Gut microbial metabolites in depression: understanding the biochemical mechanisms – Gastrointestinal and central function are intrinsically connected by the gut microbiota, an ecosystem that has co-evolved with the host to expand its biotransformational capabilities and interact with host physiological processes by means of its metabolic products. Abnormalities in this microbiota-gut-brain axis have emerged as a key component in the pathophysiology of depression, leading to more research attempting to understand the neuroactive potential of the products of gut microbial metabolism. This review explores the potential for the gut microbiota to contribute to depression and focuses on the role that microbially-derived molecules – neurotransmitters, short-chain fatty acids, indoles, bile acids, choline metabolites, lactate and vitamins – play (...)

Despite the progress in characterising the pharmacological profile of drugs of abuse, their precise biochemical impact remains unclear. The metabolome reflects the multifaceted biochemical processes occurring within a biological system. This includes those encoded in the genome but also those arising from environmental/exogenous exposures and interactions between the two. Using metabolomics, the biochemical derangements associated with substance abuse can be determined as the individual transitions from recreational drug to chronic use (dependence). By understanding the biomolecular perturbations along this time course and how they vary across individuals, metabolomics can elucidate biochemical mechanisms of the addiction cycle (dependence/withdrawal/relapse) and predict prognosis (recovery/relapse). In this review, we summarise human and animal metabolomic studies in the field of opioid and psychostimulant addiction. We highlight the importance of metabolomics as a powerful approach for biomarker discovery and its potential to guide personalised pharmacotherapeutic strategies for addiction targeted towards the individual's metabolome.LINKED ARTICLES: This article is part of a themed issue on Building Bridges in Neuropharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.8/issuetoc

One of the biggest challenges in treating depression is the heterogeneous and qualitative nature of its clinical presentations. This highlights the need to find quantitative molecular markers to tailor existing treatment strategies to the individual’s biological system. In this study, high-resolution metabolic phenotyping of urine and plasma samples from the CAN-BIND study collected before treatment with two common pharmacological strategies, escitalopram and aripiprazole, was performed. Here we show that a panel of LDL and HDL subfractions were negatively correlated with depression in males. For treatment response, lower baseline concentrations of apolipoprotein A1 and HDL were predictive of escitalopram response in males, while higher baseline concentrations of apolipoprotein A2, HDL and VLDL subfractions were predictive of aripiprazole response in females. These findings support the potential of metabolomics in precision medicine and the possibility of identifying personalized interventions for depression.

Decades of research have established the role of microbiota–brain communication in behaviour and brain function. Studies have shown that microbiota composition and diversity are influenced by a variety of factors including host genetics, diet, and other environmental exposures, with implications for the immunological and neurobiological development of the host organism. To further understand early-life interactions between environment, genetic factors, the microbiome and the central nervous system, we investigated the impact of postnatal stress in C57Bl/6 wild type and T-cell deficient mice on microbe–brain interactions and behaviour. Mice were exposed to immune challenge with lipopolysaccharide (LPS) at postnatal day (P) 3 and maternal separation at P9 (16 h overnight). Behavioural assessment of growth and development as well as behaviour (righting reflex, ultrasonic vocalizations in response to brief maternal separation, open field, sociability, and grooming) was conducted. Microbiota diversity and composition of fecal samples collected at P24 revealed reduced alpha diversity in T-cell-deficient mice as well as genotype- and stress-related taxa. Notably, integrated analyses of microbiota and behaviour in the context of immunocompromise revealed key behavioural related taxa that may be important to brain development. These findings are important to determining the influence of genetic and environmental factors on gut microbiota and advances our understanding microbiome–brain signaling pathways on neurodevelopment and behaviour.

Background: Survivors of critical illness in childhood commonly display subsequent psychiatric symptoms including emotional and behavioural difficulties, and manifestations of post-traumatic stress disorder (PTSD). Anomalies in inflammatory profiles are an established finding in these childhood psychiatric conditions. Objective: This exploratory study aimed to investigate whether abnormal peripheral blood inflammatory markers measured during paediatric intensive care unit (PICU) admission were associated with psychiatric symptoms after discharge. Methods: We performed a prospective observational cohort study on 71 children with septic illness, meningoencephalitis and other critical disorders admitted to two PICUs between 2007 and 2010. 3–6 months following discharge, subjects were assessed for global psychiatric risk (ie, presence of emotional and behavioural difficulties on the parental Strengths and Difficulties Questionnaire (SDQ)), and for PTSD risk using the child-rated Impact of Events Scale (IES-8). Inflammatory and related biological markers were transcribed from PICU admission notes (white cell count, lymphocytes, neutrophils, C reactive protein (CRP), platelets, fibrinogen and lactate). Findings: Global psychiatric risk at follow-up was associated with abnormal lymphocyte count during admission (χ²=6.757, p=0.014, n=48). In children with sepsis, partial correlation analyses controlling for age and gender highlighted associations between (i) SDQ scores and low lymphocyte count (r=−0.712; p=0.009, n=14), and (ii) IES-8 score and high CRP levels (r=0.823; p=0.006, n=11). These associations remained after correction for multiple comparisons. Conclusion: These results support the hypothesis that acute inflammation may play a role in determining the development of psychopathology following PICU admission. Clinical implications: If the findings are replicated, they may help to better highlight which children are at risk of post-PICU psychopathology and appropriately target follow-up.