Gut microbiome and the brain

The Microbiome-Gut-Brain Axis in Health and Disease.: Gut microbes are capable of producing most neurotransmitters found in the human brain. Evidence is accumulating to support the view that gut microbes influence central neurochemistry and behavior. Irritable bowel syndrome is regarded as the prototypic disorder of the brain-gut-microbiota axis that can be responsive to probiotic therapy. Translational studies indicate that certain bacteria may have an impact on stress responses and cognitive functioning. Manipulating the gut microbiota with psych

The role of gut dysbiosis in Parkinson's disease: mechanistic insights and therapeutic options.: Parkinson's disease is a common neurodegenerative disorder in which gastrointestinal symptoms may appear prior to motor symptoms. The gut microbiota of patients with Parkinson's disease shows unique changes, which may be used as early biomarkers of disease. Alterations in the gut microbiota composition may be related to the cause or effect of motor or non-motor symptoms, but the specific pathogenic mechanisms are unclear. The gut microbiota and its metabolites have been suggested to be involved

How Microbes Affect Depression: Underlying Mechanisms via the Gut-Brain Axis and the Modulating Role of Probiotics.: Accumulating evidence suggests that the gut microbiome influences the brain functions and psychological state of its host via the gut-brain axis, and gut dysbiosis has been linked to several mental illnesses, including major depressive disorder (MDD). Animal experiments have shown that a depletion of the gut microbiota leads to behavioral changes, and is associated with pathological changes, including abnormal stress response and impaired adult neurogenesis. Short-chain fatty acids such as butyr

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

Psychological comorbidity in gastrointestinal diseases: Update on the brain-gut-microbiome axis.: The high comorbidity of psychological disorders in both functional and organic gastrointestinal diseases suggests the intimate and complex link between the brain and the gut. Termed the brain-gut axis, this bidirectional communication between the central nervous system and enteric nervous system relies on immune, endocrine, neural, and metabolic pathways. There is increasing evidence that the gut microbiome is a key part of this system, and dysregulation of the brain-gut-microbiome axis (BGMA) h

Probiotics and fructo-oligosaccharide intervention modulate the microbiota-gut brain axis to improve autism spectrum reducing also the hyper-serotonergic state and the dopamine metabolism disorder.: The prevalence of autism spectrum disorders (ASD) is increasing, but its etiology remains elusive and hence an effective treatment is not available. Previous research conducted on animal models suggests that microbiota-gut-brain axis may contribute to ASD pathology and more human research is needed. This study was divided into two stages,.At the discovery stage, we compared the differences in gut microbiota profiles (using 16S rRNA sequencing), fecal SCFAs (using GC-MS) and plasma neurotransmitt

Microbiota modulation counteracts Alzheimer's disease progression influencing neuronal proteolysis and gut hormones plasma levels.

Gut microbiota has a proven role in regulating multiple neuro-chemical pathways through the highly interconnected gut-brain axis. Oral bacteriotherapy thus has potential in the treatment of central nervous system-related pathologies, such as Alzheimer's disease (AD). Current AD treatments aim to prevent onset, delay progression and ameliorate symptoms. In this work, 3xTg-AD mice in the early stage of AD were treated with SLAB51 probiotic formulation, thereby affecting the composition of gut microbiota and its metabolites. This influenced plasma concentration of inflammatory cytokines and key metabolic hormones considered therapeutic targets in neurodegeneration. Treated mice showed partial restoration of two impaired neuronal proteolytic pathways (the ubiquitin proteasome system and autophagy). Their cognitive decline was decreased compared with controls, due to a reduction in brain dama…

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Reduced anxiety-like behavior and central neurochemical change in germ-free mice.

Background: There is increasing interest in the gut-brain axis and the role intestinal microbiota may play in communication between these two systems. Acquisition of intestinal microbiota in the immediate postnatal period has a defining impact on the development and function of the gastrointestinal, immune, neuroendocrine and metabolic systems. For example, the presence of gut microbiota regulates the set point for hypothalamic-pituitary-adrenal (HPA) axis activity. Methods: We investigated basal behavior of adult germ-free (GF), Swiss Webster female mice in the elevated plus maze (EPM) and compared this to conventionally reared specific pathogen free (SPF) mice. Additionally, we measured brain mRNA expression of genes implicated in anxiety and stress-reactivity. Key results: Germ-free mice, compared to SPF mice, exhibited basal behavior in the EPM that can be interpreted as anxiolytic. …

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Oral microbiome composition, but not diversity, is associated with adolescent anxiety and depression symptoms.

Purpose: Depression and anxiety are highly prevalent disorders, whose significant burden is compounded by the presence of oral disease. Mental health disorders and oral health may be associated via changes to the oral microbiome, involving increased pro-inflammatory communication and cortisol in saliva. The present study provides the first culture-independent investigation of the oral microbiome considering depression and anxiety symptoms in adolescence, a critical age where these conditions begin to emerge and co-occur. It also investigates whether inflammation and cortisol moderate these relationships. Methods: Participants (N = 66) aged 14-18 years (69.70% female) self-reported oral health, depression and anxiety symptoms, and collected saliva samples across two days. Saliva was assayed for cortisol and C-reactive protein (CRP), and used for 16S rRNA gene sequencing to estimate the or…

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Brain-gut-microbe communication in health and disease.

Bidirectional signalling between the gastrointestinal tract and the brain is regulated at neural, hormonal, and immunological levels. This construct is known as the brain-gut axis and is vital for maintaining homeostasis. Bacterial colonization of the intestine plays a major role in the post-natal development and maturation of the immune and endocrine systems. These processes are key factors underpinning central nervous system (CNS) signaling. Recent research advances have seen a tremendous improvement in our understanding of the scale, diversity, and importance of the gut microbiome. This has been reflected in the form of a revised nomenclature to the more inclusive brain-gut-enteric microbiota axis and a sustained research effort to establish how communication along this axis contributes to both normal and pathological conditions. In this review, we will briefly discuss the critical co…

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Gut dysbiosis induces the development of depression-like behavior through abnormal synapse pruning in microglia-mediated by complement C3.

Background: Remodeling eubiosis of the gut microenvironment may contribute to preventing the occurrence and development of depression. Mounting experimental evidence has shown that complement C3 signaling is associated with the pathogenesis of depression, and disruption of the gut microbiota may be an underlying cause of complement system activation. However, the mechanism by which complement C3 participates in gut-brain crosstalk in the pathogenesis of depression remains unknown. Results: In the present study, we found that chronic unpredictable mild stress (CUMS)-induced mice exhibited obvious depression-like behavior as well as cognitive impairment, which was associated with significant gut dysbiosis, especially enrichment of Proteobacteria and elevation of microbiota-derived lipopolysaccharides (LPS). In addition, peripheral and central complement C3 activation and central C3/CR3-med…

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The microbial metabolite desaminotyrosine enhances T-cell priming and cancer immunotherapy with immune checkpoint inhibitors.

Background: Inter-individual differences in response to immune checkpoint inhibitors (ICI) remain a major challenge in cancer treatment. The composition of the gut microbiome has been associated with differential ICI outcome, but the underlying molecular mechanisms remain unclear, and therapeutic modulation challenging. Methods: We established an in vivo model to treat C57Bl/6j mice with the type-I interferon (IFN-I)-modulating, bacterial-derived metabolite desaminotyrosine (DAT) to improve ICI therapy. Broad spectrum antibiotics were used to mimic gut microbial dysbiosis and associated ICI resistance. We utilized genetic mouse models to address the role of host IFN-I in DAT-modulated antitumour immunity. Changes in gut microbiota were assessed using 16S-rRNA sequencing analyses. Findings: We found that oral supplementation of mice with the microbial metabolite DAT delays tumour growth a…

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Probiotic treatment protects against the pro-depressant-like effect of high-fat diet in Flinders Sensitive Line rats.

Major depressive disorder (MDD) is highly associated with dysmetabolic conditions, such as obesity and diabetes mellitus type 2, and the gut microbiota may interact with both disease entities. We have previously shown that a high-fat diet (HFD) exacerbated depressive-like behaviour uniquely in Flinders Sensitive Line (FSL) rats that inherently present with an increased level of depressive-like behaviour compared with Flinders Resistant Line (FRL) rats. We therefore investigated whether multispecies probiotics possessed anti-depressant-like effect in FSL rats or protected against the pro-depressant-like effect of HFD. We also examined blood and cerebral T cell subsets as well as plasma cytokines. Lastly, we investigated the effect of HFD in outbred Sprague-Dawley (SD) rats to substantiate the association between depressive-like behaviour and any immunological measures affected by HFD. HFD…

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Administration of Lactobacillus helveticus NS8 improves behavioral, cognitive, and biochemical aberrations caused by chronic restraint stress.

Increasing numbers of studies have suggested that the gut microbiota is involved in the pathophysiology of stress-related disorders. Chronic stress can cause behavioral, cognitive, biochemical, and gut microbiota aberrations. Gut bacteria can communicate with the host through the microbiota-gut-brain axis (which mainly includes the immune, neuroendocrine, and neural pathways) to influence brain and behavior. It is hypothesized that administration of probiotics can improve chronic-stress-induced depression. In order to examine this hypothesis, the chronic restraint stress depression model was established in this study. Adult specific pathogen free (SPF) Sprague-Dawley rats were subjected to 21 days of restraint stress followed by behavioral testing (including the sucrose preference test (SPT), elevated-plus maze test, open-field test (OFT), object recognition test (ORT), and object placem…

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Bifidobacteria exert strain-specific effects on stress-related behavior and physiology in BALB/c mice.

Background: Accumulating evidence suggests that commensal bacteria consumption has the potential to have a positive impact on stress-related psychiatric disorders. However, the specific bacteria influencing behaviors related to anxiety and depression remain unclear. To this end, we compared the effects of two different Bifidobacteria on anxiety and depression-like behavior; an antidepressant was also used as a comparator. Methods: Innately anxious BALB/c mice received daily Bifidobacterium longum (B.) 1714, B. breve 1205, the antidepressant escitalopram or vehicle treatment for 6 weeks. Behavior was assessed in stress-induced hyperthermia test, marble burying, elevated plus maze, open field, tail suspension test, and forced swim test. Physiological responses to acute stress were also assessed. Key results: Both Bifidobacteria and escitalopram reduced anxiety in the marble burying test; h…

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Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.

There is increasing, but largely indirect, evidence pointing to an effect of commensal gut microbiota on the central nervous system (CNS). However, it is unknown whether lactic acid bacteria such as Lactobacillus rhamnosus could have a direct effect on neurotransmitter receptors in the CNS in normal, healthy animals. GABA is the main CNS inhibitory neurotransmitter and is significantly involved in regulating many physiological and psychological processes. Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with functional bowel disorders. In this work, we show that chronic treatment with L. rhamnosus (JB-1) induced region-dependent alterations in GABA(B1b) mRNA in the brain with increases in cortical regions (cingulate and prelimbic) and concomitant reductions in expression in the hippocampus, amygdala, a…

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Characterization of gut microbiome in mice model of depression with divergent response to escitalopram treatment.

Depression is a common and heterogeneous mental disorder. Although several antidepressants are available to treat the patients with depression, the factors which could affect and predict the treatment response remain unclear. Here, we characterize the longitudinal changes of microbial composition and function during escitalopram treatment in chronic unpredictable mild stress (CUMS) mice model of depression based on 16 S rRNA sequencing and metabolomics. Consequently, we found that escitalopram (ESC) administration serves to increase the alpha-diversity of the gut microbiome in ESC treatment group. The microbial signatures between responder (R) and non-responder (NR) groups were significantly different. The R group was mainly characterized by increased relative abundances of genus Prevotellaceae_UCG-003, and depleted families Ruminococcaceae and Lactobacillaceae relative to NR group. More…

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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 m…

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High-fat diet induces depression-like behaviour in mice associated with changes in microbiome, neuropeptide Y, and brain metabolome.

Objectives: The biological mechanisms linking diet-related obesity and depression remain unclear. Therefore, we examined the impact of high-fat diet (HFD) on murine behaviour, intestinal microbiome, brain metabolome, neuropeptide Y (NPY) expression, and dipeptidyl peptidase-4 (DPP-4) activity. Methods: Male C57Bl/6J mice were fed an HFD (60 kJ% from fat) or control diet (12 kJ% from fat) for 8 weeks, followed by behavioural phenotyping. Caecal microbiome was analysed by 16S rDNA sequencing, brain metabolome by 1H nuclear magnetic resonance, NPY expression by PCR and immunoassay, and dipeptidyl peptidase-4 (DPP-4) activity by enzymatic assay. The effect of a 4-week treatment with imipramine (7 mg/kg/day) and the DPP-4 inhibitor sitagliptin (50 mg/kg/day) on HFD-induced behavioural changes was also tested. Results: HFD led to a depression-like phenotype as revealed by reduced sociability a…

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Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring.

Maternal immune activation (MIA) contributes to behavioural abnormalities associated with neurodevelopmental disorders in both primate and rodent offspring. In humans, epidemiological studies suggest that exposure of fetuses to maternal inflammation increases the likelihood of developing autism spectrum disorder. In pregnant mice, interleukin-17a (IL-17a) produced by T helper 17 (TH17) cells (CD4+ T helper effector cells involved in multiple inflammatory conditions) induces behavioural and cortical abnormalities in the offspring exposed to MIA. However, it is unclear whether other maternal factors are required to promote MIA-associated phenotypes. Moreover, the underlying mechanisms by which MIA leads to T cell activation with increased IL-17a in the maternal circulation are not well understood. Here we show that MIA phenotypes in offspring require maternal intestinal bacteria that promo…

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Gut-microbiome-expressed 3β-hydroxysteroid dehydrogenase degrades estradiol and is linked to depression in premenopausal females.

Estradiol decline can result in depressive disorders in females; nevertheless, the causes of this decline are unclear. In this study, we isolated estradiol-degrading Klebsiella aerogenes from the feces of premenopausal females with depression. In mice, gavaging with this strain led to estradiol decline and depression-like behaviors. The gene encoding the estradiol-degrading enzyme in K. aerogenes was identified as 3β-hydroxysteroid dehydrogenase (3β-HSD). Heterologously expressing 3β-HSD resulted in Escherichia coli obtaining the ability to degrade estradiol. Gavaging mice with 3β-HSD-expressing E. coli decreased their serum estradiol levels, causing depression-like behaviors. The prevalence of K. aerogene and 3β-HSD was higher in premenopausal women with depression than in those without depression. These results suggest that the estradiol-degrading bacteria and 3β-HSD enzymes are potent…

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A restructuring of microbiome niche space is associated with Elexacaftor-Tezacaftor-Ivacaftor therapy in the cystic fibrosis lung.

Background: Elexacaftor-Tezacaftor-Ivacaftor (ETI) therapy is showing promising efficacy for treatment of cystic fibrosis (CF) and is becoming more widely available since recent FDA approval. However, little is known about how these drugs will affect lung infections, which are the leading cause of morbidity and mortality among people with CF (pwCF). Methods: We analyzed sputum microbiome and metabolome data from pwCF (n=24) before and after ETI therapy using 16S rRNA gene sequencing and untargeted metabolomics. Results: The sputum microbiome diversity, particularly its evenness, was increased (p=0.036) and the microbiome profiles were different between individuals before and after therapy (PERMANOVA F=1.92, p=0.044). Despite these changes, the microbiomes remained more similar within an individual than across the sampled population. No specific microbial taxa differed in relative abundan…

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Microbial interaction promote the degradation rate of organic matter in thermophilic period.

Composting is an efficient, microbe-driven method for the biodegradation of solid organic substrates. In such a complex engineering ecosystem, microbial interaction is more important to function than relative abundance and alpha diversity. However, microbial interaction and its driving force in the composting process has been rarely reported. Thus, we combined network analysis and positive cohesion to analyze the relationship between cooperation among bacteria taxa and the degradation of organic matter in ten industrial-scale food waste composting piles. The results showed that although the complexity of network and microbial diversity were inhibited by high temperature, microbial cooperation was stimulated in the thermophilic period. The positive cohesion, which reflected the degree of microbial cooperation, tended to be positively correlated with the degradation rate of organic matter,…

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Microbial community coalescence: does it matter in the Three Gorges Reservoir?

The microbial community coalescence describes the mixing of microbial communities and the merging of their surrounding environments. Despite its prevalence in natural ecosystems and its potential influence on ecological processes, little research focused on the extent of coalescence between aquatic microbial communities. In this research, we analyzed the microbial communities in the Three Gorges Reservoir, a typical deep-water reservoir on the Yangtze River. The biogeography and the coalescence of microbial communities in water and sediment were illustrated and analyzed based on 16S rRNA gene amplicon sequence variants (ASVs). Differences in composition and diversity were identified between microbial communities in water and sediment, and microbial communities in sediment were more diverse than those in water. Between adjacent communities, by calculating the proportion of overlapped taxa…

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INTEDE: interactome of drug-metabolizing enzymes.

Drug-metabolizing enzymes (DMEs) are critical determinant of drug safety and efficacy, and the interactome of DMEs has attracted extensive attention. There are 3 major interaction types in an interactome: microbiome-DME interaction (MICBIO), xenobiotics-DME interaction (XEOTIC) and host protein-DME interaction (HOSPPI). The interaction data of each type are essential for drug metabolism, and the collective consideration of multiple types has implication for the future practice of precision medicine. However, no database was designed to systematically provide the data of all types of DME interactions. Here, a database of the Interactome of Drug-Metabolizing Enzymes (INTEDE) was therefore constructed to offer these interaction data. First, 1047 unique DMEs (448 host and 599 microbial) were confirmed, for the first time, using their metabolizing drugs. Second, for these newly confirmed DMEs…

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Variations in the oral microbiome are associated with depression in young adults.

A growing body of evidence supports an important role for alterations in the brain-gut-microbiome axis in the aetiology of depression and other psychiatric disorders. The potential role of the oral microbiome in mental health has received little attention, even though it is one of the most diverse microbiomes in the body and oral dysbiosis has been linked to systemic diseases with an underlying inflammatory aetiology. This study examines the structure and composition of the salivary microbiome for the first time in young adults who met the DSM-IV criteria for depression (n = 40) and matched controls (n = 43) using 16S rRNA gene-based next generation sequencing. Subtle but significant differences in alpha and beta diversity of the salivary microbiome were observed, with clear separation of depressed and healthy control cohorts into distinct clusters. A total of 21 bacterial taxa were foun…

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Higher temperatures generically favour slower-growing bacterial species in multispecies communities.

Temperature is one of the fundamental environmental variables that determine the composition and function of microbial communities. However, a predictive understanding of how microbial communities respond to changes in temperature is lacking, partly because it is not obvious which aspects of microbial physiology determine whether a species could benefit from a change in the temperature. Here we incorporate how microbial growth rates change with temperature into a modified Lotka-Volterra competition model and predict that higher temperatures should-in general-favour the slower-growing species in a bacterial community. We experimentally confirm this prediction in pairwise cocultures assembled from a diverse set of species and show that these changes to pairwise outcomes with temperature are also predictive of changing outcomes in three-species communities, suggesting that our theory may be…

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Cohesion: a method for quantifying the connectivity of microbial communities.

The ability to predict microbial community dynamics lags behind the quantity of data available in these systems. Most predictive models use only environmental parameters, although a long history of ecological literature suggests that community complexity should also be an informative parameter. Thus, we hypothesize that incorporating information about a community's complexity might improve predictive power in microbial models. Here, we present a new metric, called community 'cohesion,' that quantifies the degree of connectivity of a microbial community. We analyze six long-term (10+ years) microbial data sets using the cohesion metrics and validate our approach using data sets where absolute abundances of taxa are available. As a case study of our metrics' utility, we show that community cohesion is a strong predictor of Bray-Curtis dissimilarity (R2=0.47) between phytoplankton communiti…

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Enteric neurons and systemic signals couple nutritional and reproductive status with intestinal homeostasis.

The gastrointestinal tract is emerging as a key regulator of appetite and metabolism, but daunting neuroanatomical complexity has hampered identification of the relevant signals. Invertebrate models could provide a simple and genetically amenable alternative, but their autonomic nervous system and its visceral functions remain largely unexplored. Here we develop a quantitative method based on defecation behavior to uncover a central role for the Drosophila intestine in the regulation of nutrient intake, fluid, and ion balance. We then identify a key homeostatic role for autonomic neurons and hormones, including a brain-gut circuit of insulin-producing neurons modulating appetite, a vasopressin-like system essential for fluid homeostasis, and enteric neurons mediating sex peptide-induced changes in intestinal physiology. These conserved mechanisms of visceral control, analogous to those f…

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99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: darwinian medicine and the 'hygiene' or 'old friends' hypothesis.

The current synthesis of the 'hygiene hypothesis' suggests that the recent increase in chronic inflammatory disorders is at least partly attributable to immunodysregulation resulting from lack of exposure to microorganisms that have evolved an essential role in the establishment of the immune system. This document provides a background for discussion of the following propositions. 1. The essential role of these organisms is an example of 'evolved dependence'. 2. The most relevant organisms are those that co-evolved with mammals, and already accompanied early hominids in the Paleolithic. 3. More recently evolved 'childhood infections' are not likely to have evolved this role, and recent epidemiology supports this contention. 4. This mechanism is interacting with other modern environmental changes that also lead to enhanced inflammatory responses [inappropriate diet, obesity, psychological…

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Upper intestinal lipids trigger a gut-brain-liver axis to regulate glucose production.

Energy and glucose homeostasis are regulated by food intake and liver glucose production, respectively. The upper intestine has a critical role in nutrient digestion and absorption. However, studies indicate that upper intestinal lipids inhibit food intake as well in rodents and humans by the activation of an intestine-brain axis. In parallel, a brain-liver axis has recently been proposed to detect blood lipids to inhibit glucose production in rodents. Thus, we tested the hypothesis that upper intestinal lipids activate an intestine-brain-liver neural axis to regulate glucose homeostasis. Here we demonstrate that direct administration of lipids into the upper intestine increased upper intestinal long-chain fatty acyl-coenzyme A (LCFA-CoA) levels and suppressed glucose production. Co-infusion of the acyl-CoA synthase inhibitor triacsin C or the anaesthetic tetracaine with duodenal lipids …

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