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      Gut Microbiota and the Neuroendocrine System

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          Abstract

          The microbial ecosystem that inhabits the gastrointestinal tract of all mammals—the gut microbiota—has been in a symbiotic relationship with its hosts over many millennia. Thanks to modern technology, the myriad of functions that are controlled or modulated by the gut microbiota are beginning to unfold. One of the systems that is emerging to closely interact with the gut microbiota is the body’s major neuroendocrine system that controls various body processes in response to stress, the hypothalamic–pituitary–adrenal (HPA) axis. This interaction is of pivotal importance; as various disorders of the microbiota–gut–brain axis are associated with dysregulation of the HPA axis. The present contribution describes the bidirectional communication between the gut microbiota and the HPA axis and delineates the potential underlying mechanisms. In this regard, it is important to note that the communication between the gut microbiota and the HPA axis is closely interrelated with other systems, such as the immune system, the intestinal barrier and blood–brain barrier, microbial metabolites, and gut hormones, as well as the sensory and autonomic nervous systems. These communication pathways will be exemplified through preclinical models of early life stress, beneficial roles of probiotics and prebiotics, evidence from germ-free mice, and antibiotic-induced modulation of the gut microbiota.

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          The online version of this article (10.1007/s13311-017-0600-5) contains supplementary material, which is available to authorized users.

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          Most cited references69

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          Epigenetic programming by maternal behavior.

          Here we report that increased pup licking and grooming (LG) and arched-back nursing (ABN) by rat mothers altered the offspring epigenome at a glucocorticoid receptor (GR) gene promoter in the hippocampus. Offspring of mothers that showed high levels of LG and ABN were found to have differences in DNA methylation, as compared to offspring of 'low-LG-ABN' mothers. These differences emerged over the first week of life, were reversed with cross-fostering, persisted into adulthood and were associated with altered histone acetylation and transcription factor (NGFI-A) binding to the GR promoter. Central infusion of a histone deacetylase inhibitor removed the group differences in histone acetylation, DNA methylation, NGFI-A binding, GR expression and hypothalamic-pituitary-adrenal (HPA) responses to stress, suggesting a causal relation among epigenomic state, GR expression and the maternal effect on stress responses in the offspring. Thus we show that an epigenomic state of a gene can be established through behavioral programming, and it is potentially reversible.
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            Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells.

            Commensal microbes can have a substantial impact on autoimmune disorders, but the underlying molecular and cellular mechanisms remain largely unexplored. We report that autoimmune arthritis was strongly attenuated in the K/BxN mouse model under germ-free (GF) conditions, accompanied by reductions in serum autoantibody titers, splenic autoantibody-secreting cells, germinal centers, and the splenic T helper 17 (Th17) cell population. Neutralization of interleukin-17 prevented arthritis development in specific-pathogen-free K/BxN mice resulting from a direct effect of this cytokine on B cells to inhibit germinal center formation. The systemic deficiencies of the GF animals reflected a loss of Th17 cells from the small intestinal lamina propria. Introduction of a single gut-residing species, segmented filamentous bacteria, into GF animals reinstated the lamina propria Th17 cell compartment and production of autoantibodies, and arthritis rapidly ensued. Thus, a single commensal microbe, via its ability to promote a specific Th cell subset, can drive an autoimmune disease. Copyright 2010 Elsevier Inc. All rights reserved.
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              Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis.

              Although the effects of commensal bacteria on intestinal immune development seem to be profound, it remains speculative whether the gut microbiota influences extraintestinal biological functions. Multiple sclerosis (MS) is a devastating autoimmune disease leading to progressive deterioration of neurological function. Although the cause of MS is unknown, microorganisms seem to be important for the onset and/or progression of disease. However, it is unclear how microbial colonization, either symbiotic or infectious, affects autoimmunity. Herein, we investigate a role for the microbiota during the induction of experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Mice maintained under germ-free conditions develop significantly attenuated EAE compared with conventionally colonized mice. Germ-free animals, induced for EAE, produce lower levels of the proinflammatory cytokines IFN-γ and IL-17A in both the intestine and spinal cord but display a reciprocal increase in CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs). Mechanistically, we show that gut dendritic cells from germ-free animals are reduced in the ability to stimulate proinflammatory T cell responses. Intestinal colonization with segmented filamentous bacteria (SFB) is known to promote IL-17 production in the gut; here, we show that SFBs also induced IL-17A-producing CD4(+) T cells (Th17) in the CNS. Remarkably, germ-free animals harboring SFBs alone developed EAE, showing that gut bacteria can affect neurologic inflammation. These findings reveal that the intestinal microbiota profoundly impacts the balance between pro- and antiinflammatory immune responses during EAE and suggest that modulation of gut bacteria may provide therapeutic targets for extraintestinal inflammatory diseases such as MS.
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                Author and article information

                Contributors
                aitak.farzi@medunigraz.at
                Journal
                Neurotherapeutics
                Neurotherapeutics
                Neurotherapeutics
                Springer US (New York )
                1933-7213
                1878-7479
                27 January 2018
                27 January 2018
                January 2018
                : 15
                : 1
                : 5-22
                Affiliations
                [1 ]ISNI 0000 0000 8988 2476, GRID grid.11598.34, Otto Loewi Research Center, Pharmacology Section, , Medical University of Graz, ; Graz, Austria
                [2 ]GRID grid.452216.6, BioTechMed-Graz, ; Graz, Austria
                Author information
                http://orcid.org/0000-0001-9606-3871
                Article
                600
                10.1007/s13311-017-0600-5
                5794709
                29380303
                5483b9a6-dd44-48e5-9fe2-703da94dc6e1
                © The Author(s) 2018

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100002428, Austrian Science Fund;
                Award ID: P23097-B18
                Award ID: P25912-B23
                Award ID: W1241-B18
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100004955, Österreichische Forschungsförderungsgesellschaft;
                Categories
                Review
                Custom metadata
                © The American Society for Experimental NeuroTherapeutics, Inc. 2018

                Neurology
                antibiotics,corticosterone,germ-free mice,hpa axis,probiotics,stress
                Neurology
                antibiotics, corticosterone, germ-free mice, hpa axis, probiotics, stress

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