The understanding that the gut influences the brain and behaviour, and vice versa, has long been appreciated (Dinan and Cryan, 2013). This bidirectional system is finely controlled by neural, endocrine and immune pathways which coordinate gastrointestinal function, and link the gut to the brain, in particular, to emotional and cognitive areas. Recently, the gut microbiome has been shown to play a significant role in these interactions. Disruptions to these pathways of neuro-immune signalling to and from the gut have been implicated in depression (Evrensel and Ceylan, 2015).
Depression is one of the leading cause of disability worldwide, with 350 million people affected around the world (World Health Organisation, 2016). Despite this, the pathophysiology of this highly debilitating disorder is not entirely understood, and overall remission rate via drug or cognitive behavioural therapy is only 60-70%, with many patients either un-responsive or only partially responsive to treatment (Rush et al., 2006). The most common first-line therapies for major depressive disorder, including selective serotonin reuptake inhibitors (SSRIs) and selective serotonin-noradrenaline reuptake inhibitors (SNRIs), have a delayed onset of efficacy and exhibit adverse side effects including weight gain and sexual dysfunction (National Institute for Health and Care Excellence, 2009). These treatment therapies target the serotonin hypothesis of the pathogenesis of depression. This hypothesis suggests a central serotonin/noradrenaline deficiency induces the characteristic symptoms of depression, and can be corrected by preventing the clearance and reuptake, as well as promoting further synthesis, of these neurotransmitters (Clarke et al., 2012). However, increasing interest in the inflammatory hypothesis of depression, which suggests chronic inflammation induces neurological changes associated with depression, has implicated the gut microbiome as a possible source of this inflammation (Maes et al., 2009). This review will examine the extent to which the gut microbiome and its interactions with the neuroendocrine and immune system contributes to the pathogenesis of depression.
The Gut and the Microbiota
The gut interacts with the largest population of commensal organisms in the body, the microbiota, and is supported by the enteric nervous system, the gut associated immune system, and the entero-endocrine system (Dinan et al., 2015). The microbiome consists of wide a range of bacteria, archaea, fungi and viruses. Under physiological conditions the gut microbiome plays many roles in maintaining gastrointestinal homeostasis. These roles include defence against pathogens, reinforcing the intestinal epithelial barrier, inducing the secretion and synthesis of immunoglobulin A, which limits pathogenic penetration through the gut, facilitation of nutrient absorption, vitamin synthesis, as well as various roles in the function, education and maintenance of the immune system (Foster and Neufeld, 2013). The microbiota also plays various roles in development, including the maturation of the mucosal and systemic immune system and the lymphoid system (Petra et al., 2015). Studies conducted using germ free mice show reduced Peyer’s Patch size and CD4+T cell count (Bouskra et al., 2008). Further studies have also shown germ free mice have immature mucosal and systemic immune systems, with reduced numbers of B lymphocytes and T lymphocytes (Mazmanian et al., 2005). The microbiota have also been shown to direct the differentiation of T-helper cells, including Th17 which produces IL-17, and IL-22. These cytokines can act on the epithelial cells of the gut to maintain homeostasis, and highlight the important role the gut microbiota plays in gut health (Ivanov et al., 2008).
The Microbiota and the Gut-Brain-Axis
The communication between the brain, gut and microbiota is bidirectional, and involves neural, endocrine and immune systems (Foster and Neufeld, 2013). The vagus nerve is the major neural pathway between the brain and the gut, and provides parasympathetic innervation to regulate gastrointestinal function, as well as feedback to the brain via afferent fibres (Breit et al., 2018). These afferent fibres, as well as peripheral cytokines, are involved in the activation of the HPA axis, which coordinates the organism’s response to stress. The interaction between the microbiota and this major neuroendocrine pathway is reflected in the disturbances of both systems in depression (Farzi et al., 2018). Studies on germ free mice show exaggerated plasma corticosterone and adrenocorticotrophic levels in response to stress, compared to controls (Sudo et al., 2004) suggesting that the microbiota play a role in mediating the stress response pathway and the behavioural responses to stress (Bailey et al., 2011). HPA axis dysregulation has also been shown to correlate with morphological and functional brain changes associated with depression, including decreased hippocampal neurogenesis and increased apoptosis of neurons (Holsboer, 2000). HPA axis activation has also been shown to influence the composition of the microbiota and increase gastrointestinal permeability. These changes to the permeability of the gastrointestinal wall is associated with bacterial translocation and systemic inflammation associated with depression (Slyepchenko et al., 2017). The role of microbial dysbiosis in the pathogenesis of depression is further implicated through faecal transplantation studies. Transplantation of microbiota from patients with major depressive disorder into germ free mice has been shown to induce depression-like behaviours (Zheng et al., 2016).
The immune system is another major route of communication between the gut microbiota and the brain. Emerging research has implicated dysbiosis of the microbiota with increased inflammation and depression (Maes et al., 2012). Translocation of commensal bacteria due to impaired gastrointestinal permeability leads to an increase in immunoglobulin A (IgA) and immunoglobulin M (IgM) directed against the translocated bacteria (Maes et al., 2012). The LPS, which is part of the bacterial cell wall, activates immune cells through the CD14-toll like receptor 4 complex (TLR4) and induces the production of pro inflammatory cytokines such as tumour necrosis factor ? (TNF?) and interleukin-1 (IL-1) (Check et al., 2010). This activation of immune cells by the translocation of commensal bacteria also induces increased production of reactive oxygen species including peroxides and superoxide (Check et al., 2010). This increase in gastrointestinal permeability and bacterial translocation in response to stress leads to an increased inflammatory profile and increased plasma IgA levels. This increased systemic inflammation feeds back onto the brain and has been implicated in the pathogenesis of depression (Maes et al., 2012).
Recent research into the interaction between peripheral inflammation and the brain indicates that inflammatory molecules can access the brain via three ways: a leaky blood brain barrier, which occurs in patients with major depressive disorder, the activation of endothelial cells which line the cerebral vasculature and secrete inflammatory mediators into the brain, or via the binding of cytokines onto receptors of the vagus nerve which in turn leads to inflammatory signalling via the hypothalamus (Raison et al., 2009). The inflammatory signals then activate cells in the brain including neurons, microglia and astrocytes. An experimental example of peripheral cytokines reaching the brain was shown during the therapeutic administration of interferon alpha (IFN) to hepatitis patients. Peripheral IFN lead to an increase of both IFN and IL-6 and monocyte chemoattractant protein in the cerebrospinal fluid. MCP-1 induces the release of IL-1 and TNF from microglia. In this way, peripheral inflammatory mediators activate central inflammatory pathways in the brain, which in turn direct the synthesis and secretion of neurotransmitters (Miller et al., 2009). Increased central inflammatory activation has also been shown to alter the tryptophan-serotonin pathway, and instead promote the synthesis of kynurenine. In this alternate pathway, tryptophan is metabolised by indoleamine 2,3 dioxygenase (IDO) which is activated by proinflammatory cytokines, and tryptophan 2,3 dioxygenase (TDO), which is activated by glucocorticoids (Myint et al., 2003.). Both cytokines and cortisol have been shown to be increased in depression and lead to the shunting of tryptophan metabolism into kynurenine. The bi-products of this pathway include quinolinic acid, which has been shown to damage neurons and induce apoptosis of astrocytes (Myint et al., 2007).
These pathways implicate peripheral inflammation in central inflammatory pathways which in turn induce the structural and biological changes in the brain associated with depression. These changes include a decrease in the size of the hippocampus and a decrease in the number of astrocytes in the pre-frontal cortex. Chronic depression has also been shown to induce neuronal loss in the prefrontal cortex and the striatum. Peripheral inflammation has also been shown to alter neurotransmitter pathways in the brain. For example, cytokines, including IL-1 and TNF have been shown to increase neurotransmitter re-uptake from the synaptic cleft by activating the serotonin transporter on neurons (Zhu et al., 2006). This evidence contributes to the hypothesis that inflammatory pathways induce structural and chemical changes in the brain which contribute to depression.
The Microbiota and Inflammatory Bowel Disease
The high incidence of co-morbidity of depression and functional gastrointestinal disorders, such as inflammatory bowel disease (IBD) may indicate that an underlying pathology in the microbiota influences the progression of both diseases. IBD, which includes both ulcerative colitis and Crohn’s disease, is associated with chronic inflammation of the gastrointestinal tract, and is thought to involve the interaction between genetic factors, environmental triggers and microbial dysbiosis in the gut (Figure 1). A loss of microbiome diversity, dysregulation of mucosal immune system and a chronic inflammatory state have all been implicated in the pathogenesis of IBD (Manichanh, 2006). Many of the genes which have been associated with IBD are involved in the recognition and processing of microbes (Matsuoka and Kanai, 2015). The NOD2 protein is an intracellular receptor which senses a component of the bacterial cell wall, muramyl dipeptide (MDP), and is involved in the autophagy and antigen presentation of infected cells. Mutations to the NOD2 gene leads to impaired production of antimicrobial peptides and reduced production of anti-inflammatory cytokines such as IL-10 in Crohn’s disease (Cooney et al., 2009). Further research into susceptibility genes in Crohn’s disease has highlighted the role of Paneth cells in the pathophysiology of this disease. Paneth cells line the intestinal crypts and secrete anti-microbial peptides which help maintain the homeostasis between the gut and microbiota (Matsuoka and Kanai, 2015). Abnormalities in the structure and composition of Paneth cells have been observed in Crohn’s disease, which may contribute to the progression of dysbiosis and inflammation of the disease (Matsuoka and Kanai, 2015). An increase in microbial genes associated with oxidative stress has also been observed in ulcerative colitis. This increased oxidative stress from the microbiota may contribute to the inflammatory insult on the intestinal wall (Li et al., 2015) These findings provide convincing evidence of the role of the microbiota in the dysregulation of the mucosal immune system which characterises IBD. Further research is required to understand how this chronic inflammatory state contributes to the development of depression in patients with IBD.