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      Current Perspectives on Gut Microbiome Dysbiosis and Depression

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          Abstract

          The human gut microbiome partakes in a bidirectional communication pathway with the central nervous system (CNS), named the microbiota–gut–brain axis. The microbiota–gut–brain axis is believed to modulate various central processes through the vagus nerve as well as production of microbial metabolites and immune mediators which trigger changes in neurotransmission, neuroinflammation, and behavior. Little is understood about the utilization of microbiome manipulation to treat disease. Though studies exploring the role of the microbiome in various disease processes have shown promise, mechanisms remain unclear and evidence-based treatments for most illnesses have not yet been developed. The animal studies reviewed here offer an excellent array of basic science research that continues to clarify mechanisms by which the microbiome may affect mental health. More evidence is needed, particularly as it relates to translating this work to human subjects. The studies presented in this paper largely demonstrate encouraging results in the treatment of depression. Limitations include small sample sizes and heterogeneous methodology. The exact mechanism by which the gut microbiota causes or alters neuropsychiatric disease states is not fully understood. In this review, we focus on recent studies investigating the relationship between gut microbiome dysbiosis and the pathogenesis of depression. This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.

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          Most cited references19

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          Short-Term Antibiotic Treatment Has Differing Long-Term Impacts on the Human Throat and Gut Microbiome

          Antibiotic administration is the standard treatment for the bacterium Helicobacter pylori, the main causative agent of peptic ulcer disease and gastric cancer. However, the long-term consequences of this treatment on the human indigenous microbiota are relatively unexplored. Here we studied short- and long-term effects of clarithromycin and metronidazole treatment, a commonly used therapy regimen against H. pylori, on the indigenous microbiota in the throat and in the lower intestine. The bacterial compositions in samples collected over a four-year period were monitored by analyzing the 16S rRNA gene using 454-based pyrosequencing and terminal-restriction fragment length polymorphism (T-RFLP). While the microbial communities of untreated control subjects were relatively stable over time, dramatic shifts were observed one week after antibiotic treatment with reduced bacterial diversity in all treated subjects in both locations. While the microbiota of the different subjects responded uniquely to the antibiotic treatment some general trends could be observed; such as a dramatic decline in Actinobacteria in both throat and feces immediately after treatment. Although the diversity of the microbiota subsequently recovered to resemble the pre treatment states, the microbiota remained perturbed in some cases for up to four years post treatment. In addition, four years after treatment high levels of the macrolide resistance gene erm(B) were found, indicating that antibiotic resistance, once selected for, can persist for longer periods of time than previously recognized. This highlights the importance of a restrictive antibiotic usage in order to prevent subsequent treatment failure and potential spread of antibiotic resistance.
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            Gastrointestinal flora and gastrointestinal status in children with autism -- comparisons to typical children and correlation with autism severity

            Background Children with autism have often been reported to have gastrointestinal problems that are more frequent and more severe than in children from the general population. Methods Gastrointestinal flora and gastrointestinal status were assessed from stool samples of 58 children with Autism Spectrum Disorders (ASD) and 39 healthy typical children of similar ages. Stool testing included bacterial and yeast culture tests, lysozyme, lactoferrin, secretory IgA, elastase, digestion markers, short chain fatty acids (SCFA's), pH, and blood presence. Gastrointestinal symptoms were assessed with a modified six-item GI Severity Index (6-GSI) questionnaire, and autistic symptoms were assessed with the Autism Treatment Evaluation Checklist (ATEC). Results Gastrointestinal symptoms (assessed by the 6-GSI) were strongly correlated with the severity of autism (assessed by the ATEC), (r = 0.59, p < 0.001). Children with 6-GSI scores above 3 had much higher ATEC Total scores than those with 6-GSI-scores of 3 or lower (81.5 +/- 28 vs. 49.0 +/- 21, p = 0.00002). Children with autism had much lower levels of total short chain fatty acids (-27%, p = 0.00002), including lower levels of acetate, proprionate, and valerate; this difference was greater in the children with autism taking probiotics, but also significant in those not taking probiotics. Children with autism had lower levels of species of Bifidobacter (-43%, p = 0.002) and higher levels of species of Lactobacillus (+100%, p = 0.00002), but similar levels of other bacteria and yeast using standard culture growth-based techniques. Lysozyme was somewhat lower in children with autism (-27%, p = 0.04), possibly associated with probiotic usage. Other markers of digestive function were similar in both groups. Conclusions The strong correlation of gastrointestinal symptoms with autism severity indicates that children with more severe autism are likely to have more severe gastrointestinal symptoms and vice versa. It is possible that autism symptoms are exacerbated or even partially due to the underlying gastrointestinal problems. The low level of SCFA's was partly associated with increased probiotic use, and probably partly due to either lower production (less sacchrolytic fermentation by beneficial bacteria and/or lower intake of soluble fiber) and/or greater absorption into the body (due to longer transit time and/or increased gut permeability).
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              Ketamine blocks bursting in the lateral habenula to rapidly relieve depression

              The N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine has attracted enormous interest in mental health research owing to its rapid antidepressant actions, but its mechanism of action has remained elusive. Here we show that blockade of NMDAR-dependent bursting activity in the 'anti-reward center', the lateral habenula (LHb), mediates the rapid antidepressant actions of ketamine in rat and mouse models of depression. LHb neurons show a significant increase in burst activity and theta-band synchronization in depressive-like animals, which is reversed by ketamine. Burst-evoking photostimulation of LHb drives behavioural despair and anhedonia. Pharmacology and modelling experiments reveal that LHb bursting requires both NMDARs and low-voltage-sensitive T-type calcium channels (T-VSCCs). Furthermore, local blockade of NMDAR or T-VSCCs in the LHb is sufficient to induce rapid antidepressant effects. Our results suggest a simple model whereby ketamine quickly elevates mood by blocking NMDAR-dependent bursting activity of LHb neurons to disinhibit downstream monoaminergic reward centres, and provide a framework for developing new rapid-acting antidepressants.
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                Author and article information

                Contributors
                iurits@bidmc.harvard.edu
                Journal
                Adv Ther
                Adv Ther
                Advances in Therapy
                Springer Healthcare (Cheshire )
                0741-238X
                1865-8652
                4 March 2020
                4 March 2020
                2020
                : 37
                : 4
                : 1328-1346
                Affiliations
                [1 ]GRID grid.213910.8, ISNI 0000 0001 1955 1644, Georgetown University School of Medicine, ; Washington, DC USA
                [2 ]GRID grid.38142.3c, ISNI 000000041936754X, Department of Anesthesiology, Critical Care, and Pain Medicine, Beth Israel Deaconess Medical Center, , Harvard Medical School, ; Boston, MA USA
                [3 ]GRID grid.134563.6, ISNI 0000 0001 2168 186X, University of Arizona College of Medicine-Phoenix, ; Phoenix, AZ USA
                [4 ]GRID grid.38142.3c, ISNI 000000041936754X, Harvard-MIT Division of Health Sciences and Technology, , Harvard Medical School, ; Boston, MA USA
                [5 ]GRID grid.410396.9, ISNI 0000 0004 0430 4458, Department of Anesthesiology, , Mt. Sinai Medical Center of Florida, ; Miami Beach, FL USA
                [6 ]Pain Specialty Group, Department of Pain Medicine, Newington, NH USA
                [7 ]GRID grid.38142.3c, ISNI 000000041936754X, Harvard Medical School, ; Boston, MA USA
                [8 ]GRID grid.14003.36, ISNI 0000 0001 2167 3675, Department of Anesthesiology, , University of Wisconsin School of Medicine and Public Health, ; Madison, WI USA
                [9 ]GRID grid.411417.6, ISNI 0000 0004 0443 6864, Department of Anesthesiology, , Louisiana State University Health Sciences Center, ; Shreveport, LA USA
                [10 ]Valley Anesthesiology and Pain Consultants-Envision Physician Services, Phoenix, AZ USA
                [11 ]GRID grid.254748.8, ISNI 0000 0004 1936 8876, Department of Anesthesiology, , Creighton University School of Medicine, ; Omaha, NE USA
                [12 ]GRID grid.134563.6, ISNI 0000 0001 2168 186X, Department of Anesthesiology, , University of Arizona College of Medicine-Phoenix, ; Phoenix, AZ USA
                Author information
                http://orcid.org/0000-0002-3652-6085
                Article
                1272
                10.1007/s12325-020-01272-7
                7140737
                32130662
                6c87ce6e-36e7-48aa-96ce-d196ae38c6d8
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

                History
                : 13 January 2020
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                Review
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                © Springer Healthcare Ltd., part of Springer Nature 2020

                depression,dysbiosis,gut microbiome
                depression, dysbiosis, gut microbiome

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