Микробиом кишечника и психика

Anxiety and fear are vital, evolutionarily conserved emotions which arise in response to potential or real threats. The neurobiological process by which such responses become excessive, prolonged and pathological, as is the case with anxiety disorders, remains poorly understood. A portion of the variance in susceptibility risk for anxiety disorders can be explained by genetic risk and the epigenetic impact of environmental factors such as trauma and chronic stress [10]. Basic neuroscience research suggests that impaired threat responses involve dysfunction of brain circuity that deals with attention, emotion, learning and memory, findings which have been effectively translated in humans using functional neuroimaging [5]. At a systems level, the hypothalamic–pituitary–adrenal (HPA) axis and peripheral immune system have been studied. Findings with regards to HPA activity at baseline and after stress stimuli are inconsistent in anxiety disorders [11, 12]. The reasons for such variability are unknown but may represent differences in the course and chronicity of the disorder, symptom severity and sex differences. Peripheral blood inflammatory markers appear to be altered in anxiety disorders but findings are preliminary and require further investigation [13, 14]. Neurotransmitter abnormalities have been implicated in anxiety, leading to the existing pharmacotherapy options which include serotonergic, noradrenergic and GABAergic medications [15]. More recent novel therapeutic drug targets involve the glutamatergic and endocannabinoid systems as well as various neuropeptides such as vasopressin, oxytocin, orexin [16]. Additionally, natural plant compounds and plant extracts are being studied for their anxiolytic potential. Those ‘phytochemicals’ which have demonstrated anxiolytic activity include Piper methysticum (kava), Centella asiatica (pennywort), Humulus lupulus (hops), Ginkgo biloba (maiden hair), Matricaria chamomilla (chamomile), Melissa officinalis (lemon balm), Passiflora incarnata (maypop), Scuterllaria leriflora (skullcap), Valeriana officinalis (valerian), Withania somnifera (ashwagandha), Magnolia officinalis (magnolia bark) and Lavendula angustifolia (lavender), among others [16]. Although the mechanisms underlying their effects are largely unknown, modulation of the GABA system is implicated [17]. Recent clinical guidelines for the treatment of mental disorders with nutraceuticals and phytoceuticals support the use of ashwagandha, galphimia and lavender in the treatment of anxiety disorders [18].

Microbiome-gut-brain signalling pathways encompass a wide variety of the physiological systems implicated in anxiety disorders (Fig. 1). A large body of evidence exists supporting a role for the microbiome in the early development and ongoing regulation of stress responsivity. Preclinical studies indicate that disruption in microbiome composition early in life using antibiotics, bacterial infections, Caesarean-section births, various acute and chronic stress exposures and other environmental influences can result in significant, enduring alterations in HPA axis activity and stress response [19]. Similar preclinical methods have been used to demonstrate the substantial immunomodulatory properties of the gut microbiome at birth and throughout the lifespan [20]. Although the stress response system and immune function are perhaps the most studied gut-brain signalling pathways, numerous other gut-brain cross-talk mechanisms are at play. Microbial regulation of the metabolism of tryptophan is important in stress-related psychiatric disorders, both due to the role of tryptophan as a precursor to serotonin and its metabolism via the neuroactive kynurenine pathway [21]. We have previously demonstrated an alteration in kynurenine pathway metabolites in social anxiety disorder [22]. Microbial metabolites are important mediators of gut-brain communication. Short-chain-fatty-acids (SCFA) are key metabolites produced by bacterial fermentation of fibre and exert both direct and indirect effects in the brain. They influence intestinal barrier integrity [23], which we have recently found to be disrupted in people with social anxiety disorder (unpublished data). SCFAs augment blood brain barrier tight junction expression and protect against central neurotoxin infiltration in addition to regulating host GI immunity and peripheral immunity, modulating HPA axis response and directly impacting the concentrations of neurotransmitters and neurotrophic factors in the gut lumen [23]. Moreover, exciting work has demonstrated that the SCFA, acetate, is one of the mechanisms underlying the known impact of the gut microbiota on the maturation and function of brain microglia [24, 25]. The endocannabinoid system, which is thought to buffer against many of the effects of stress [26], is also influenced by gut microbiota composition [27]. It has been demonstrated that the impact of the gut microbiota on depressive-like behaviours in mice is mediated by the endocannabinoid system [28]. An additional mechanism of gut-brain signalling is via hippocampal neurogenesis. Faecal microbiota transplant and probiotic supplementation in animal models has demonstrated that microbial signalling can alter levels of hippocampal BDNF and influence adult hippocampal neurogenesis, with subsequent consequences for cognition, stress and emotional regulation [29]. The myriad pathways through which the gut microbiota impact brain function and behaviour highlight the complexity of gut-brain interplay and the many potential avenues for the development of anxiety disorders.

Generalised Anxiety Disorder

Coprococcus and Faecalibacterium, other prominent butyrate-producers in the human gut, also appear important in anxiety disorders. Chen et al. [37] reported depleted levels of Coprococcus in GAD patients, with a similar finding seen in perimenopausal PD [42]. Such outcomes are consistent with a large cross-sectional study which used data from 7,656 participants of the Dutch Lifelines Microbiome Project (DMP) cohort [43].  The study reported that any anxiety disorder (defined as GAD, SAD or PD), and GAD analysed individually, were significantly associated with a decreased relative abundance of Coprococcus eutactus, even after adjusting for psychotropic drug use. The overall conclusion from this study was that mood and anxiety disorders rather than psychotropic drugs are associated with compositional gut microbiome differences relative to controls. Faecalibacterium is another bacterial group that repeatedly emerges in the literature about psychiatric disorders and the gut microbiome. One GAD study found it to be significantly depleted in the patient group [36] and another study in GAD patients reported that Faecalibacterium negatively correlated with total plasma cortisol [38]. Additionally, Faecalibacterium was more abundant is people with GAD in remission compared with the active state [36]. An important metagenomics study using a large microbiome population cohort (Flemish Gut Flora Project, n = 1,054) with validation in independent datasets (n = 1,070) has previously found Faecalibacterium and Coprococcus bacteria to be consistently associated with higher quality of life indicators [44]. Depleted levels of Faecalibacterium and Coprococcus and enriched levels of Eggerthella were consistently shared between major depressive disorder, bipolar affective disorder, psychosis (undefined) and schizophrenia, and anxiety.

While Eubacterium, Faecalibacterium and Copcococcus are depleted in GAD, several bacterial groups may be more abundant in these individuals. Genera associated with GAD included Ruminococcus gnavus and Fusobacterium [36]. In a subgroup analysis of treatment-naïve patients, Escherichia–Shigella and Bacteroides were also enriched [36]. These taxa were also elevated in a subsequent cross-sectional study where their abundance was positively correlated with GAD symptom severity [37]. Additionally, a high abundance of Bacteroides eggerthii immediately after a two-month frontline work period during the Covid-19 pandemic was associated with future PTSD symptoms [41]. Bacteroides are a complex group of bacteria. While they represent a significant proportion of human gut commensals, these gram-negative obligate anaerobes can be highly pathogenic [45]. Similarly, Escherichia–Shigella is another pathogen which is associated with several human diseases [46]. Stress-induced proliferation of Escherichia coli in mice is associated with increased anxiety-like behaviours, decreased hippocampal BDNF expression and elevated gastrointestinal and hippocampal inflammation [47]. Data in relation to functional microbiome differences in GAD is limited.Each GBM corresponds to a single neuroactive compound production or degradation process [44]. A small study exploring microbiome differences between GAD, MDD and a control group reported differences in 69 Kegg Orthologues between the three groups, thus suggesting some differences in predicted microbiome function [38]. However, the numbers in each group were small and this observation requires further replication.

Panic Disorder and Agoraphobia

Studies exploring microbiome composition are limited in PD .. Similar to findings in GAD, butyrate-producing groups, including Faecalibacterium, Copcococcus and Roseburia were depleted in relative abundance in perimenopausal PD, while the genus Bacteroides was elevated.

Social Anxiety Disorder

Our research group has recently reported the first findings on the gut microbiota in social anxiety disorder [49]. While there had long been interest in the gut microbiota in anxiety and stress regulation, a growing appreciation for the role of the microbiome in social development and behaviour has developed in recent years [50].  However, we found that overall microbiota composition, as measured by beta-diversity, differed between the SAD and control groups. Several taxonomic differences were seen at a genus- and species-level: the relative abundance of the genera Anaeromassillibacillus and Gordonibacter were elevated in SAD, while Parasuterella was enriched in healthy controls. Anaeromassilibacillus is a member of the Clostridiales order of bacteria, a group which appears to show altered abundance in many psychiatric disorders and may represent disease-shared microbial responses [51]. In relation to functional differences, the gut metabolic module ‘aspartate degradation I’ was elevated in SAD patients. This functional pathway is associated with tryptophan-kynurenine metabolism, which we have previously demonstrated to be altered in SAD [22] nterestingly, the mice who received the SAD microbiome demonstrated a specific heightened social fear response, a validated mouse model of SAD [55]. They performed normally across other tests evaluating general anxiety-like and depression-like behaviours, an important feature of the study highlighting specificity for social fear responses. Additionally, changes in central and peripheral immune function and oxytocin expression in the bed nucleus of the stria terminalis were evident in the SAD-FMT-recipient mice.

Probiotics, Synbiotics and Prebiotics

Numerous systematic reviews and meta-analyses have explored the impact of probiotics and prebiotics on stress and anxiety symptoms over the past five years [56,57,58,59,60,61]. For the most part, probiotics appear to be a promising intervention for reducing stress and anxiety symptoms, although results can vary depending on study inclusion criteria and the type of probiotic used, since strain-specific effects and different mechanisms of action are likely.  A meta-analysis of 1146 healthy subjects found that probiotics reduced subjective stress and improved stress‐related subthreshold anxiety/depression levels. A larger meta-analysis of 29 randomised controlled trials (RCTs) (n = 2035 participants) found that probiotics and synbiotics were effective in reducing anxiety symptoms, but prebiotics had no effect [59]. This was similar to an earlier meta-analysis, which included 34 RCTs involving healthy subjects, medical patients (with a range of medical problems including IBS, multiple sclerosis, obesity, fibromyalgia, rheumatoid arthritis and laryngeal cancer) and subjects with MDD, which reported a small anxiolytic effect of probiotics but not prebiotics [56]. A recent meta-analysis reported that a probiotic reduced depression scores but not anxiety scores. Only one randomised controlled trial to date has investigated the impact of a probiotic in GAD [63]. This Iranian study randomised 48 medication-free patients with GAD to receive either a placebo or multispecies probiotic (18*10⁹ CFU Bifidobacterium longom, Bifidobacterium bifidum, Bifidobacterium lactis, Lactobacillus acidophilus) in addition to 25 mg of Sertraline for eight weeks. The group receiving the adjunctive probiotic had significantly greater reductions in the clinician-rated Hamilton-Anxiety Rating Scale, although no differences were seen in Beck Anxiety Inventory or the State Trait Anxiety Inventory. To our knowledge, there have been no clinical trials using microbiota-based therapies in SAD, PD or agoraphobia. However, a cross-sectional study of over 1000 university students found that higher intake of fermented foods appeared to be protective against developing SAD in those at higher genetic risk, as measured by trait neuroticism [64]. High intake of fermented foods may also be protective against general anxiety symptoms [65]. Fermented foods are an important source of potentially beneficial bacteria, generally containing various strains of lactic acid bacteria [66]. When consumed in high amounts by humans, certain fermented foods have anti-inflammatory effects [67] which may, in part account for the benefit in mental health.

Diet is a major determinant of microbiome composition [68] and a promising intervention for psychiatric disorders, recently reframed under the banner of Nutritional Psychiatry [69]. Conversely, a diet characterised by high-fat, high-sugar and low fruit and vegetable intake, characteristic of the ‘Western style’ pattern of eating, is associated with elevated anxiety symptoms [75]. The mental health benefits of a Mediterranean diet extend beyond prevention. In 2017, the SMILES trial demonstrated for the first time that a Mediterranean diet intervention could improve depressive symptoms in Australian patients with MDD alongside standard treatment including psychotherapy and/or pharmacotherapy. [76]. Several subsequent clinical trials, also in Australia, demonstrated similar findings in depressed patients [77,78,79]. ..in the aforementioned SMILES trial, a reduction in the Hospital Anxiety and Depression Scale (HADS)-anxiety subscale score was reported as a secondary outcome. Interestingly, a Mediterranean diet intervention results in an increased abundance of Faecalibacterium and Roseburia [80, 81] taxa, which are depleted in GAD and PD [36, 42]. A study from our research group recently investigated the impact of a ‘psychobiotic diet’ in healthy volunteers [82]. The ‘psychobiotic diet’ included aspects of the Mediterranean diet like fruits, vegetables, whole grains, legumes, and seeds, as well as fermented foods. After four weeks of adhering to this diet, subjects reported reductions in perceived stress which were greatest in those with high adherence. Dietary intervention remains a promising therapeutic strategy for anxiety disorders and needs to be explored further.

A key priority now must be extending the evidence base for microbiome interventions from studies in healthy, non-psychiatric populations to people with clinically diagnosed anxiety disorders, and with an increased focus on function over form. This applies to the spectrum of microbiome-based interventions, including probiotics, prebiotics, synbiotics, whole-diet interventions and individual dietary components such as fermented foods. There is reasonably robust evidence for using specific adjunctive probiotics in patients with MDD [56, 83, 84]. Additionally, a Mediterranean diet intervention can also be recommended to depressed patients [85]. However, evidence is lacking in patients with clinical anxiety disorders and although similar interventions do hold promise, they cannot confidently be recommended by psychiatrists at present.

Further exploration of the impact of probiotics, dietary components such as fermented foods and bacterial metabolites such as short-chain fatty acids on HPA axis function [86, 87], immune response, tryptophan metabolism, vagal nerve communication, BDNF expression, blood–brain-barrier integrity and other physiological processes involved in brain function and mental health is needed. Moreover, while much attention has focused on gut bacteria, the gut virome is also an important component of the human microbiome. It was recently demonstrated in rodents that the virome plays a role in the modulation of the microbiota–gut–brain axis during stress [88] indicating that viral populations should be considered when designing future microbiome-directed therapies. The limitation of a symptomatic ‘floor effect’ when exploring the anxiolytic properties of microbiome interventions in healthy non-clinical populations may have underestimated the potential of this option and strain-specific effects also need to be taken into account. It is time for microbiome researchers to turn their attention towards people suffering with GAD, PD, agoraphobia and SAD, as well as those with sub-threshold anxiety symptoms, in order to fully elucidate the potential of the microbiome-gut-brain axis in such conditions.