The live biotherapeutic Blautia stercoris MRx0006 attenuates social deficits, repetitive behaviour, and anxiety-like behaviour in a mouse model relevant to autism.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterised by deficits in social behaviour, increased repetitive behaviour, anxiety and gastrointestinal symptoms. The aetiology of ASD is complex and involves an interplay of genetic and environmental factors. Emerging pre-clinical and clinical studies have documented a potential role for the gut microbiome in ASD, and consequently, the microbiota represents a potential target in the development of novel therapeutics for this neurodevelopmental disorder. In this study, we investigate the efficacy of the live biotherapeutic strain, Blautia stercoris MRx0006, in attenuating some of the behavioural deficits in the autism-relevant, genetic mouse model, BTBR T+ Itpr3tf/J (BTBR). We demonstrate that daily oral administration with MRx0006 attenuates social deficits while also decreasing repetitive and anxiety-like behaviour. MRx0006 administration increases the gene expression of oxytocin and its receptor in hypothalamic cells in vitro and increases the expression of hypothalamic arginine vasopressin and oxytocin mRNA in BTBR mice. Additionally at the microbiome level, we observed that MRx0006 administration decreases the abundance of Alistipes putredinis, and modulates the faecal microbial metabolite profile. This alteration in the metabolite profile possibly underlies the observed increase in expression of oxytocin, arginine vasopressin and its receptors, and the consequent improvements in behavioural outcomes. Taken together, these findings suggest that the live biotherapeutic MRx0006 may represent a viable and efficacious treatment option for the management of physiological and behavioural deficits associated with ASD.

Depletion of dietary phytoestrogens reduces hippocampal plasticity and contextual fear memory stability in adult male mouse.

Introduction: Phytoestrogens are non-steroidal estrogen analogues and are found primarily in soy products. They have received increasing attention as dietary supplements for estrogen deficiency and as modulators of endogenous estrogen functions, including cognition and emotion. In addition to modifying the levels of circulating sex hormones, phytoestrogens also exert direct effects on estrogen and androgen receptors in the brain and thus effectively modulate the neural circuit functions.Objective: The aim of this study was to investigate the long-term effects of low phytoestrogen intake (∼6 weeks) on the hippocampal plasticity and hippocampus-dependent memory formation in the adult C57BL/6 male mice.Methods and Results: In comparison to mice on a diet with normal phytoestrogen content, mice on low phytoestrogen diet showed a significant reduction in the phosphorylation of NR2B subunit, a molecular correlate of plasticity in the Schaffer collateral-CA1 synapse. We observed a profound decrease in long-term potentiation (LTP) in the ventral hippocampus, whereas no effect on plasticity was evident in its dorsal portion. Furthermore, we demonstrated that acute perfusion of slices with an estrogen analogue equol, an isoflovane metabolized from daidzein produced by the bacterial flora in the gut, was able to rescue the observed LTP deficit. Examining potential behavioral correlates of the plasticity attenuation, we found that mice on phytoestrogen-free diet display decreased contextual fear memory at remote but not at recent time points after training.Conclusions: Our data suggests that nutritional phytoestrogens have profound effects on the plasticity in the ventral hippocampus and ventral hippocampus-dependent memory.

Glutamic acid decarboxylase 67 haplodeficiency in mice: consequences of postweaning social isolation on behavior and changes in brain neurochemical systems.

Reductions of glutamate acid decarboxylase (GAD67) and subsequent GABA levels have been consistently observed in neuropsychiatric disorders like schizophrenia and depression, but it has remained unclear how GABAergic dysfunction contributes to different symptoms of the diseases. To address this issue, we investigated male mice haplodeficient for GAD67 (GAD67+/GFP mice), which showed a reduced social interaction, social dominance and increased immobility in the forced swim test. No differences were found in rotarod performance and sensorimotor gating. We also addressed potential effects of social deprivation, which is known, during early life, to affect GABAergic function and induces behavioral abnormalities similar to the symptoms found in psychiatric disorders. Indeed, social isolation of GAD67+/GFP mice provoked increased rearing activity in the social interaction test and hyperlocomotion on elevated plus maze. Since GABA closely interacts with the dopaminergic, serotonergic and cholinergic neurotransmitter systems, we investigated GAD67+/GFP and GAD67+/+ mice for morphological markers of the latter systems and found increased tyrosine hydroxylase (TH)-IR fiber densities in CA1 of dorsal hippocampus. By contrast, no differences in numbers and densities of TH-positive neurons of the midbrain dopamine regions, serotonin (5-HT) neurons of the raphe nuclei, or choline acetyltransferase (ChAT)-expressing neurons of basal forebrain and their respective terminal fields were observed. Our results indicate that GAD67 haplodeficiency impairs sociability and increases vulnerability to social stress, provokes depressive-like behavior and alters the catecholaminergic innervation in brain areas associated with schizophrenia. GAD67+/GFP mice may provide a useful model for studying the impact of GABAergic dysfunction as related to neuropsychiatric disorders.

Mid-life microbiota crises: middle age is associated with pervasive neuroimmune alterations that are reversed by targeting the gut microbiome.

Male middle age is a transitional period where many physiological and psychological changes occur leading to cognitive and behavioural alterations, and a deterioration of brain function. However, the mechanisms underpinning such changes are unclear. The gut microbiome has been implicated as a key mediator in the communication between the gut and the brain, and in the regulation of brain homeostasis, including brain immune cell function. Thus, we tested whether targeting the gut microbiome by prebiotic supplementation may alter microglia activation and brain function in ageing. Male young adult (8 weeks) and middle-aged (10 months) C57BL/6 mice received diet enriched with a prebiotic (10% oligofructose-enriched inulin) or control chow for 14 weeks. Prebiotic supplementation differentially altered the gut microbiota profile in young and middle-aged mice with changes correlating with faecal metabolites. Functionally, this translated into a reversal of stress-induced immune priming in middle-aged mice. In addition, a reduction in ageing-induced infiltration of Ly-6Chi monocytes into the brain coupled with a reversal in ageing-related increases in a subset of activated microglia (Ly-6C+) was observed. Taken together, these data highlight a potential pathway by which targeting the gut microbiome with prebiotics can modulate the peripheral immune response and alter neuroinflammation in middle age. Our data highlight a novel strategy for the amelioration of age-related neuroinflammatory pathologies and brain function.

The gut microbiome in neurological disorders.

Research into the role of the gut microbiome in modulating brain function has rapidly increased over the past 10 years, albeit chiefly in animal models. Increasing clinical and preclinical evidence implicates the microbiome as a possible key susceptibility factor for neurological disorders, including Alzheimer's disease, autism spectrum disorder, multiple sclerosis, Parkinson's disease, and stroke. Cross-sectional clinical studies are bolstering the concept of altered microbial composition contributing to the pathophysiology of such diseases. However, the field is nascent, and interpretation of such data is often difficult given that the composition of the microbiome is influenced by various factors such as diet and exercise. Longitudinal studies and randomised controlled trials in humans are needed to find out if targeting the microbiome can yield novel therapeutic strategies. Systems biology approaches will also be important in integrating such data with genomic and metabolomic datasets from clinical cohorts with neurological disease to help guide individual treatment selection.

Dietary phytoestrogens modulate aggression and activity in social behavior circuits of male mice.

Phytoestrogens comprise biologically active constituents of human and animal diet that can impact on systemic and local estrogen functions in the brain. Here we report on the importance of dietary phytoestrogens for maintaining activity in a brain circuit controlling aggressive and social behavior of male mice. After six weeks of low-phytoestrogen chronic diet (diadzein plus genistein <20 µg/g) a reduction of intermale aggression and altered territorial marking behavior could be observed, compared to littermates on a standard soy-bean based diet (300 µg/g). Further, mice on low-phyto diet displayed a decrease in sociability and a reduced preference for social odors, indicating a general disturbance of social behavior. Underlying circuits were investigated by analysing the induction of the activity marker c-Fos upon social encounter. Low-phyto diet led to a markedly reduced c-Fos induction in the medial as well as the cortical amygdala, the lateral septum, medial preoptic area and bed nucleus of the stria terminalis. No difference between groups was observed in the olfactory bulb. Together our data suggest that dietary phytoestrogens critically modulate social behavior circuits in the male mouse brain.

The Gut Microbiome and Mental Health: What Should We Tell Our Patients?: Le microbiote Intestinal et la Santé Mentale : que Devrions-Nous dire à nos Patients?

The gut microbiome as a potential therapeutic target for mental illness is a hot topic in psychiatry. Trillions of bacteria reside in the human gut and have been shown to play a crucial role in gut-brain communication through an influence on neural, immune, and endocrine pathways. Patients with various psychiatric disorders including depression, bipolar disorder, schizophrenia, and autism spectrum disorder have been shown to have significant differences in the composition of their gut microbiome. Enhancing beneficial bacteria in the gut, for example, through the use of probiotics, prebiotics, or dietary change, has the potential to improve mood and reduce anxiety in both healthy people and patient groups. Much attention is being given to this subject in the general media, and patients are becoming increasingly interested in the potential to treat mental illness with microbiome-based therapies. It is imperative that those working with people with mental illness are aware of the rationale and current evidence base for such treatment strategies. In this review, we provide an overview of the gut microbiome, what it is, and what it does in relation to gut-brain communication and psychological function. We describe the fundamental principles and basic techniques used in microbiome-gut-brain axis research in an accessible way for a clinician audience. We summarize the current evidence in relation to microbiome-based strategies for various psychiatric disorders and provide some practical advice that can be given to patients seeking to try a probiotic for mental health benefit.

The Microbiota-Gut-Brain Axis.

The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within and on our bodies) as one of the key regulators of gut-brain function and has led to the appreciation of the importance of a distinct microbiota-gut-brain axis. This axis is gaining ever more traction in fields investigating the biological and physiological basis of psychiatric, neurodevelopmental, age-related, and neurodegenerative disorders. The microbiota and the brain communicate with each other via various routes including the immune system, tryptophan metabolism, the vagus nerve and the enteric nervous system, involving microbial metabolites such as short-chain fatty acids, branched chain amino acids, and peptidoglycans. Many factors can influence microbiota composition in early life, including infection, mode of birth delivery, use of antibiotic medications, the nature of nutritional provision, environmental stressors, and host genetics. At the other extreme of life, microbial diversity diminishes with aging. Stress, in particular, can significantly impact the microbiota-gut-brain axis at all stages of life. Much recent work has implicated the gut microbiota in many conditions including autism, anxiety, obesity, schizophrenia, Parkinson's disease, and Alzheimer's disease. Animal models have been paramount in linking the regulation of fundamental neural processes, such as neurogenesis and myelination, to microbiome activation of microglia. Moreover, translational human studies are ongoing and will greatly enhance the field. Future studies will focus on understanding the mechanisms underlying the microbiota-gut-brain axis and attempt to elucidate microbial-based intervention and therapeutic strategies for neuropsychiatric disorders.

From isoniazid to psychobiotics: the gut microbiome as a new antidepressant target.

An awareness of the importance of the gut-brain axis in psychiatric disorders such as depression is increasing. The gut microbiome is a key component of this axis. Gut bacteria can communicate with the brain through a variety of pathways including the hypothalamic-pituitary-adrenal axis, immune modulation, tryptophan metabolism and the production of various neuroactive compounds. Patients with depression, and other mood and anxiety disorders, show distinct compositional changes in their gut bacteria profile, raising the question about a possible aetiological role for the microbiome in these disorders. Evidence is emerging that the gut microbiome may represent a new potential antidepressant target and the term 'psychobiotic' has been coined to describe bacteria which confer mental health benefits. Gut bacteria are easily accessible and can be altered in a variety of ways including through the use of probiotics, prebiotics and dietary change. Psychobiotics containing various Lactobacillus and Bifidobacterium species have demonstrated the ability to improve mood, reduce anxiety and enhance cognitive function in both healthy populations and patient groups. This article provides an overview of the identification and development of antidepressant psychobiotics, from the preclinical evidence in the laboratory to the more recent encouraging results from human trials.

Gut Reactions: Breaking Down Xenobiotic-Microbiome Interactions.

The microbiome plays a key role in health and disease, and there has been considerable interest in therapeutic targeting of the microbiome as well as mining this rich resource in drug discovery efforts. However, a growing body of evidence suggests that the gut microbiota can itself influence the actions of a range of xenobiotics, in both beneficial and potentially harmful ways. Traditionally, clinical studies evaluating the pharmacokinetics of new drugs have mostly ignored the important direct and indirect effects of the gut microbiome on drug metabolism and efficacy. Despite some important observations from xenobiotic metabolism in general, there is only an incomplete understanding of the scope of influence of the microbiome specifically on drug metabolism and absorption, and how this might influence systemic concentrations of parent compounds and toxic metabolites. The significance of both microbial metabolism of xenobiotics and the impact of the gut microbiome on host hepatic enzyme systems is nonetheless gaining traction and presents a further challenge in drug discovery efforts, with implications for improving treatment outcomes or counteracting adverse drug reactions. Microbial factors must now be considered when determining drug pharmacokinetics and the impact that an evolving and dynamic microbiome could have in this regard. In this review, we aim to integrate the contribution of the gut microbiome in health and disease to xenobiotic metabolism focusing on therapeutic interventions, pharmacological drug action, and chemical biotransformations that collectively will have implications for the future practice of precision medicine.

The Neuroendocrinology of the Microbiota-Gut-Brain Axis: A Behavioural Perspective.

The human gut harbours trillions of symbiotic bacteria that play a key role in programming different aspects of host physiology in health and disease. These intestinal microbes are also key components of the gut-brain axis, the bidirectional communication pathway between the gut and the central nervous system (CNS). In addition, the CNS is closely interconnected with the endocrine system to regulate many physiological processes. An expanding body of evidence is supporting the notion that gut microbiota modifications and/or manipulations may also play a crucial role in the manifestation of specific behavioural responses regulated by neuroendocrine pathways. In this review, we will focus on how the intestinal microorganisms interact with elements of the host neuroendocrine system to modify behaviours relevant to stress, eating behaviour, sexual behaviour, social behaviour, cognition and addiction.

Finding the needle in the haystack: systematic identification of psychobiotics.

The brain-gut-microbiota axis is increasingly viewed as a novel paradigm in neuroscience with the capacity to generate innovative therapies for patients with psychiatric illnesses. Psychobiotics, defined as live bacteria, which when ingested in adequate amounts, confer mental health benefits, are increasingly of interest, as preclinical trials continue to show promising results. Particularly in stress-related, anxiety and depressive disorders, there is potential for psychobiotics to deliver new therapies. The question of which microbes may prove to be the most promising psychobiotic in delivering such therapies at a clinical level is of great importance. Here we look at the characteristics of psychobiotics, in an attempt to present an outline from which the identification of potential new psychobiotics may be possible. LINKED ARTICLES: This article is part of a themed section on When Pharmacology Meets the Microbiome: New Targets for Therapeutics? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.24/issuetoc.

Feeding the microbiota-gut-brain axis: diet, microbiome, and neuropsychiatry.

The microbial population residing within the human gut represents one of the most densely populated microbial niche in the human body with growing evidence showing it playing a key role in the regulation of behavior and brain function. The bidirectional communication between the gut microbiota and the brain, the microbiota-gut-brain axis, occurs through various pathways including the vagus nerve, the immune system, neuroendocrine pathways, and bacteria-derived metabolites. This axis has been shown to influence neurotransmission and the behavior that are often associated with neuropsychiatric conditions. Therefore, research targeting the modulation of this gut microbiota as a novel therapy for the treatment of various neuropsychiatric conditions is gaining interest. Numerous factors have been highlighted to influence gut microbiota composition, including genetics, health status, mode of birth, and environment. However, it is diet composition and nutritional status that has repeatedly been shown to be one of the most critical modifiable factors regulating the gut microbiota at different time points across the lifespan and under various health conditions. Thus the microbiota is poised to play a key role in nutritional interventions for maintaining brain health.

Between hype and veracity; privatization of municipal solid waste management and its impacts on the informal waste sector.

The informal waste recycling sector has been an indispensable but ironically invisible part of the waste management systems in developing countries as India, often completely disregarded and overlooked by decision makers and policy frameworks. The turn towards liberalization of economy since 1991 in India opened the doors for privatization of urban services and the waste sector found favor with private companies facilitated by the local governments. In joining the privatization bandwagon, the local governments aim to create an image of a progressive city demonstrated most visibly through apt management of municipal solid waste. Resultantly, the long important stakeholder, the informal sector has been sidelined and left to face the adverse impacts of privatization. There is hardly any recognition of its contributions or any attempt to integrate it within the formal waste management systems. The study investigates the impacts of privatization on the waste pickers in waste recycling operations. Highlighting the other dimension of waste collection and management in urban India the study focuses on the waste pickers and small time informal scrap dealers and this is done by taking the case study of Amritsar city, which is an important historic centre and a metropolitan city in the state of Punjab, India. The paper develops an analytical framework, drawing from literature review to analyze the impacts. In conclusion, it supports the case for involving informal waste sector towards achieving sustainable waste management in the city.

May the Force Be With You: The Light and Dark Sides of the Microbiota-Gut-Brain Axis in Neuropsychiatry.

The role of the gut microbiota in health and disease is becoming increasingly recognized. The microbiota-gut-brain axis is a bi-directional pathway between the brain and the gastrointestinal system. The bacterial commensals in our gut can signal to the brain through a variety of mechanisms, which are slowly being resolved. These include the vagus nerve, immune mediators and microbial metabolites, which influence central processes such as neurotransmission and behaviour. Dysregulation in the composition of the gut microbiota has been identified in several neuropsychiatric disorders, such as autism, schizophrenia and depression. Moreover, preclinical studies suggest that they may be the driving force behind the behavioural abnormalities observed in these conditions. Understanding how bacterial commensals are involved in regulating brain function may lead to novel strategies for development of microbiota-based therapies for these neuropsychiatric disorders.

Clinical diagnostics for homocysteine: a rogue amino acid?

Homocysteine has gathered considerable interest in recent years after being implicated in the pathogenesis of various clinical conditions. It has been an elusive target with many conflicting studies casting some confusion over its significance, and much more needs to be done to ascertain its pathophysiological role--especially with respect to regimes aimed at lowering its plasma concentration. Central to this is the development of robust analytical strategies for its determination. This review summarizes the clinical relevance of homocysteine as a diagnostic marker of disease and explores and critically assesses the detection methods that have been developed.

Mutation in the lysA gene impairs the symbiotic properties of Mesorhizobium ciceri.

A Tn5-induced mutant of Mesorhizobium ciceri, TL28, requiring the amino acid lysine for growth on minimal medium was isolated and characterized. The Tn5 insertion in the mutant strain TL28 was located on a 6.8-kb EcoRI fragment of the chromosomal DNA. Complementation analysis with cloned DNA indicated that 1.269 kb of DNA of the 6.8-kb EcoRI fragment restored the wild-type phenotype of the lysine-requiring mutant. This region was further characterized by DNA sequence analysis and was shown to contain a coding sequence homologous to lysA gene of different bacteria. The lys (-) mutant TL28 was unable to elicit development of effective nodules on the roots of Cicer arietinum L. There was no detectable level of lysine in the root exudates of chickpea. However, addition of lysine to the plant growth medium restored the ability of the mutant to produce effective nodules with nitrogen fixation ability on the roots of C. arietinum.