Importance of good hosting: reviewing the bi-directionality of the microbiome-gut-brain-axis.

Gut microorganisms have been shown to significantly impact on central function and studies that have associated brain disorders with specific bacterial genera have advocated an anomalous gut microbiome as the pathophysiological basis of several psychiatric and neurological conditions. Thus, our knowledge of brain-to-gut-to microbiome communication in this bidirectional axis seems to have been overlooked. This review examines the known mechanisms of the microbiome-to-gut-to-brain axis, highlighting how brain-to-gut-to-microbiome signaling may be key to understanding the cause of disrupted gut microbial communities. We show that brain disorders can alter the function of the brain-to-gut-to-microbiome axis, which will in turn contribute to disease progression, while the microbiome-to gut-to brain direction presents as a more versatile therapeutic axis, since current psychotropic/neurosurgical interventions may have unwanted side effects that further cause disruption to the gut microbiome. A consideration of the brain-to-gut-to-microbiome axis is imperative to better understand how the microbiome-gut-brain axis overall is involved in brain illnesses, and how it may be utilized as a preventive and therapeutic tool.

Evaluating the efficacy and mechanisms of a ketogenic diet as adjunctive treatment for people with treatment-resistant depression: A protocol for a randomised controlled trial.

BACKGROUND: One-third of people with depression do not respond to antidepressants, and, after two adequate courses of antidepressants, are classified as having treatment-resistant depression (TRD). Some case reports suggest that ketogenic diets (KDs) may improve some mental illnesses, and preclinical data indicate that KDs can influence brain reward signalling, anhedonia, cortisol, and gut microbiome which are associated with depression. To date, no trials have examined the clinical effect of a KD on TRD. METHODS: This is a proof-of-concept randomised controlled trial to investigate the efficacy of a six-week programme of weekly dietitian counselling plus provision of KD meals, compared with an intervention involving similar dietetic contact time and promoting a healthy diet with increased vegetable consumption and reduction in saturated fat, plus food vouchers to purchase healthier items. At 12 weeks we will assess whether participants have continued to follow the assigned diet. The primary outcome is the difference between groups in the change in Patient Health Questionnaire-9 (PHQ-9) score from baseline to 6 weeks. PHQ-9 will be measured at weeks 2, 4, 6 and 12. The secondary outcomes are the differences between groups in the change in remission of depression, change in anxiety score, functioning ability, quality of life, cognitive performance, reward sensitivity, and anhedonia from baseline to 6 and 12 weeks. We will also assess whether changes in reward sensitivity, anhedonia, cortisol awakening response and gut microbiome may explain any changes in depression severity. DISCUSSION: This study will test whether a ketogenic diet is an effective intervention to reduce the severity of depression, anxiety and improve quality of life and functioning ability for people with treatment-resistant depression.

Psycho-Pharmacomicrobiomics: A Systematic Review and Meta-Analysis.

BACKGROUND: Understanding the interactions between the gut microbiome and psychotropic medications (psycho-pharmacomicrobiomics) could improve treatment stratification strategies in psychiatry. In this systematic review and meta-analysis, we first explored whether psychotropics modify the gut microbiome; second, we investigated whether the gut microbiome affects the efficacy and tolerability of psychotropics. METHODS: Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we searched (November 2022) for longitudinal and cross-sectional studies that investigated the effect of psychotropics on the gut microbiome. The primary outcome was the difference in diversity metrics (alpha and beta) before and after treatment with psychotropics (longitudinal studies) and in medicated compared with unmedicated individuals (cross-sectional studies). Secondary outcomes included the association between gut microbiome and efficacy and tolerability outcomes. Random effect meta-analyses were conducted on alpha diversity metrics, while beta diversity metrics were pooled using distance data extracted from graphs. Summary statistics included standardized mean difference and Higgins I2 for alpha diversity metrics and F and R values for beta diversity metrics. RESULTS: Nineteen studies were included in our synthesis; 12 investigated antipsychotics and 7 investigated antidepressants. Results showed significant changes in alpha (4 studies; standard mean difference: 0.12; 95% CI: 0.01-0.23; p = .04; I2: 14%) and beta (F = 15.59; R2 = 0.05; p < .001) diversity metrics following treatment with antipsychotics and antidepressants, respectively. Altered gut microbiome composition at baseline was associated with tolerability and efficacy outcomes across studies, including response to antidepressants (2 studies; alpha diversity; standard mean difference: 2.45; 95% CI: 0.50-4.40; p < .001, I2: 0%). CONCLUSIONS: Treatment with psychotropic medications is associated with altered gut microbiome composition, and the gut microbiome may in turn influence the efficacy and tolerability of these medications.

Live or heat-killed probiotic administration reduces anxiety and central cytokine expression in BALB/c mice, but differentially alters brain neurotransmitter gene expression.

While the potential for probiotic supplements to act as adjunctive treatments for mood disorders has been widely demonstrated, the precise mode of action remains unclear. To investigate the psychotropic effects of a multi-species probiotic on emotional behaviour in male BALB/c mice, we explored the potential mechanisms of action relating to the temporal changes in the mRNA expression of brain cytokines, BDNF, central 5HT receptor and serotonin transporter (SERT) and GABA receptor in the context of probiotic induced behavioural changes. The effects of a heat-killed probiotic, independent of microbial metabolic processes were also evaluated on the same outcomes to understand whether the host response to the bacteria is more or less important than the contribution of the metabolic activity of the bacteria themselves. Results showed that probiotic supplementation reduced anxiety-like behaviours, increased time spent in the light area of the light-dark box, and decreased the expression of pro-inflammatory cytokines in the brain. Furthermore, probiotic administration elevated hippocampal BDNF and decreased GABAB1ß expression. Interestingly, the heat-killed probiotic and its membrane fraction had similar effects on emotional behaviours and gene expression in the brain. The ingestion of live and heat-killed probiotic preparations also reduced TLR2 expression in the gut. Thus, the present study reveals that the anxiolytic action of a multispecies probiotic in BALB/c mice is independent of bacterial viability. This suggests that it is the host response to probiotics, rather than microbial metabolism that facilitates the molecular changes in the brain and downstream behaviours. This article is part of the Special Issue on "Microbiome & the Brain: Mechanisms & Maladies".

Multispecies probiotic administration reduces emotional salience and improves mood in subjects with moderate depression: a randomised, double-blind, placebo-controlled study.

BACKGROUND: The potential antidepressant properties of probiotics have been suggested, but their influence on the emotional processes that may underlie this effect is unclear. METHODS: Depressed volunteers (n = 71) were recruited into a randomised double-blind, placebo-controlled study to explore the effects of a daily, 4-week intake of a multispecies probiotic or placebo on emotional processing and cognition. Mood, anxiety, positive and negative affect, sleep, salivary cortisol and serum C-reactive peptide (CRP) were assessed before and after supplementation. RESULTS: Compared with placebo, probiotic intake increased accuracy at identifying faces expressing all emotions (+12%, p < 0.05, total n = 51) and vigilance to neutral faces (mean difference between groups = 12.28 ms ± 6.1, p < 0.05, total n = 51). Probiotic supplementation also reduced reward learning (-9%, p < 0.05, total n = 51), and interference word recall on the auditory verbal learning task (-18%, p < 0.05, total n = 50), but did not affect other aspects of cognitive performance. Although actigraphy revealed a significant group × night-time activity interaction, follow up analysis was not significant (p = 0.094). Supplementation did not alter salivary cortisol or circulating CRP concentrations. Probiotic intake significantly reduced (-50% from baseline, p < 0.05, n = 35) depression scores on the Patient Health Questionnaire-9, but these did not correlate with the changes in emotional processing. CONCLUSIONS: The impartiality to positive and negative emotional stimuli or reward after probiotic supplementation have not been observed with conventional antidepressant therapies. Further studies are required to elucidate the significance of these changes with regard to the mood-improving action of the current probiotic.

Sociability in a non-captive macaque population is associated with beneficial gut bacteria.

The relationship between social behaviour and the microbiome is known to be reciprocal. Research in wild animal populations, particularly in primate social groups, has revealed the role that social interactions play in microbial transmission, whilst studies in laboratory animals have demonstrated that the gut microbiome can affect multiple aspects of behaviour, including social behaviour. Here we explore behavioural variation in a non-captive animal population with respect to the abundance of specific bacterial genera. Social behaviour based on grooming interactions is assessed in a population of rhesus macaques (Macaca mulatta), and combined with gut microbiome data. We focus our analyses on microbiome genera previously linked to sociability and autistic behaviours in rodents and humans. We show in this macaque population that some of these genera are also related to an individual's propensity to engage in social interactions. Interestingly, we find that several of the genera positively related to sociability, such as Faecalibacterium, are well known for their beneficial effects on health and their anti-inflammatory properties. In contrast, the genus Streptococcus, which includes pathogenic species, is more abundant in less sociable macaques. Our results indicate that microorganisms whose abundance varies with individual social behaviour also have functional links to host immune status. Overall, these findings highlight the connections between social behaviour, microbiome composition, and health in an animal population.

Brain Derived Neurotrophic Factor and Cognitive Dysfunction in the Schizophrenia-Bipolar Spectrum: A Systematic Review and Meta-Analysis.

Background: Cognitive impairment is a core feature of disorders on the schizophrenia-bipolar spectrum, i.e., schizophrenia, bipolar disorder, and schizoaffective disorder. Brain-derived neurotrophic factor (BDNF) has been proposed to be a biomarker of cognitive impairment in these disorders as it plays a critical role in neuroplasticity and proposed to mediate some of the psychotropic effects of medication. However, despite numerous studies investigating the association between circulating BDNF and these disorders, no solid conclusions have been drawn regarding its involvement in cognitive impairment. Objectives: The current systematic review and meta-analysis aims to examine blood BDNF levels and cognitive dysfunction in patients on the schizophrenia-bipolar spectrum as well as to evaluate whether circulating BDNF measurements can act as a biomarker for cognitive dysfunction. Methods: Studies were identified by searching Embase and Medline databases for English language articles published in peer-reviewed journals between 2000 January and 2021 June according to the PRISMA guidelines. A total of 815 articles were identified of which 32 met the inclusion criteria for the systematic review - reporting on comparisons between blood BDNF levels and cognitive functions of schizophrenia or bipolar disorder patients versus healthy controls (no studies involving schizoaffective patients were specifically obtained for the time being). Twenty-four of these studies (19 with schizophrenia and 5 with bipolar disorder patients) were eligible to be included in the meta-analysis. Results: Our findings indicated that circulating BDNF levels were significantly reduced in patients experiencing an acute episode of schizophrenia or bipolar disorder compared to healthy controls. Cognitive function was also found to be significantly worse in patients, however, correlations between BDNF levels and cognitive impairment were not always detected. Interventions, especially pharmacotherapy seemed to improve certain aspects of cognition and increase circulating BDNF levels. Conclusion: Circulating BDNF alone does not seem to be a valid biomarker of cognitive dysfunction in patients with disorders on the schizophrenia-bipolar spectrum, owing to several confounding factors. Changes of the circulating levels of BDNF should be evaluated in a wider context of other stress-, immune-, and inflammatory-related factors.

Modifying the maternal microbiota alters the gut-brain metabolome and prevents emotional dysfunction in the adult offspring of obese dams.

Maternal obesity disturbs brain-gut-microbiota interactions and induces negative affect in the offspring, but its impact on gut and brain metabolism in the offspring (F1) are unknown. Here, we tested whether perinatal intake of a multispecies probiotic could mitigate the abnormal emotional behavior in the juvenile and adult offspring of obese dams. Untargeted NMR-based metabolomic profiling and gene-expression analysis throughout the gut-brain axis were then used to investigate the biology underpinning behavioral changes in the dams and their offspring. Prolonged high-fat diet feeding reduced maternal gut short-chain fatty acid abundance, increased markers of peripheral inflammation, and decreased the abundance of neuroactive metabolites in maternal milk during nursing. Both juvenile (postnatal day [PND] 21) and adult (PND112) offspring of obese dams exhibited increased anxiety-like behavior, which were prevented by perinatal probiotic exposure. Maternal probiotic treatment increased gut butyrate and brain lactate in the juvenile and adult offspring and increased the expression of prefrontal cortex PFKFB3, a marker of glycolytic metabolism in astrocytes. PFKFB3 expression correlated with the increase in gut butyrate in the juvenile and adult offspring. Maternal obesity reduced synaptophysin expression in the adult offspring, while perinatal probiotic exposure increased expression of brain-derived neurotrophic factor. Finally, we showed that the resilience of juvenile and adult offspring to anxiety-like behavior was most prominently associated with increased brain lactate abundance, independent of maternal group. Taken together, we show that maternal probiotic supplementation exerts a long-lasting effect on offspring neuroplasticity and the offspring gut-liver-brain metabolome, increasing resilience to emotional dysfunction induced by maternal obesity.

Gut dysbiosis in severe mental illness and chronic fatigue: a novel trans-diagnostic construct? A systematic review and meta-analysis.

Reduced gut-microbial diversity ("gut dysbiosis") has been associated with an anhedonic/amotivational syndrome ("sickness behavior") that manifests across severe mental disorders and represent the key clinical feature of chronic fatigue. In this systematic review and meta-analysis, we investigated differences in proxy biomarkers of gut dysbiosis in patients with severe mental illness and chronic fatigue vs. controls and the association of these biomarkers with sickness behavior across diagnostic categories. Following PRISMA guidelines, we searched from inception to April 2020 for all the studies investigating proxy biomarkers of gut dysbiosis in patients with severe mental illness and chronic fatigue. Data were independently extracted by multiple observers, and a random-mixed model was used for the analysis. Heterogeneity was assessed with the I2 index. Thirty-three studies were included in the systematic review; nineteen in the meta-analysis (N = 2758 patients and N = 1847 healthy controls). When compared to controls, patients showed increased levels of zonulin (four studies reporting data on bipolar disorder and depression, SMD = 0.97; 95% Cl = 0.10-1.85; P = 0.03, I2 = 86.61%), lipopolysaccharide (two studies reporting data on chronic fatigue and depression, SMD = 0.77; 95% Cl = 0.42-1.12; P < 0.01; I2 = 0%), antibodies against endotoxin (seven studies reporting data on bipolar disorder, depression, schizophrenia, and chronic fatigue, SMD = 0.99; 95% CI = 0.27-1.70; P < 0.01, I2 = 97.14%), sCD14 (six studies reporting data on bipolar disorder, depression, schizophrenia, and chronic fatigue, SMD = 0.54; 95% Cl 0.16-0.81; P < 0.01, I2 = 90.68%), LBP (LBP, two studies reporting data on chronic fatigue and depression, SMD = 0.87; 95% Cl = 0.25-1.48; P < 0.01; I2 = 56.80%), alpha-1-antitripsin (six studies reporting data on bipolar disorder, depression, and schizophrenia, SMD = 1.23; 95% Cl = 0.57-1.88; P < 0.01, I2: 89.25%). Elevated levels of gut dysbiosis markers positively correlated with severity of sickness behavior in patients with severe mental illness and chronic fatigue. Our findings suggest that gut dysbiosis may underlie symptoms of sickness behavior across traditional diagnostic boundaries. Future investigations should validate these findings comparing the performances of the trans-diagnostic vs. categorical approach. This will facilitate treatment breakthrough in an area of unmet clinical need.

Postnatal prebiotic supplementation in rats affects adult anxious behaviour, hippocampus, electrophysiology, metabolomics, and gut microbiota.

We have shown previously that prebiotic (Bimuno galacto-oligosacharides, B-GOS®) administration to neonatal rats increased hippocampal NMDAR proteins. The present study has investigated the effects of postnatal B-GOS® supplementation on hippocampus-dependent behavior in young, adolescent, and adult rats and applied electrophysiological, metabolomic and metagenomic analyses to explore potential underlying mechanisms. The administration of B-GOS® to suckling, but not post-weaned, rats reduced anxious behavior until adulthood. Neonatal prebiotic intake also reduced the fast decay component of hippocampal NMDAR currents, altered age-specific trajectories of the brain, intestinal, and liver metabolomes, and reduced abundance of fecal Enterococcus and Dorea bacteria. Our data are the first to show that prebiotic administration to rats during a specific postnatal period has long-term effects on behavior and hippocampal physiology. The study also suggests that early-life prebiotic intake may affect host brain function through the reduction of stress-related gut bacteria rather than increasing the proliferation of beneficial microbes.

What Is Our Understanding of the Influence of Gut Microbiota on the Pathophysiology of Parkinson's Disease?

Microbiota have increasingly become implicated in predisposition to human diseases, including neurodegenerative disorders such as Parkinson's disease (PD). Traditionally, a central nervous system (CNS)-centric approach to understanding PD has predominated; however, an association of the gut with PD has existed since Parkinson himself reported the disease. The gut-brain axis refers to the bidirectional communication between the gastrointestinal tract (GIT) and the brain. Gut microbiota dysbiosis, reported in PD patients, may extend this to a microbiota-gut-brain axis. To date, mainly the bacteriome has been investigated. The change in abundance of bacterial products which accompanies dysbiosis is hypothesised to influence PD pathophysiology via multiple mechanisms which broadly centre on inflammation, a cause of alpha-synuclein (a-syn) misfolding. Two main routes are hypothesised by which gut microbiota can influence PD pathophysiology, the neural and humoral routes. The neural route involves a-syn misfolding peripherally in the enteric nerves which can then be transported to the brain via the vagus nerve. The humoral route involves transportation of bacterial products and proinflammatory cytokines from the gut via the circulation which can cause central a-syn misfolding by inducing neuroinflammation. This article will assess whether the current literature supports gut bacteria influencing PD pathophysiology via both routes.

Endocannabinoid system mediates the association between gut-microbial diversity and anhedonia/amotivation in a general population cohort.

Anhedonia and amotivation are debilitating symptoms and represent unmet therapeutic needs in a range of clinical conditions. The gut-microbiome-endocannabinoid axis might represent a potential modifiable target for interventions. Based on results obtained from animal models, we tested the hypothesis that the endocannabinoid system mediates the association between gut-microbiome diversity and anhedonia/amotivation in a general population cohort. We used longitudinal data collected from 786 volunteer twins recruited as part the TwinsUK register. Our hypothesis was tested with a multilevel mediation model using family structure as random intercept. The model was set using alpha diversity (within-individual gut-microbial diversity) as predictor, serum and faecal levels of the endocannabinoid palmitoylethanolamide (PEA) as mediator, and anhedonia/amotivation as outcome. PEA is considered the endogenous equivalent of cannabidiol, with increased serum levels believed to have anti-depressive effects, while increased stool PEA levels, reflecting increased excretion, are believed to have opposite, detrimental, effects on mental health. We therefore expected that either reduced serum PEA or increased stool PEA would mediate the association between microbial diversity and anhedonia amotivation. Analyses were adjusted for obesity, diet, antidepressant use, sociodemographic and technical covariates. Data were imputed using multiple imputation by chained equations. Mean age was 65.2 ± 7.6; 93% of the sample were females. We found a direct, significant, association between alpha diversity and anhedonia/amotivation (ß = -0.37; 95%CI: -0.71 to -0.03; P = 0.03). Faecal, but not serum, levels of the endocannabinoid palmitoylethanolamide (PEA) mediated this association: the indirect effect was significant (ß = -0.13; 95%CI: -0.24 to -0.01; P = 0.03), as was the total effect (ß = -0.38; 95%CI: -0.72 to -0.04; P = 0.03), whereas the direct effect of alpha diversity on anhedonia/amotivation was attenuated fully (ß = -0.25; 95%CI: -0.60 to 0.09; P = 0.16). Our results suggest that gut-microbial diversity might contribute to anhedonia/amotivation via the endocannabinoid system. These findings shed light on the biological underpinnings of anhedonia/amotivation and suggest the gut microbiota-endocannabinoid axis as a promising therapeutic target in an area of unmet clinical need.

Anxiolytic effects of a galacto-oligosaccharides prebiotic in healthy females (18-25 years) with corresponding changes in gut bacterial composition.

Current research implicates pre- and probiotic supplementation as a potential tool for improving symptomology in physical and mental ailments, which makes it an attractive concept for clinicians and consumers alike. Here we focus on the transitional period of late adolescence and early adulthood during which effective interventions, such as nutritional supplementation to influence the gut microbiota, have the potential to offset health-related costs in later life. We examined multiple indices of mood and well-being in 64 healthy females in a 4-week double blind, placebo controlled galacto-oligosaccharides (GOS) prebiotic supplement intervention and obtained stool samples at baseline and follow-up for gut microbiota sequencing and analyses. We report effects of the GOS intervention on self-reported high trait anxiety, attentional bias, and bacterial abundance, suggesting that dietary supplementation with a GOS prebiotic may improve indices of pre-clinical anxiety. Gut microbiota research has captured the imagination of the scientific and lay community alike, yet we are now at a stage where this early enthusiasm will need to be met with rigorous research in humans. Our work makes an important contribution to this effort by combining a psychobiotic intervention in a human sample with comprehensive behavioural and gut microbiota measures.

The gut-microbiome as a target for the treatment of schizophrenia: A systematic review and meta-analysis of randomised controlled trials of add-on strategies.

The gut-microbiome has been hypothesised as a novel potential target for intervention for schizophrenia. We tested this hypothesis with a systematic review and meta-analysis of studies investigating the efficacy and acceptability of add-on strategies known to affect the gut-microbiome for the treatment of schizophrenia. Following PRISMA guidelines, we searched from inception to August 2019 all the randomised double-blind controlled trials of add-on antibiotics, antimicrobials, pre/probiotics, and faecal transplant in schizophrenia. Primary outcomes were severity of negative symptoms and acceptability of treatment. Data were independently extracted by multiple observers and a random-mixed model was used for the analysis. Heterogeneity was assessed with the I2 index. We identified 28 eligible trials: 21 investigated antibiotics, 4 antimicrobials (Artemisinin, Artemether, and Sodium Benzoate), 3 pre/probiotics, none faecal transplant. Results showed no effect of D-Cycloserine (10 studies; SMD, -0.16; 95% CI -0.40, 0.08; P = .20; I2: 28.2%), Minocycline (7 studies; SMD: -0.35; 95% CI -0.70, 0.00; P = .05, I2:77.7%), other antibiotics (2 studies), probiotics alone (1 study), and Artemisinin (1 study) on negative symptoms of schizophrenia when compared to placebo. Limited evidence suggests efficacy on negative symptoms for Sodium benzoate (2 studies; SMD, -0.63; 95%CI -1.03, -0.23; P < .001; I2:0%), Artemether (1 study), and probiotics combined with Vitamin D (1 study) when compared to placebo. Acceptability of intervention was similar to placebo. Negative findings were mainly led by antibiotics trials, with paucity of evidence available on pre/probiotics. There is a need of expanding our knowledge on the clinical relevance of gut-microbiome-host interaction in psychosis before engaging in further trials.

Mom's diet matters: Maternal prebiotic intake in mice reduces anxiety and alters brain gene expression and the fecal microbiome in offspring.

Compelling evidence links enteric microbes to brain function and behavior. Galacto-oligosaccharide prebiotics have been shown to modulate the composition of gut flora and induce metabolic, neurochemical, and behavioral changes in adult rodents. Despite the brain being most susceptible to environmental factors, such as nutrients and toxins, during the earliest stages of development, it is unknown whether maternal prebiotic supplementation during gestation and lactation influences the offspring gut microbiome, brain, or behavior. The aim of this study was to test whether maternal galacto-oligosaccharide intake during pregnancy and lactation alters the brain and behavior in naïve and endotoxin-challenged offspring. CD1 female mice received either normal drinking water or water supplemented with Bimuno® galacto-oligosaccharides (B-GOS) during gestation and suckling. Offspring behavior was tested at weaning age or adulthood, and a cross-foster design was employed in a separate cohort to differentiate between effects of prenatal and postnatal maternal B-GOS intake. Lipopolysaccharide was also administered to pups at postnatal day 9 to determine whether maternal B-GOS influences the neurobiological and behavioral effects of a neonatal pro-inflammatory challenge in adulthood. Fecal microbiome composition and metabolites were analyzed to explore potential relationships between the maternal microbiome, the offspring gut microbiome, and the offspring brain and behavior. Maternal B-GOS supplementation increased exploratory behavior and reduced expression of hippocampal glutamate receptor genes in young, weaning-age offspring. In addition, postnatal, but not prenatal, B-GOS supplementation increased fecal butyrate and propionate levels. Finally, in adult offspring, perinatal B-GOS intake increased cortical glutamate receptor subunits in females, increased social preference, and reduced anxiety. We provide novel and comprehensive evidence for the influence of maternal prebiotic intake on offspring behavior, brain gene expression, and gut microbiome composition in mice.

Post-inflammatory behavioural despair in male mice is associated with reduced cortical glutamate-glutamine ratios, and circulating lipid and energy metabolites.

Post-inflammatory behaviours in rodents are widely used to model human depression and to test the efficacy of novel anti-depressants. Mice injected with lipopolysaccharide (LPS) display a depressive-like phenotype twenty-four hours after endotoxin administration. Despite the widespread use of this model, the mechanisms that underlie the persistent behavioural changes after the transient peripheral inflammatory response remain elusive. The study of the metabolome, the collection of all the small molecule metabolites in a sample, combined with multivariate statistical techniques provides a way of studying biochemical pathways influenced by an LPS challenge. Adult male CD-1 mice received an intraperitoneal injection of either LPS (0.83 mg/kg) or saline, and were assessed for depressive-like behaviour 24 h later. In a separate mouse cohort, pro-inflammatory cytokine gene expression and 1H nuclear magnetic resonance (NMR) metabolomics measurements were made in brain tissue and blood. Statistical analyses included Independent Sample t-tests for gene expression data, and supervised multi-variate analysis using orthogonal partial least squares discriminant analysis for metabolomics. Both plasma and brain metabolites in male mice were altered following a single peripheral LPS challenge that led to depressive-like behaviour in the forced swim test. The plasma metabolites altered by LPS are involved in energy metabolism, including lipoproteins, glucose, creatine, and isoleucine. In the brain, glutamate, serine, and N-acetylaspartate (NAA) were reduced after LPS, whereas glutamine was increased. Serine-modulated glutamatergic signalling and changes in bioenergetics may mediate the behavioural phenotype induced by LPS. In light of other data supporting a central imbalance of glutamate-glutamine cycling in depression, our results suggest that aberrant central glutaminergic signalling may underpin the depressive-like behaviours that result from both inflammation and non-immune pathophysiology. Normalising glutaminergic signalling, rather than seeking to increase serotonergic signalling, might prove to be a more coherent approach to the development of new treatments for mood disorder.

Opposing effects of antibiotics and germ-free status on neuropeptide systems involved in social behaviour and pain regulation.

BACKGROUND: Recent research has revealed that the community of microorganisms inhabiting the gut affects brain development, function and behaviour. In particular, disruption of the gut microbiome during critical developmental windows can have lasting effects on host physiology. Both antibiotic exposure and germ-free conditions impact the central nervous system and can alter multiple aspects of behaviour. Social impairments are typically displayed by antibiotic-treated and germ-free animals, yet there is a lack of understanding of the underlying neurobiological changes. Since the µ-opioid, oxytocin and vasopressin systems are key modulators of mammalian social behaviour, here we investigate the effect of experimentally manipulating the gut microbiome on the expression of these pathways. RESULTS: We show that social neuropeptide signalling is disrupted in germ-free and antibiotic-treated mice, which may contribute to the behavioural deficits observed in these animal models. The most notable finding is the reduction in neuroreceptor gene expression in the frontal cortex of mice administered an antibiotic cocktail post-weaning. Additionally, the changes observed in germ-free mice were generally in the opposite direction to the antibiotic-treated mice. CONCLUSIONS: Antibiotic treatment when young can impact brain signalling pathways underpinning social behaviour and pain regulation. Since antibiotic administration is common in childhood and adolescence, our findings highlight the potential adverse effects that antibiotic exposure during these key neurodevelopmental periods may have on the human brain, including the possible increased risk of neuropsychiatric conditions later in life. In addition, since antibiotics are often considered a more amenable alternative to germ-free conditions, our contrasting results for these two treatments suggest that they should be viewed as distinct models.

Microbial transmission in animal social networks and the social microbiome.

Host-associated microbiomes play an increasingly appreciated role in animal metabolism, immunity and health. The microbes in turn depend on their host for resources and can be transmitted across the host's social network. In this Perspective, we describe how animal social interactions and networks may provide channels for microbial transmission. We propose the 'social microbiome' as the microbial metacommunity of an animal social group. We then consider the various social and environmental forces that are likely to influence the social microbiome at multiple scales, including at the individual level, within social groups, between groups, within populations and species, and finally between species. Through our comprehensive discussion of the ways in which sociobiological and ecological factors may affect microbial transmission, we outline new research directions for the field.

A single administration of the antibiotic, minocycline, reduces fear processing and improves implicit learning in healthy volunteers: analysis of the serum metabolome.

Minocycline has shown therapeutic promise in pre-clinical animal models and early phase clinical trials for a variety of psychiatric disorders. Previous studies on minocycline have shown its ability to suppress microglia activity and reduce inflammatory cytokine levels, and its amelioration of depressive-like behaviour in animals and humans. However, the underlying mechanisms that lead to minocycline's psychotropic effects are not clear. In this study, we investigated the psychological and biochemical effects of an acute dose of minocycline or placebo in 40 healthy adult volunteers. Psychological changes in emotional processing, implicit learning, and working memory were assessed. Plasma inflammatory markers, measured with enzyme-linked immunosorbent assays, and serum metabolites, measured with proton nuclear magnetic resonance combined with multi-variate analysis techniques, were also studied. Results showed that minocycline administration decreased fear misclassification and increased contextual learning, which suggested that reducing negative biases and improving cognition, respectively, may underlie the antidepressant actions of this agent. An examination of serum metabolites revealed higher levels of lipoproteins, particularly cholesterol, in the minocycline group. Minocycline also decreased circulating concentrations of the inflammatory marker C-Reactive Peptide, which is consistent with previous research. These effects highlight two important psychological mechanisms that may be relevant to the efficacy of minocycline reported in clinical trials, and also suggest a possible largely unexplored lipid-related biochemical pathway for the action of this drug.

The role of the microbiome in the neurobiology of social behaviour.

Microbes colonise all multicellular life, and the gut microbiome has been shown to influence a range of host physiological and behavioural phenotypes. One of the most intriguing and least understood of these influences lies in the domain of the microbiome's interactions with host social behaviour, with new evidence revealing that the gut microbiome makes important contributions to animal sociality. However, little is known about the biological processes through which the microbiome might influence host social behaviour. Here, we synthesise evidence of the gut microbiome's interactions with various aspects of host sociality, including sociability, social cognition, social stress, and autism. We discuss evidence of microbial associations with the most likely physiological mediators of animal social interaction. These include the structure and function of regions of the 'social' brain (the amygdala, the prefrontal cortex, and the hippocampus) and the regulation of 'social' signalling molecules (glucocorticoids including corticosterone and cortisol, sex hormones including testosterone, oestrogens, and progestogens, neuropeptide hormones such as oxytocin and arginine vasopressin, and monoamine neurotransmitters such as serotonin and dopamine). We also discuss microbiome-associated host genetic and epigenetic processes relevant to social behaviour. We then review research on microbial interactions with olfaction in insects and mammals, which contribute to social signalling and communication. Following these discussions, we examine evidence of microbial associations with emotion and social behaviour in humans, focussing on psychobiotic studies, microbe-depression correlations, early human development, autism, and issues of statistical power, replication, and causality. We analyse how the putative physiological mediators of the microbiome-sociality connection may be investigated, and discuss issues relating to the interpretation of results. We also suggest that other candidate molecules should be studied, insofar as they exert effects on social behaviour and are known to interact with the microbiome. Finally, we consider different models of the sequence of microbial effects on host physiological development, and how these may contribute to host social behaviour.