Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.
20 Sep 2011-Proceedings of the National Academy of Sciences of the United States of America (National Academy of Sciences)-Vol. 108, Iss: 38, pp 16050-16055
TL;DR: Chronic treatment with L. rhamnosus induced region-dependent alterations in GABAB1b mRNA in the brain with increases in cortical regions and concomitant reductions in expression in the hippocampus, amygdala, and locus coeruleus, in comparison with control-fed mice, highlighting the important role of bacteria in the bidirectional communication of the gut–brain axis.
Abstract: 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 GABAB1b mRNA in the brain with increases in cortical regions (cingulate and prelimbic) and concomitant reductions in expression in the hippocampus, amygdala, and locus coeruleus, in comparison with control-fed mice. In addition, L. rhamnosus (JB-1) reduced GABAAα2 mRNA expression in the prefrontal cortex and amygdala, but increased GABAAα2 in the hippocampus. Importantly, L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety- and depression-related behavior. Moreover, the neurochemical and behavioral effects were not found in vagotomized mice, identifying the vagus as a major modulatory constitutive communication pathway between the bacteria exposed to the gut and the brain. Together, these findings highlight the important role of bacteria in the bidirectional communication of the gut–brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stress-related disorders such as anxiety and depression.
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TL;DR: The emerging concept of a microbiota–gut–brain axis suggests that modulation of the gut microbiota may be a tractable strategy for developing novel therapeutics for complex CNS disorders.
Abstract: Recent years have witnessed the rise of the gut microbiota as a major topic of research interest in biology. Studies are revealing how variations and changes in the composition of the gut microbiota influence normal physiology and contribute to diseases ranging from inflammation to obesity. Accumulating data now indicate that the gut microbiota also communicates with the CNS — possibly through neural, endocrine and immune pathways — and thereby influences brain function and behaviour. Studies in germ-free animals and in animals exposed to pathogenic bacterial infections, probiotic bacteria or antibiotic drugs suggest a role for the gut microbiota in the regulation of anxiety, mood, cognition and pain. Thus, the emerging concept of a microbiota-gut-brain axis suggests that modulation of the gut microbiota may be a tractable strategy for developing novel therapeutics for complex CNS disorders.
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TL;DR: A gut-microbiome-brain connection in a mouse model of ASD is supported and a potential probiotic therapy for GI and particular behavioral symptoms in human neurodevelopmental disorders is identified.
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Cites background from "Ingestion of Lactobacillus strain r..."
...with Neurodevelopmental Disorders...
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...See also Figure S1. and depression inmice (Bravo et al., 2011; Ochoa-Repáraz et al., 2010), and the reported efficacy of probiotics in treating emotional symptoms of chronic fatigue syndrome and psychological distress in humans (Messaoudi et al., 2011; Rao et al., 2009)....
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...Furthermore, microbial treatment can ameliorate depressive (Bravo et al., 2011) and anxiety-like behavior (Bercik et al., 2011) in SPF mice, and probiotic treatment has been beneficial in treating psychological distress and chronic fatigue symptoms in humans (Messaoudi et al., 2011; Rao et al.,…...
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University of Wisconsin-Madison1, University of Hawaii2, University of Kiel3, Cornell University4, Max Planck Society5, Pasteur Institute6, Stanford University7, University of Helsinki8, University of Würzburg9, University of California, Berkeley10, University of New South Wales11, Harvard University12, California Institute of Technology13, University of Colorado Boulder14, University of Southern California15, University of North Carolina at Chapel Hill16, University of Connecticut17, Duke University18
TL;DR: Recent technological and intellectual advances that have changed thinking about five questions about how have bacteria facilitated the origin and evolution of animals; how do animals and bacteria affect each other’s genomes; how does normal animal development depend on bacterial partners; and how is homeostasis maintained between animals and their symbionts are highlighted.
Abstract: In the last two decades, the widespread application of genetic and genomic approaches has revealed a bacterial world astonishing in its ubiquity and diversity. This review examines how a growing knowledge of the vast range of animal–bacterial interactions, whether in shared ecosystems or intimate symbioses, is fundamentally altering our understanding of animal biology. Specifically, we highlight recent technological and intellectual advances that have changed our thinking about five questions: how have bacteria facilitated the origin and evolution of animals; how do animals and bacteria affect each other’s genomes; how does normal animal development depend on bacterial partners; how is homeostasis maintained between animals and their symbionts; and how can ecological approaches deepen our understanding of the multiple levels of animal–bacterial interaction. As answers to these fundamental questions emerge, all biologists will be challenged to broaden their appreciation of these interactions and to include investigations of the relationships between and among bacteria and their animal partners as we seek a better understanding of the natural world.
2,103 citations
Cites background from "Ingestion of Lactobacillus strain r..."
...synthesis in sight? Trends Genet 25(11):473–475....
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...AI-3 (quorum signal) (1) Epidermal growth-factor receptor (EGFr) Homoserine lactone(quorum signal) (2–4) ? Acetate(5) ? Butyrate (6, 7) G protein–coupled receptors (GPR41 and GPR43) Bile-acid derivatives (8) G protein–coupled bile acid receptor 1 (Gpbar1) Polysaccharide A (PSA) (9) ? Trimethylamine (TMA) (10) Macrophage scavenger receptor ? GABAA and GABAB (11) Tripeptides (12) Angiotensin converting enzyme (ACE) Invasion (13) Integrin Peptidoglycan (PGN) (14–16) NOD1 Lipopolysaccharide (LPS) (17) Toll-like receptor 4 (TLR4) Indole (18) Toll-like receptor 3/9 (TLR3/9) N-formyl peptides (19) Formyl peptide receptors Several other ligands (20) Other TLRs, NLRs, RLRs, lectins, etc....
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TL;DR: 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.
Abstract: 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 ...
1,775 citations
TL;DR: Recent findings showing that microbiota are important in normal healthy brain function are reviewed, and ongoing and future animal and clinical studies aimed at understanding the microbiota-gut-brain axis may provide novel approaches for prevention and treatment of mental illness.
1,710 citations
References
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TL;DR: A novel test for the selective identification of anxiolytic and anxiogenic drug effects in the rat is described, using an elevated + -maze consisting of two open arms and two enclosed arms, which showed that behaviour on the maze was not clearly correlated either with exploratory head-dipping or spontaneous locomotor activity.
5,391 citations
"Ingestion of Lactobacillus strain r..." refers methods in this paper
...The stress-induced hyperthermia (SIH) and elevated plus maze (EPM) tests are widely used for assessing functional consequences of alterations in GABA neurotransmission (22, 23)....
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TL;DR: An associative roles for the amygdala and a sensory relay role for the hippocampus are suggested in fear conditioning, which is involved in the conditioning of fear responses to simple, modality-specific conditioned stimuli as well as to complex, polymodal stimuli.
Abstract: The contribution of the amygdala and hippocampus to the acquisition of conditioned fear responses to a cue (a tone paired with footshock) and to context (background stimuli continuously present in the apparatus in which tone-shock pairings occurred) was examined in rats. In unoperated controls, responses to the cue conditioned faster and were more resistant to extinction than were responses to contextual stimuli. Lesions of the amygdala interfered with the conditioning of fear responses to both the cue and the context, whereas lesions of the hippocampus interfered with conditioning to the context but not to the cue. The amygdala is thus involved in the conditioning of fear responses to simple, modality-specific conditioned stimuli as well as to complex, polymodal stimuli, whereas the hippocampus is only involved in fear conditioning situations involving complex, polymodal events. These findings suggest an associative role for the amygdala and a sensory relay role for the hippocampus in fear conditioning.
2,891 citations
TL;DR: It is demonstrated that germ free (GF) mice display increased motor activity and reduced anxiety, compared with specific pathogen free (SPF) mice with a normal gut microbiota, suggesting that the microbial colonization process initiates signaling mechanisms that affect neuronal circuits involved in motor control and anxiety behavior.
Abstract: Microbial colonization of mammals is an evolution-driven process that modulate host physiology, many of which are associated with immunity and nutrient intake. Here, we report that colonization by gut microbiota impacts mammalian brain development and subsequent adult behavior. Using measures of motor activity and anxiety-like behavior, we demonstrate that germ free (GF) mice display increased motor activity and reduced anxiety, compared with specific pathogen free (SPF) mice with a normal gut microbiota. This behavioral phenotype is associated with altered expression of genes known to be involved in second messenger pathways and synaptic long-term potentiation in brain regions implicated in motor control and anxiety-like behavior. GF mice exposed to gut microbiota early in life display similar characteristics as SPF mice, including reduced expression of PSD-95 and synaptophysin in the striatum. Hence, our results suggest that the microbial colonization process initiates signaling mechanisms that affect neuronal circuits involved in motor control and anxiety behavior.
2,461 citations
"Ingestion of Lactobacillus strain r..." refers background in this paper
...Moreover, it has been shown that the absence and/or modification of the gut microflora in mice affects the hypothalamic–pituitary–adrenal (HPA) axis response to stress (6, 7) and anxiety behavior (8, 9), which is important given the high comorbidity between functional gastrointestinal disorders and stress-related psychiatric disorders, such as anxiety and depression (10)....
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TL;DR: Exposure to microbes at an early developmental stage is required for the HPA system to become fully susceptible to inhibitory neural regulation, and results suggest that commensal microbiota can affect the postnatal development of the Hpa stress response in mice.
Abstract: Indigenous microbiota have several beneficial effects on host physiological functions; however, little is known about whether or not postnatal microbial colonization can affect the development of brain plasticity and a subsequent physiological system response. To test the idea that such microbes may affect the development of neural systems that govern the endocrine response to stress, we investigated hypothalamic–pituitary–adrenal (HPA) reaction to stress by comparing germfree (GF), specific pathogen free (SPF) and gnotobiotic mice. Plasma ACTH and corticosterone elevation in response to restraint stress was substantially higher in GF mice than in SPF mice, but not in response to stimulation with ether. Moreover, GF mice also exhibited reduced brain-derived neurotrophic factor expression levels in the cortex and hippocampus relative to SPF mice. The exaggerated HPA stress response by GF mice was reversed by reconstitution with Bifidobacterium infantis. In contrast, monoassociation with enteropathogenic Escherichia coli, but not with its mutant strain devoid of the translocated intimin receptor gene, enhanced the response to stress. Importantly, the enhanced HPA response of GF mice was partly corrected by reconstitution with SPF faeces at an early stage, but not by any reconstitution exerted at a later stage, which therefore indicates that exposure to microbes at an early developmental stage is required for the HPA system to become fully susceptible to inhibitory neural regulation. These results suggest that commensal microbiota can affect the postnatal development of the HPA stress response in mice.
2,023 citations
"Ingestion of Lactobacillus strain r..." refers background in this paper
...Moreover, it has been shown that the absence and/or modification of the gut microflora in mice affects the hypothalamic–pituitary–adrenal (HPA) axis response to stress (6, 7) and anxiety behavior (8, 9), which is important given the high comorbidity between functional gastrointestinal disorders and stress-related psychiatric disorders, such as anxiety and depression (10)....
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TL;DR: Strains of mice that show characteristic patterns of behavior are critical for research in neurobehavioral genetics and experiments characterizing mutants may yield results that are idiosyncratic to a particular laboratory.
Abstract: Strains of mice that show characteristic patterns of behavior are critical for research in neurobehavioral genetics. Possible confounding influences of the laboratory environment were studied in several inbred strains and one null mutant by simultaneous testing in three laboratories on a battery of six behaviors. Apparatus, test protocols, and many environmental variables were rigorously equated. Strains differed markedly in all behaviors, and despite standardization, there were systematic differences in behavior across labs. For some tests, the magnitude of genetic differences depended upon the specific testing lab. Thus, experiments characterizing mutants may yield results that are idiosyncratic to a particular laboratory.
1,581 citations
"Ingestion of Lactobacillus strain r..." refers background in this paper
...One of the important aspects of these studies is that the behavioral changes observed were consistent across two different laboratories using slightly different protocols, which is important, given the perceived problems in replication of behavioral data between laboratories (47)....
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