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      Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders

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          The emerging links between our gut microbiome and the central nervous system (CNS) are regarded as a paradigm shift in neuroscience with possible implications for not only understanding the pathophysiology of stress-related psychiatric disorders, but also their treatment. Thus the gut microbiome and its influence on host barrier function is positioned to be a critical node within the brain-gut axis. Mounting preclinical evidence broadly suggests that the gut microbiota can modulate brain development, function and behavior by immune, endocrine and neural pathways of the brain-gut-microbiota axis. Detailed mechanistic insights explaining these specific interactions are currently underdeveloped. However, the concept that a “leaky gut” may facilitate communication between the microbiota and these key signaling pathways has gained traction. Deficits in intestinal permeability may underpin the chronic low-grade inflammation observed in disorders such as depression and the gut microbiome plays a critical role in regulating intestinal permeability. In this review we will discuss the possible role played by the gut microbiota in maintaining intestinal barrier function and the CNS consequences when it becomes disrupted. We will draw on both clinical and preclinical evidence to support this concept as well as the key features of the gut microbiota which are necessary for normal intestinal barrier function.

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          Most cited references 202

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          Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis.

          Toll-like receptors (TLRs) play a crucial role in host defense against microbial infection. The microbial ligands recognized by TLRs are not unique to pathogens, however, and are produced by both pathogenic and commensal microorganisms. It is thought that an inflammatory response to commensal bacteria is avoided due to sequestration of microflora by surface epithelia. Here, we show that commensal bacteria are recognized by TLRs under normal steady-state conditions, and this interaction plays a crucial role in the maintenance of intestinal epithelial homeostasis. Furthermore, we find that activation of TLRs by commensal microflora is critical for the protection against gut injury and associated mortality. These findings reveal a novel function of TLRs-control of intestinal epithelial homeostasis and protection from injury-and provide a new perspective on the evolution of host-microbial interactions.
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            Worlds within worlds: evolution of the vertebrate gut microbiota.

            In this Analysis we use published 16S ribosomal RNA gene sequences to compare the bacterial assemblages that are associated with humans and other mammals, metazoa and free-living microbial communities that span a range of environments. The composition of the vertebrate gut microbiota is influenced by diet, host morphology and phylogeny, and in this respect the human gut bacterial community is typical of an omnivorous primate. However, the vertebrate gut microbiota is different from free-living communities that are not associated with animal body habitats. We propose that the recently initiated international Human Microbiome Project should strive to include a broad representation of humans, as well as other mammalian and environmental samples, as comparative analyses of microbiotas and their microbiomes are a powerful way to explore the evolutionary history of the biosphere.
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              An ecological and evolutionary perspective on human-microbe mutualism and disease.

              The microbial communities of humans are characteristic and complex mixtures of microorganisms that have co-evolved with their human hosts. The species that make up these communities vary between hosts as a result of restricted migration of microorganisms between hosts and strong ecological interactions within hosts, as well as host variability in terms of diet, genotype and colonization history. The shared evolutionary fate of humans and their symbiotic bacteria has selected for mutualistic interactions that are essential for human health, and ecological or genetic changes that uncouple this shared fate can result in disease. In this way, looking to ecological and evolutionary principles might provide new strategies for restoring and maintaining human health.

                Author and article information

                Front Cell Neurosci
                Front Cell Neurosci
                Front. Cell. Neurosci.
                Frontiers in Cellular Neuroscience
                Frontiers Media S.A.
                14 October 2015
                : 9
                1Laboratory of Neurogastroenterology, APC Microbiome Institute, University College Cork Cork, Ireland
                2Department of Psychiatry and Neurobehavioural Science, University College Cork Cork, Ireland
                3Department of Anatomy and Neuroscience, University College Cork Cork, Ireland
                4Department of Pharmacology and Therapeutics, University College Cork Cork, Ireland
                Author notes

                Edited by: Brian David Gulbransen, Michigan State University, USA

                Reviewed by: Guillermo Tellez, University of Arkansas, USA; Wallace MacNaughton, University of Calgary, Canada

                *Correspondence: Gerard Clarke, Department of Psychiatry and Neurobehavioural Science, 1.15 Biosciences Institute, University College Cork, Cork, Ireland g.clarke@
                Copyright © 2015 Kelly, Kennedy, Cryan, Dinan, Clarke and Hyland.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 2, Tables: 3, Equations: 0, References: 309, Pages: 20, Words: 17789
                Funded by: Science Foundation Ireland 10.13039/501100001602
                Award ID: SFI/12/RC/2273
                Funded by: Health Research Board 10.13039/501100001590
                Award ID: HRA_POR/2011/23, HRA_POR/2012/32, HRA-POR-2-14-647
                Funded by: Seventh Framework Programme 10.13039/501100004963
                Award ID: FP7-KBBE-2013-7
                Funded by: Brain and Behavior Research Foundation 10.13039/100000874
                Award ID: 20771


                psychobiotics, gut microbiota, probiotics, depression, gut-brain axis, intestinal barrier


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