Abstract

There is mounting evidence that the trillions of microbes that inhabit our gut are a substantial contributing factor to mental health and, equally, to the progression of neuropsychiatric disorders. The extraordinary complexity of the gut ecosystem, and how it interacts with the intestinal epithelium to manifest physiological changes in the brain to influence mood and behaviour, has been the subject of intense scientific scrutiny over the last 2 decades. To further complicate matters, we each harbour a unique microbiota community that is subject to change by a number of factors including diet, exercise, stress, health status, genetics, medication, and age, amongst others. The microbiota-gut-brain axis is a dynamic matrix of tissues and organs including the gastrointestinal (GI) microbiota, immune cells, gut tissue, glands, the autonomic nervous system (ANS), and the brain that communicate in a complex multidirectional manner through a number of anatomically and physiologically distinct systems. Long-term perturbations to this homeostatic environment may contribute to the progression of a number of disorders by altering physiological processes including hypothalamic-pituitary-adrenal axis activation, neurotransmitter systems, immune function, and the inflammatory response. While an appropriate, co-ordinated physiological response, such as an immune or stress response, is necessary for survival, a dysfunctional response can be detrimental to the host, contributing to the development of a number of central nervous system disorders.

© 2019 S. Karger AG, Basel

Introduction

Over thousands of years, the gut ecosystem has evolved to contain a diverse population of microorganisms including yeasts, archaea, parasites, helminth, viruses, and protozoa, but the bacterial population is currently the most well characterized [1-5]. Current estimates suggest that our microbial cells outnumber human cells by a ratio of 1.3:1 [6], while at a genetic level more than 99% of the genes in our bodies are microbial, comprising over 10 million microbial genes [7-9]. The contribution of these microbes to human health and disease cannot be understated, as they play key roles in such functions as metabolism, satiety, and immune regulation and more recently they have been shown to play a role in mood and behaviour. In certain circumstances, our microbes possess the genetic machinery for the metabolism of important dietary compounds that would otherwise be non-digestible to the host [8, 10]. Interestingly, while our inherited genome (that we inherited from our parents) is relatively stable throughout our lifetimes, the microbial genome is immensely diverse [11, 12], dynamic [13], and responsive to external inputs including diet, exercise, stress, health status, medication, and age amongst others.

The composition of the bacteria that inhabit our GI tract throughout our adult life is established early in our first few years of life and at this early-life stage they are particularly sensitive to manipulation by a number of environmental factors including mode of delivery (vaginal or C-section), whether we are breastfed or bottle-fed, diet, medication (in particular antibiotic medication), and exposure to viral or bacterial infections and stress [14]. It is worth noting that this critical seeding of our core microbiota occurs in parallel with the growth, maturation, and sprouting of neurons in the young brain [14, 15], and a similar profile is evident in old age where a decline in microbiota complexity and diversity occurs in parallel with a decrease in neuronal complexity [16], and this may contribute to the onset or progression of mood disorders including anxiety, depressive-like symptoms, mania, anhedonia, irritability, or suicidal ideology.

Concomitantly with the birth process or C-section delivery (or perhaps even prenatally [17, 18], our GI tract comes into contact with, and maintains constant communication with, the microbes that inhabit our gut, either through direct physical contact or the release of secreted compounds. Current hypotheses suggest that these microbiota-host interactions at the level of the gut release cytokines, chemokines, neurotransmitters, neuropeptides, endocrine messengers, and microbial by-products that can infiltrate the blood and lymphatic systems, or influence neural messages carried by the vagal and spinal afferent neurons to constantly communicate with the brain and update as to the health status and possibly to regulate mood and behaviour. However, it seems unlikely that any single class of compounds is wholly responsible for mediation of microbiota-gut-brain interactions and these will be discussed below.

Communication along the Microbiota-Gut-Brain Axis

The gut microbiota is part of a complex network termed the microbiota-gut-brain axis along with the sympathetic and parasympathetic divisions of the ANS, the enteric nervous system (ENS), and the neuroendocrine and neuroimmune components of the central nervous system (CNS) [19-21]. However, the mechanisms underpinning this bi-directional communication in the microbiota-gut-brain axis remain, as yet, unresolved [22]. Modes of communication likely involve neural mechanisms, immune response, neurotransmitter and neuropeptide release, and/or microbial by-products (Fig. 1), which will be discussed below. The consequential dynamic molecules that are released may infiltrate multiple anatomical environments to communicate within their local environment to regulate complex co-ordinated responses in multiple physiological systems. Molecular candidates thought to be involved in these processes include neurotransmitters, neuropeptides, short-chain fatty acids (SCFA), bile moieties, endocrine hormones, and immunomodulators amongst others.

Gut-Microbe Interactions

Despite the many beneficial functions of the gut microbes, the host has to maintain a physical barrier between the host and the microbiota to prevent infection. The epithelial lining of the gut contains predominantly secretory cells, enterocytes, chemosensory cells, and gut-associated lymphoid tissue [23] and is interspersed with tight junction proteins [194] that maintain protection against a “leaky” gut. A key function of the single-celled epithelial layer of our gut is to limit the direct contact of intestinal microbiota with the visceral tissue, which it does by secreting a protective viscous mucus layer from goblet cells lining the gut wall that increases in thickness as we travel from proximal to distal gut. This luminal-mucosal interface is where the majority of host-microbe interactions occur, and the exchange of molecules back and forth through the mucous layer and epithelium serve to facilitate communication between the microbiota, the gut, the immune, endocrine and ANS and the brain [24].

Endothelial secretory cells play a key role in gut function. Bacterial colonization in the gut is kept in check by antimicrobial peptides, expressed by secretory Paneth cells within small intestinal crypts. Further host protection from the gut microbes is guaranteed by protective mucus layer from secretory goblet cells, defensins, and anti-bacterial lectins shielding the epithelium from direct contact with the microbes as well as the innate (immune cells in the lamina propria of the ENS) and adaptive (immunoglobulin A-secreting plasma B cells) roles of the mucosal immune system. The secretory cells also control of the release of substances from enteroendocrine cells (EEC) such as ghrelin, somatostatin, cholecystokinin, peptide YY and serotonin amongst others [25].

There are many microbes that are only found in the mucosal layer, while some are restricted to the lumen of the gut. Host-microorganism interactions from luminal and mucosal microbiota occur, and are highly dependent on immune response. The enterocytes express innate immune receptors and once activated prompt the release of cytokines and chemokines, chemosensory cells play a key role in defence against helminths [26], while the gut-associated lymphoid tissue utilize lymphocytes to mount a more specific immune response if warranted.

GI bacteria possess a polysaccharide coating that protects them from degradation but also serves to identify the multitude of bacteria to the host. In turn, the host immune system can monitor and regulate commensal bacteria and identify invading pathogens. Specific pattern recognition receptors, of which members of the Toll-like receptor family are the most studied, line the epithelium and are capable of recognizing specific molecular signatures unique to bacteria [27] and other microorganisms (pathogen-associated molecular patterns, or PAMP) [28, 29]. Once activated, these receptors can initiate a cascade of events including the recruitment of inflammatory mediators, cytokine production and chemokine-mediated recruitment of acute inflammatory cells [30, 31]. This in turn helps to regulate the microbial population and diversity in the gut. Whilst this innate immune response is necessary to maintain gut homeostasis, a dysfunctional or prolonged response (e.g., to invading pathogens or as a consequence of a chronically high inflammatory tone) can weaken the integrity of the intestinal barrier and the mucosal layer, facilitating an increase in plasma lipopolysaccharide levels as a consequence of increased bacteria infiltration across the gut [32].

Microbe-Mediated Synthesis and Release of Bioactive Compounds

Along with activation of the innate immune system, commensal bacteria can also directly or indirectly (through endothelial cells) synthesize and release other bioactive compounds including neurotransmitters, neuromodulators, bacteriocins, bile acids, choline, and SCFA that are integral to host health.

Two ongoing large collaborative efforts from the Human Microbiome Project (HMP) [33, 34] and MetaHIT [8, 35] have been instrumental in surveying and describing the gut microbiota at a population level. Current combined HMP and MetaHIT data estimate that there are at least 2,776 species that have been isolated from human faecal matter. These have been classified into 11 different phyla, with Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes comprising over 90% of the microbiome [35-37], while Fusobacteria and Verrucomicrobia phyla are present in low abundance [2]. Furthermore, the indigenous micobiota diversity changes as one moves from proximal to distal gut [38, 39]. These commensal bacteria are capable of synthesizing and releasing many neurotransmitters and neuromodulators themselves or evoke EEC into the synthesis and release of neuropeptides. For example, Lactobacillus and Bifidobacterium species can produce γ-aminobutyric acid (GABA); Escheridia, Bacillus, and Saccharomycesspp. can produce norepinephrine; Bacilluscan produce dopamine; Lactobacillus can produce acetylcholine; and Candida, Streptococcus, Escheridia, and Enterococcus spp. can produce serotonin [40-42]. Serotonin is a key neurotransmitter implicated in many psychiatric disorders. It has been estimated that approximately 95% of the serotonin in the body is compartmentalized in the gut, predominantly in enterochromaffin cells of the mucosa and in nerve terminals of the ENS. Studies using germ-free mice have implicated GI microbiota in impacting on tryptophan metabolism, the precursor of serotonin [43]. These neurotransmitters are critical in centrally mediated events and bodily functions, and it is possible that these microbially synthesized neurotransmitters can cross the mucosal layer of the intestines, and possibly mediate effects locally in the gut, or enter the bloodstream and impact on physiological events in the brain.

GI bacteria can also secrete bioactive chemicals such as bacteriocins, bile acids, choline, and SCFA that are integral to host health and disease. Bacteriocins are antibiotic proteins that inhibit the growth of other bacteria in the vicinity, while bile acids are best known for facilitating the absorption of dietary lipids and lipid-soluble vitamins from the gut lumen but can play a role in regulating the number of bacteria in the small intestine [44-46]. Strikingly, all major gut-associated bacterial divisions, including Lactobacillus, Bifidobacterium, and Bacteroidetes taxa, were shown to express bile salt hydrolase [47] enzymes which allow de-conjugation of bile acid from taurine and glycine [48, 49], which are beneficial for the survival of the microbiota secreting them. SCFA including butyric acid, acetic acid, proprionic acid, and lactic acid are dietary by-products derived from the fermentation of polysaccharides [50] by colonic bacteria. These fatty acids can enter the blood and activate free fatty acid receptors (FFAR) in the gut, periphery, and brain and have been reported to have neuroactive properties [51-53] and to play a role in anorexia nervosa [54], Parkinson’s disease [55], and animal models of chronic stress [56] and Alz­heimer’s disease [57]. Conversely, increased SCFA levels have been associated with obesity [58-60], autism spectrum disorder [61], and chronic psychosocial stress in children [62]. Such data implicates the potential of SCFA to be a key player in microbiota-gut-brain axis communication. Interestingly, SCFA can pass directly through the epithelium via transporters [63-66] or indirectly by diffusing through epithelia as un-ionized SCFA [67]; and they have receptors along the epithelium [68-72], in the periphery [47], along the vagus nerve and ANS ganglia [73-76], and even in the brain epithelium [52, 77].

As well as influencing local immune responses at the epithelium, and synthesizing and releasing neurotransmitters and SCFA, the gut microbes can influence the release of neuropeptides and hormones from EEC of the intestines. Gut peptides such as ghrelin, gastrin, orexin, galanin, cholecystokinin, leptin, and neuropeptide Y are thought to influence peripheral neural communication and can also act centrally to influence behaviour. Though EEC represent only 1% of the epithelial cells in the GI tract, they are critically important for the maintenance of gut homeostasis due to the pleiotropic effects of secreted signalling molecules. To date, about 10 different types of EEC have been characterized, all of which are sensory cells that coordinate changes in the gut-nutrient luminal content with metabolic and behavioural responses, such as the regulation of insulin secretion or food intake [78]. The receptors to many of these peptides are expressed locally in the gut enteric neurons and vagal afferents and in the CNS, including the brainstem and the hypothalamus [79, 80].

From Gut to Brain

Under homeostatic conditions there exists a healthy, resting inflammatory tone where the microbiota stimulate cytokines and chemokine release, which in turn regulates local levels of bacteria in the gut. As well as influencing local immune responses at the epithelium, microbiota can synthesize and release neurotransmitters and SCFA and influence the release of neuropeptides and hormones from EEC of the intestines. Gut peptides such as ghrelin, gastrin, orexin, galanin, cholecystokinin, leptin, and neuropeptide Y are thought to influence peripheral neural communication and can also act centrally to influence behaviour. Current hypotheses suggest that these circulating cytokines, chemokines, endocrine messengers, and microbial by-products can infiltrate the blood and lymphatic systems or influence neural messages carried by the vagal and spinal afferent neurons to impact on centrally mediated events, including regulation of hypothalamic-pituitary-adrenal (HPA) axis activity and neuroinflammation.

At the interface between the microbiota and the host lies a network of neurons, i.e., the ENS, positioned to respond, either directly or indirectly, to the microbiota and/or microbiota-derived metabolites. The ENS can be crudely sub-divided into the submucosal plexus and the myenteric plexus and is largely responsible for the coordination of gut functions such as motility and control of fluid movement [81]. The ANS is best described as a neural relay network within the central and peripheral nervous systems that governs bodily functions that are normally controlled without a conscious effort (autonomously), such as breathing, regulation of our heartbeat, and digestion. The vagus nerve is the principal neuron within the ANS and innervates the stomach, the small intestine, and the proximal portion of the colon and works in concert with the neural network lining the layers of the gut, the ENS, and the CNS to regulate GI functions such as gut motility and permeability, epithelial fluid maintenance, luminal osmolarity, secretion of bile, carbohydrate levels, mechanical distortion of the mucosa, and bicarbonate and mucus production as well as the mucosal immune response and intestinal-fluid handling [82] and as such can regulate microbiota diversity and complexity in the gut. Conversely, local events at the level of the gut including homeostasis, and potential harmful pathogens, are communicated via the ENS and the vagal nerve from the gut to the brain.

From an anatomical perspective, the current consensus is that there are 2 neuroanatomical routes for neural signalling from the intestine to the brain. Primary afferents from the gut can be crudely separated into “non-painful” (satiety, distension, motility, and other homeostatic functions) mediated predominantly by vagal/pelvic innervation and “painful” sensory stimuli conveyed by splanchnic innervation [83]. Physiological information relating to the status of the gut including distension, motility, inflammation, pain, pH change, cellular damage, or temperature generates neural signals [84] via the release of bioactive chemicals including globulin, protein kinases, serine proteases, arachidonic acid, prostaglandins, cytokines, histamine, nerve growth factor, substance P, calcitonin gene-related peptide, serotonin, acetylcholine, and ATP as well as changes in pH [83, 85, 86]. These neural messages are transmitted systematically from the enteric neural networks that include the glial cells, myenteric and submucosal ganglia in the gut [87, 88] to the prevertebral (dorsal root) ganglia that regulate peripheral visceral reflex responses [89-91], to the spinal cord and the nucleus tractus solitarius of the brainstem [92, 93], and to higher centres in the brain.

Regulation of the Stress Response by GI Microbiota

Stress, and the subsequent activation of the HPA axis is an evolutionary conserved response to a perturbation of the homeostatic environment of the organism in response to an actual or perceived threat [94]. Upon activation, the HPA axis ultimately results in the release of behaviour-altering endocrine messengers including glucocorticoids and mineralocorticoids, as well as catecholamines, and it returns to normal homeostatic levels once the threat or perceived threat has subsided. While a deficient or blunted HPA axis is commonly observed in the clinic in a wide range of autoimmune and inflammatory diseases; chronic or prolonged exposure to stress can contribute to the precipitation, maintenance, and/or neuroprogression of a number of neuroinflammatory and stress-related disorders including anxiety [95, 96], depression [95, 96], bipolar disorder [97], post-traumatic stress disorder [98], Alzheimer’s disease [99, 100], and schizophrenia [101] amongst others. A clear reciprocal role for microbiota and stress response has been extensively reviewed over the last 2 decades. It has been shown in animal models that different types of psychological stress including maternal separation, chronic social defeat, restraint conditions, crowding, heat stress, and acoustic stress can alter the composition of GI microbiota [102-109]. Conversely, a number of experimental models and conditions have been employed, demonstrating a key role of the microbiota in regulating the stress response including prebiotic and probiotic [110-116] intervention, antibiotic administration [116-119], faecal transplantation, and the use of germ-free and specific pathogen-free animals [43, 106, 120-123]. Limited studies have also seen beneficial health reports in humans [124, 125]. Whilst the precise mechanisms behind GI microbiota and stress interactions remain to be elucidated, the intricate relationship of the immune system with both the stress response and GI microbiota makes it a likely biochemical candidate.

Regulation of the Neuroinflammatory Response by GI Microbiota

The passage of immune cells, cytokines, chemokines, endocrine (stress) messengers, and microbial by-products to the brain is tightly regulated by the blood-brain barrier, which is under vigilant surveillance by resident macrophage and microglia [126]. Recently, it was determined that a diverse GI microbiota is necessary the maintenance and maturation of microglia in a healthy functional state [47], and that this is regulated by microbially synthesized SCFA. Furthermore, the integrity of the blood-brain barrier is under the control of GI microbiota [127]. As with the epithelium of the gut, pattern recognition receptors on these immune cells recognize microbial by-products or respond to local changes in the environment as a consequence of cytokines, chemokines, and endocrine messengers ultimately resulting in neuroinflammation and recruit peripheral monocytes to traffic from the spleen to the brain [128]. Interestingly, the spleen expresses a high density of FFAR2[48], the receptor for SCFA, on trafficking lymphocytes [129]. Moreover, these FFAR2-expressing trafficking lymphocytes also express glucocorticoid receptors and respond to stress stimuli. Collectively, the evidence suggests a multimodal influence of microbiota on physiological events at the level of the CNS via intervention in the recruitment of local immune regulators from the periphery to the brain.

Thus far we have introduced some of the proposed mechanisms of action of microbially driven control of the gut-brain axis and their role in regulating the stress and immune response. We will further address the role of the GI microbiota in psychiatric disorders including Alzheimer’s disease, Parkinson’s disease, autism, schizophrenia, anxiety disorders, depression, and bipolar disorder.

The Role of GI Microbiota in Psychiatric Disorders

Given the myriad of complex physiological processes by which gut microbes could affect brain function, it is hardly surprising that current research has linked dysregulation of gut microbes to various psychiatric illnesses. Given the limitations of current treatments for psychiatric disorders, and the rates of remission, treatment resistance, and side effects, the possibility of low-risk but potentially microbiome-modulating treatments represents an attractive target for manipulation.

However, despite the persuasive data from animal studies for a role of the microbiota in regulating mood, cognition, stress, and social behaviour, amongst others, relevant studies from human cohorts are extremely limited. From a translational perspective, double blind, crossover studies in naive subjects are required in order to advance the field in this research area.

Clinical evidence for a role of the microbiome in psychiatric disorders is provided by an alteration in microbiota diversity and complexity when compared to healthy controls as determined for autism [130-135], schizophrenia [136-139], and attention deficit disorder [140], as well as mood disorders including bipolar disorder [141-144], anxiety, stress, and depression [138, 145-150] and neuroinflammatory linked disorders including Alzheimer’s [151-153] and Parkinson’s [55, 154-157] diseases. However, whether these alterations are causal in these disorders or the changes are an appropriate response to a shift in their host environment remains, as yet, unresolved.

Positive Modulation of the Microbiota to Improve Psychiatric Disorders

Positive modulation of the gut microbiota with the introduction of living microorganisms has been proven to be successful in ameliorating some negative effects in various disorders, yet many technical and pragmatic difficulties exist with this therapeutic approach. Once ingested, the fate of these organisms is somewhat uncertain as it traverses a number of somewhat hostile physiological environments including the oropharangeal area with its high density of digestive enzymes, the acidic pH levels of the stomach, the alkali bile environment of the small intestine, the immune-active interface with the epithelium, and the competitive local environment within the lumen of the gut.

Recently, studies investigating the effects of a probiotic mix of Bifidobacterium anamalissubsp. Lactis, Streptococcus thermophiles, Lactobacillus bulgaricus,and Lactococcus lactissubsp. Lactis on mood reported a positive effect in the brains of healthy female volunteers using fMRI after 4 weeks [159]. Another 4-week double-blind, placebo-controlled randomized fMRI study demonstrated that a probiotic formulation containing L. casei, L. acidophilus, L. paracasei, B. lactis, L. salivarius, L. lactis, B. lactis, L. plantarum, and B. bifidum altered brain activation patterns in response to emotional memory and emotional decision-making tasks, which were also accompanied by subtle shifts in the gut microbiome profile [159]. A 3-week study in a healthy, aged population reported a positive effect of L. casei Shirota [160] on mood, whilst the same probiotic was effective in ameliorating anxiety in chronic fatigue patients following 2 months treatment [161] and reduced abdominal discomfort and sleep quality in healthy medical students exposed to exam stress [162, 163]. Similarly, a L. plantarum 299v probiotic was shown to decrease exam stress levels in healthy controls following a 2-week administration [164]. Anxiety and depressive readouts were decreased with a concomitant decrease in cortisol levels following 30 days probiotic (L. helveticus and B. longum) treatment in healthy adults [165], while a mix of S. thermophiles, L. bulgaricus, L. lactis subsp. Lactis, L. acidophilus, S. thermophiles, L. plantarum, B. lactis,and L. reuteridecreased anxiety behaviour in healthy controls after 3 weeks [166]. L. gasseri CP2305 ameliorated stress-related symptoms and sleep quality in healthy male and female volunteers after 5 weeks of treatment [167]. B. longum 1714, already proven to reduce anxiety and stress responses during acute stress in mice [168], similarly reduced stress and anxiety measures after 4 weeks treatment in a population of healthy adults [169], and it improved the cognitive performance [113, 169]. However, not all probiotics that show beneficial effects pre-clinically translate to a beneficial effect in human studies. A study in healthy volunteers undergoing exam stress demonstrated that L. rhamnosus (JB-1) had no effect on mood, anxiety, stress, or sleep [170].

Alterations in GI microbiota have also been linked to bipolar disorder, although the data is somewhat limited [141-144] and intervention studies have mostly been mostly inconclusive [136, 171]. Further evidence for a role of the microbiota in bipolar disorder is provided by a study where patients presenting with bipolar mania were nearly twice as likely as other patients to have been recently treated with systemic antibiotics [172]. Specifically, bipolar disorder has been linked to decreased Firmicutes, specifically Faecalibacterium [142], which also correlated with self-reporting symptom severity. In females undergoing atypical antipsychotic treatment, a decreased species diversity, in particular Lachnospiraceae, Akkermansia, and Sutterella, was observed compared to treatment-naive controls [143]. Recent clinical probiotic studies in biplor disorder suggest that probiotic therapy could reduce the rate of re-hospitalization of patients over a 24-week adjunctive probiotic treatment with L. rhamnosus strain GG and B. animalis subsp. lactis strain Bb12 who were recently discharged following hospitalization for mania [136], and a subtle effect on “cognitive reactivity to sad mood” following 3 month treatment with L. casei, L. acidophilus, L. paracasei, B. lactis, L. salivarius, L. lactis, B. lactis, L. plantarum, and B. bifidum[171].

While a number of studies have reported an altered microbiota in individuals with autism, schizophrenia, or ADHD, there is limited or no evidence to demonstrate whether targeting the microbiota through probiotic or dietary interventions can improve their symptoms in humans. However, a small open-label clinical intervention study using faecal matter transplant of a standardized microbiota cocktail to children with ASD was efficacious in improving the GI and behavioural symptoms [173]. Although the sample size was small and the experimental design lacked a randomized double-blind structure, the study provided promising preliminary evidence to demonstrate that the microbiota may indeed be targeted as a potential treatment strategy for ASD. Similarly, clinical studies investigating the role of probiotics in ADHD are lacking, but one promising study where children aged up to 6 months were given L. rhamnosus GG (ATCC 53103) and followed until 13 years of age and, while 6 of 35 control students presented with ADHD, none of the 40 probiotic-treated students presented with ADHD symptoms [174].

A limited number of studies investigating the therapeutic role of probiotics in individuals suffering from mood disorders including stress, anxiety, bipolar disorder, and depression have been conducted. In a recent 8-week, randomized, double-blind, placebo-controlled clinical trial including 40 patients with a diagnosis of MDD based on DSM-IV criteria whose age ranged between 20 and 55 years, a triple-strain probiotic (L. acidophilus, L. casei, and B. bifidum) resulted in improvements in depression scores in addition to beneficial metabolic effects in an MDD cohort [175]. Another 8-week, randomized, double-blind, placebo-controlled clinical trial included 81 patients and examined the effect of a probiotic mix of L. helveticus and B. longum on mild to moderate MDD in a placebo-controlled parallel study [176] and reported a decrease in depression scores as well as improvements in tryptophan signalling. Interestingly, a randomized, placebo-controlled, double-blind study with 380 participants reported that daily L. rhamnosus HN001 during pregnancy (gestational weeks 14–16) and into the post-partum period (6 months post-partum if breastfeeding) significantly decreased post-natal anxiety and depression scores [177]. However, other studies in the literature failed to show any benefit for depression scores following the administration of probiotics in patients presenting with depression [178]. Overall, systematic reviews of probiotics as a potential adjunct therapy in MDD are encouraging, describing that probiotics effectively improve mood in humans [179-181]. However, another recent meta-analysis called into question the significance of these findings, highlighting the confounding comparability of studies due to strain differences and disease severity [182].

In patients suffering from Alzheimer’s disease or Parkinson’s disease, there are as yet no published studies reporting the effects of probiotics in ameliorating the symptoms of these disorders.

Psychiatric Medication and the Microbiome

A growing body of evidence suggests that medication used in the treatment of psychiatric disorders can also affect the composition of the gut microbiota, with potential implications for behaviour, as well as the involvement of the microbiota in drug pharmacokinetics in general [183]. Benzodiazepines and antidepressants were listed as co-variates influencing microbiota in the Belgian Flemish Gut Flora Project [184]. Similarly, in another population-based study with Dutch participants, i.e., LifeLines-DEEP, deep-sequencing of the gut microbiotas revealed a relationship between the medication used in the treatment of psychiatric disorders, particularly antidepressants, and the diversity and complexity of the gut microbiota [185].

Given the comorbidity of psychiatric disorders with other ailments, polypharmacy (the concurrent use of multiple medications by a patient) has also been investigated. One study demonstrated that there was a significant negative correlation between the number of different drugs consumed and microbial diversity, although it is unknown whether the lower diversity resulted in a reduced cognitive function [186]. Specifically, the drug classes that had the strongest association with single taxa abundance were PPI, anti-depressants, and anti-psychotics. Several studies have been performed in vitro in order to determine the anti-microbial activity of non-antibiotic drugs [187-190] and again antidepressants, benzodiazepines, and antipsychotics and they have been shown to possess antimicrobial activity, with a strong potential for subsequent functional neural effects.

While the microbes in our gut are susceptible to modulation by treatments in psychiatric disorders, they in turn also play a key role in metabolizing orally administered natural products and drugs [191, 192]. This area of research investigating the role of the gut microbiota in the kinetic profile of xenobiotics is termed “pharmacomicrobiomics” and it is in its infancy. However, the reciprocal influence of medication used in the treatment of psychiatric disorders and gut microbiota diversity and complexity may unlock information on personalized therapeutic treatment – in terms of onset of action, dose, treatment resistance, and relapse.

The Prospects for Microbiota Manipulation as a Therapy for Psychiatric Disorders

Given the role that the microbiome plays in health maintenance, and with the evidence from preclinical studies, microbiota manipulation represents a promising tool or adjunct therapy in the treatment of a number of disorders and/or their associated symptoms. By and large, the rather limited clinical studies in this research field have been performed in healthy adults, at 1 dose and with only 1 or 2 probiotic treatment groups – and often the cohorts are quite small. However, the majority of these studies have reported positive effects. Clinicians, while considering the potentially beneficial effects of these microbiota manipulations, cannot neglect the treatment of their patients with the appropriate psychiatric medicine and, as such, the true beneficial outcomes of this research field will remain somewhat stunted until we better understand the effects of the psychiatric treatments on the microbiota and the role of the microbiota in the efficacy of the psychiatric treatment.

A profound advantage of microbiota manipulation as a treatment strategy is that the microbiota is extremely dynamic and can be positively altered quite readily by a number of factors including diet, exercise, and stress reduction. A quote from Hippocrates, “Let food be thy medicine and medicine be thy food,” remains as true today as it was over 2,000 years ago. Research into positive modulation of the microbiota through diet with a view to improving health has dramatically increased in the last 2 decades, with various dietary compounds including carbohydrates (sugars, oligosaccharides, and inulin), proteins (branched chain amino acids, SCFA, and essential amino acids), linoleic acids, bile acids, polyunsaturated fatty acids, and polyphenols being explored for health promotion [193].

Given the recent advances in sequencing technologies, and computational approaches to data mining, the integration of data from clinical datasets from taxonomic profiles of the microbiota, pharmacomicrobiomics, metabolic and immune readouts from metagenomics, proteomics, and lipidomics combined with functional imaging and behavioural readouts should allow significant leaps forward in this research field. Given the unique signature of the trillions of microbiota we each harbour in our gut, perhaps these tiny microbes may explain the range of responders and non-responders in treatment resistance, side effect profiles, and/or tolerance. Indeed, personalized medicine based on our unique microbiome signature may represent the future of psychiatric treatment or an adjunct therapy.

Acknowledgement

This research was conducted with the financial support of Science Foundation Ireland (SFI) under grant No. SFI/12/RC/2273.



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References

Author Contacts

John F. Cryan Laboratory of Neurogastroenterology, APC Microbiome Ireland University College Cork, 386 Western Gateway Building Cork T12 XF62 (Ireland) E-Mail j.cryan@ucc.ie

Article / Publication Details

Received: July 27, 2018

Accepted: October 31, 2019

Published online: November 14, 2019

Issue release date: February 2020 Number of Print Pages: 13

Number of Figures: 1

Number of Tables: 0 ISSN: 0302-282X (Print)

eISSN: 1423-0224 (Online) For additional information: https://www.karger.com/NPS

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