals [14, 15]. A. muciniphila and the outer membrane coat of the bacteria (Amuc_1100) have been found to ameliorate depressive-like behaviour, and increase circulatory levels of 5-HT.

Comparatively few clinical studies have been conducted to determine the association between the gut microbiome and stress-related disorders. Thus far, the only published data on the gut microbiome in PTSD emanates from our research group [16], where a consortium of four bacterial genera was found to predict PTSD status with 66.4% accuracy. In addition, MDD diagnosis in the sample was found to be associated with increased relative abundance of the phylum Bacteroidetes. Other studies indicate that bacterial taxa associated with both depression and anxiety disorders are characterised by a higher relative abundance of taxa that induce a proinflammatory environment and a reduced abundance of SCFA-producing bacteria [17].

This field of research is, however, still in its infancy, currently limited by the lack of standardisation in gut microbiome analysis, from sample collection to the analytical pipeline. In many cases, factors that may confound results, including diet, medication use, ethnicity and host genetics, were not accounted for in the studies reviewed above. Moreover, most of the studies conducted have been cross-sectional in design, limiting our ability to disentangle cause from consequence, and very few have investigated potential mechanisms underlying the associations.

MODULATION OF THE MGB AXIS: PROBIOTICS

The gut microbiome is tractable and has the potential to be modulated, making the search for gut microbiome markers associated with stress-related disorders particularly attractive. Probiotics are defined as living microorganisms which, when administered in adequate amounts, confer a health benefit on the host; psychobiotics refer to probiotics which confer a benefit on mental health, cognition and behaviour. Recent publications have indicated moderate beneficial effects of psychobiotics in alleviating depressive and anxiety symptoms in both healthy and clinically-defined cohorts [18]. It is, however, important to remain cautious when interpreting results from current studies, as they are variable with regards to probiotic formulation and dosage, sample characteristics (clinical phenotype and severity of depression/anxiety), and follow-up time. In addition, the benefit of psychobiotics over, and interactions with, antidepressant medication has not yet been extensively investigated, although some intriguing results from preclinical studies suggest that certain probiotics, when administered in multi-strain format, possess antidepressant effects similar to, and sometimes with larger effect than, current first-line antidepressants [19]. Such psychobiotics, when used in conjunction with antidepressants, may have particular use in individuals with treatment-resistant depression.