Brain and gut bugs: how they rule our emotions and mental health
We often heard that the gut microbes exceed human cells in number, being 10¹³-10¹⁴ micro-organisms, ten times the number of our won cells, and weighing approximately 1 kg, or about the weight of the human brain, (Dinan et al. 2015) and containing 150 times as many genes as our genome. The learning of such overwhelming number and importance on what we thought was our own body is has developed research into the human microbiome in relation to both health and disease at a very fast pace and is making the news in a fashionable manner on every magazine and newspaper, facebook and twitter.
That the gut microbiome has effect on our physical health is well accepted and supported by a wealth of research. Gut microbiota influences normal physiology and if out of equilibrium can contribute to diseases ranging from inflammation to obesity. We now know that he microbiota regulates immune function and blood brain barrier integrity. But that this same microbiome has important effects on our mental status and on the regulation of anxiety, mood, cognition and pain (Cryan and Dinan 2012) is of more recent appreciation.
Gut, its microbe and our mental status. Current research efforts are indeed focusing on gut microbes as part of the unconscious system regulating and impacting cognitive function and fundamental behaviours, such as social interaction and stress management (Dinan et a. 2015, Luczynski et al. 2016 ). The impacts of the microbiome on behaviour and psychopathology are driven by complex molecular mechanisms that link the gut microbiota, the immune, the endocrine and the peripheral and central nervous systems in a network of communication between the gut symbionts and the brain (Dinan et Crean, 2017).
The recognition that gut microbes greatly impact our being at all these levels (Collins and Berck, 2013; El Aidy and Kleerebezem, 2013a; Wang and Kasper, 2013; Moloney et al., 2014) leads medical science to accept that the classically separated domains of neurology, endocrinology, immunology and microbiology, with their controlled organs (brain, glands, gut, immune cells and microbiota), should be considered instead parts of a multidirectional single network of communication. We would now have to add “microbiome” to the definition of “psychoneuroimmunology” or the later “psychoimmunoendocrinology” (Perth, ElAidy et al. 2014); moreover the gut-brain axis is now referred to as the ‘microbiome-gut-brain axis’.
How do the systems of the “psychoimmunoendocrinomicrobiology” communicate? Communication among nervous, immune, endocrine systems and microbiome is responsibility of multiple-functioning molecules such as neurotransmitters, neuropeptides, endocrine hormones, cytokines as well as of their receptors, moving from one system to another and linking brain, gut, liver, immune system and microbiota (El Aidy et al 2013). Neurotransmitters, such as norepinephrine and acetylcholine, are produced by both neurons in the brain and immune cells throughout the body. The vagus nerve carries such neurotransmitters from the gut to the brain directly affecting mood and behaviour (Harbour-McMenamin et al. 1985, Rühl et al. 1994, Rühl and Collins 1997, Bravo et al 2011). However, the vagus nerve is also activated by cytokines (Sternberg 1997), produced by immune cells (Borovikova et al. 2000, Spengler et al. 1990) that cause disturbance to neuropeptides and induce changes in mood and behaviour such as depression and anxiety (Clarke et al., 2009, Dinan and Cryan, 2012).
How does the microbe fit in this already complex impact on behaviour? The microbiota can also signal to the brain via the immune system, the vagus nerve (Bravo et al. 2011) and through modulation of microbial metabolites, such as short chain fatty acids, affecting brain activity. Also, the microbiome is directly or indirectly involved in the production or modulation of neurotransmitters or gut hormones: neuropeptide Y, peptide YY, pancreatic polypeptide, cholecystokinin, glucagon-like peptide, corticotropin-releasing factor, oxytocin, ghrelin, norepinephrine, serotonin, GABA, acetylcholine, dopamine and serotonin are produced or modulated by Escherichia, Streptococcus, Mycobacterium vaccae (Lowry et al. 2007), Lactobacillus and Bifidobacterium (Desbonnet 2008, Roshchina 2010, Lyte 2011, Reardon et al. 2013). Furthermore, the microbiota interacts with synaptic signalling system as well as with neurogenesis (Luczynski et al. 2016) and its genetic material can be swapped between microbe and host (Liu et al., 2012, Stilling et al. 2014).
All such signals from the microbiota affect not only behaviour but also brain development and function (Lach et al. 2018m Kelly et al. 2017). Indeed, the microbiota intervenes in diverse neural functions such as myelination, microglia function, neuronal morphology and blood-brain barrier integrity across the life span.
But how can the signal incoming from gut microbiota been transferred to the central nervous system? One example of possible explanation would involve gut-microbial products affecting DNA plasticity in the brain leading to changes in transcription and consequently to altered behaviour. The microbiota would thus be an important mediator of gene-environment interactions, or even be itself viewed as an epigenetic entity, suggesting to some scientists the need of a new field of study: (neuro)epigenetics (Styilling et al. 2014). Epigenetic regulation has been shown in the host's gut epithelium and immune system. The effects are largely mediated by butyrate produced by some bacteria and leading to altered histone deacetylase activity (one of the enzymes intervening in epigenetic mechanism of gene regulation). Histone acetylation in neurons facilitates memory consolidation, neurogenesis and neuroprotection which may be impaired when the normal microbiota is disturbed or completely absent. (Stilling et al. 2014). Short chain fatty acids are also believed to be implicated in modulating social behaviours.
Why would the microbiota be interested in producing molecules that regulate the immune and neuroendocrine system, particularly in the colonization period? One answer would reside in the effort by the bacteria of avoiding an attack response by the host against the commensals. In exchange, the “healthy” microbiota will offer decreased susceptibility of the host to diseases and ensure normal development of the mucosal and systemic immunity as well as the development of HPA axis, which impacts on the gut (Sudo et al. 2004, Shreiner et al. 2008).
Therapeutic use of bacteria in mental disease. Due to the role of bacteria in the regulation of host behaviour, research has focused on the possible therapeutic use of certain mixes of bacteria for application in altering brain activity in mental diseases (Dynan and Cryan 2017). Probiotics (live bacteria) and prebiotics (specific food that enhance the growth of beneficial gut bacteria) together constitute the so called psychobiotics which can confer mental health benefits by acting at the emotional, cognitive and neural level (Sarkar et al. 2016). Effects of specific bacteria on mood have been shown for several strains; for example Lactobacillus rhamnosus, L. bulgaricus, L. helveticus, L. plantarum C29 , Bifidobacterium longum, B. animalis subsp lactis, Streptococcus thermophilus, Lactococcus lactis subsp lactis, Mycobacterium vaccae have been found to reduce stress, anxiety, depression, anger and in general can influence activity of brain regions that control processing of emotion and sensation by inducing alterations of neurotransmitters in different parts of the brain (Nobuyuki 2004, Cryan and Kaupmann 2005, Girard 2009, Bravo et al. 201 Messaoudi et al 2011, Shen 2011, Jung et al. 2012, Matthews 2013 Burokas et al. 2017). Use of probiotic therapy is considered for example, for ASD conditions which exhibit altered composition of the intestinal microbiota impacting in turn the immune, metabolic and nervous systems (Dinan et al. 2014).
It is clear then why it is so important to provide the right colonization and the maintenance of our gut guests. Due to the high significance of gut microbiota in the regulation of brain activity and especially behaviour, two factors are in serious need of consideration: early colonization of the gut by the ‘right’ bacteria and their maintenance throughout life.
Early colonization of the gut by microbiota is of extreme significance. Growth of a diverse gut microbiota is vital for physiology (immune and endocrine systems) and emotional and cognitive development, as well as for many fundamental aspects of both structure and function of the brain. Increasing evidence demonstrates maternal transmission of certain microbes, already happening in utero and continuing after birth (Funkhouser and Bordenstein, 2013). Such maternal transmission to the offspring is dependent on genetics, mode of delivery, gestational age at birth, infection, stress, use of antibiotics in early life, modes of feeding, hygiene practices and other environmental influences. Disturbances of the proper colonization can have effects on development of different systems (maturation of the central nervous, immune and endocrine systems) in the new born and consequently on both physiology and behaviour (Dinan and Cryan 2017), becoming a central focus of the early development of diseases such as obesity, type 1 diabetes, asthma, allergies, and neurodevelopmental disorders like ADD, ASD and others (Borre et al. 2014, Kohane et al. 2012).
Maintenance of a good biota versus dysbiosis: the same obesity, diabetes, inflammatory diseases and neuropsychiatric illnesses, including anxiety and depression (Wiley et al 2017) can also be induced later in life by an unbalanced microbiota (dysbiosis). Nutritional status has been shown to be one of the most critical modifiable factors regulating the gut microbiota (Sandhu et al. 2017). Western dietary habits and/or the administration of antimicrobial agents induce dysbiosis and can promote anxiety and cognitive dysfunction.
On the other hand, psychological stress itself can lead to dysbiosis (Bested et al 2013, Selhub 2014). Stress at any life stages, (along with malnutrition and antibiotic use) increases permeability of the gut and early life stress can have a lifelong impact on the microbial content of the intestine, resulting in altered brain-gut axis (O'Mahony et al. 2009) and permanently altered immune functioning leading to neurodevelopmental disorders such as autism (Borre et al. 2014) and adult psychopathology (Dinan and Cryan 2017). This is explained by the fact that when gut permeability is increased, bacteria and bacterial antigens (lipopolysaccharides, or LPS) cross the epithelial barrier and activate a mucosal immune response which directly alters the composition of the microbiome and leads to inflammation and enhanced HPA response (Dinan and Cryan 2012). Elevations in blood LPS levels induce inflammation and penetration of pro-inflammatory cytokines into the blood-brain barrier and production of central pro-inflammatory cytokines by microglial cells in brain regions involved in mood regulation and reward processing (Miller et al 2009). Inflammation at the gut epithelium results also in decreased availability of tryptophan and zinc, which further negatively influences neurotransmission. Vice versa negative moods are associated with activation of the HPA axis and release of cortisol, which increase production of pro-inflammatory cytokines (Sanchez-Villegas and Martínez-González 2013). Thus oxidative stress and inflammation are both a cause and a consequence of depression (Messay and Marsland 2012).
However, qualitative/quantitative changes to the intestinal microbiota and increased intestinal permeability are not the only causes of mental health and cognition related to microbiota: small intestinal bacterial overgrowth (SIBO), hypochlorydria, carbohydrate intolerance, colonic microbiota transfer are also relevant (Bested et al 2013).
Conclusion: in order to keep a physical and mental wellbeing we need to take good care of our microbiome, from the moment we are conceived. If as foetuses we do not have much control, our life as conscious beings should be carried with attention to the food we eat, the reaction to negative stimuli (stress), the overuse of antibiotics, considering that the consequences will affect trillions of living beings, directly impacting us in return.