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      Abnormal composition of gut microbiota contributes to delirium‐like behaviors after abdominal surgery in mice

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          Summary

          Aims

          Anesthesia and surgery can cause delirium‐like symptoms postoperatively. Increasing evidence suggests that gut microbiota is a physiological regulator of the brain. Herein, we investigated whether gut microbiota plays a role in postoperative delirium (POD).

          Methods

          Mice were separated into non‐POD and POD phenotypes after abdominal surgery by applying hierarchical clustering analysis to behavioral tests. Fecal samples were collected, and 16S ribosomal RNA gene sequencing was performed to detect differences in gut microbiota composition among sham, non‐POD, and POD mice. Fecal bacteria from non‐POD and POD mice were transplanted into antibiotics‐induced pseudo‐germ‐free mice to investigate the effects on behaviors.

          Results

          α‐diversity and β‐diversity indicated differences in gut microbiota composition between the non‐POD and POD mice. At the phylum level, the non‐POD mice had significantly higher levels of Tenericutes, which were not detected in the POD mice. At the class level, levels of Gammaproteobacteria were higher in the POD mice, whereas the non‐POD mice had significantly higher levels of Mollicutes, which were not detected in the POD mice. A total of 20 gut bacteria differed significantly between the POD and non‐POD mice. Interestingly, the pseudo‐germ‐free mice showed abnormal behaviors prior to transplant. The pseudo‐germ‐free mice that received fecal bacteria transplants from non‐POD mice but not from POD mice showed improvements in behaviors.

          Conclusions

          Abnormal gut microbiota composition after abdominal surgery may contribute to the development of POD. A therapeutic strategy that targets gut microbiota could provide a novel alterative for POD treatment.

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          Most cited references30

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          Therapeutic potential of Bifidobacterium breve strain A1 for preventing cognitive impairment in Alzheimer’s disease

          It has previously been shown that the consumption of probiotics may have beneficial effects not only on peripheral tissues but also on the central nervous system and behavior via the microbiota–gut–brain axis, raising the possibility that treatment with probiotics could be an effective therapeutic strategy for managing neurodegenerative disorders. In this study, we investigated the effects of oral administration of Bifidobacterium breve strain A1 (B. breve A1) on behavior and physiological processes in Alzheimer’s disease (AD) model mice. We found that administration of B. breve A1 to AD mice reversed the impairment of alternation behavior in a Y maze test and the reduced latency time in a passive avoidance test, indicating that it prevented cognitive dysfunction. We also demonstrated that non-viable components of the bacterium or its metabolite acetate partially ameliorated the cognitive decline observed in AD mice. Gene profiling analysis revealed that the consumption of B. breve A1 suppressed the hippocampal expressions of inflammation and immune-reactive genes that are induced by amyloid-β. Together, these findings suggest that B. breve A1 has therapeutic potential for preventing cognitive impairment in AD.
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            Postoperative delirium in the elderly: risk factors and outcomes.

            The purpose of this study was to describe the natural history, identify risk factors, and determine outcomes for the development of postoperative delirium in the elderly. Postoperative delirium is a common and deleterious complication in geriatric patients. Subjects older than 50 years scheduled for an operation requiring a postoperative intensive care unit admission were recruited. After preoperative informed written consent, enrolled subjects had baseline cognitive and functional assessments. Postoperatively, subjects were assessed daily for delirium using the confusion assessment method-intensive care unit. Patients were also followed for outcomes. During the study period, 144 patients were enrolled before major abdominal (40%), thoracic (53%), or vascular (7%) operations. The overall incidence of delirium was 44% (64/144). The average time to onset of delirium was 2.1 +/- 0.9 days and the mean duration of delirium was 4.0 +/- 5.1 days. Several preoperative variables were associated with an increased risk of delirium including older age (P < 0.001), hypoalbuminemia (P < 0.001), impaired functional status (P < 0.001), pre-existing dementia (P < 0.001), and pre-existing comorbidities (P < 0.001). In a multivariable logistic regression model, pre-existing dementia remains the strongest risk factor for the development of postoperative delirium. Worse outcomes, including increased length of stay (P < 0.001), postdischarge institutionalization (P < 0.001), and 6 month mortality (P = 0.001), occurred in subjects who developed delirium. In the current study, delirium occurred in 44% of elderly patients after a major operation. Pre-existing cognitive dysfunction was the strongest predictor of the development of postoperative delirium. Outcomes, including an increased rate of 6 month mortality, were worse in patients who developed postoperative delirium.
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              Phylogeny of gammaproteobacteria.

              The phylogeny of the large bacterial class Gammaproteobacteria has been difficult to resolve. Here we apply a telescoping multiprotein approach to the problem for 104 diverse gammaproteobacterial genomes, based on a set of 356 protein families for the whole class and even larger sets for each of four cohesive subregions of the tree. Although the deepest divergences were resistant to full resolution, some surprising patterns were strongly supported. A representative of the Acidithiobacillales routinely appeared among the outgroup members, suggesting that in conflict with rRNA-based phylogenies this order does not belong to Gammaproteobacteria; instead, it (and, independently, "Mariprofundus") diverged after the establishment of the Alphaproteobacteria yet before the betaproteobacteria/gammaproteobacteria split. None of the orders Alteromonadales, Pseudomonadales, or Oceanospirillales were monophyletic; we obtained strong support for clades that contain some but exclude other members of all three orders. Extreme amino acid bias in the highly A+T-rich genome of Candidatus Carsonella prevented its reliable placement within Gammaproteobacteria, and high bias caused artifacts that limited the resolution of the relationships of other insect endosymbionts, which appear to have had multiple origins, although the unbiased genome of the endosymbiont Sodalis acted as an attractor for them. Instability was observed for the root of the Enterobacteriales, with nearly equal subsets of the protein families favoring one or the other of two alternative root positions; the nematode symbiont Photorhabdus was identified as a disruptor whose omission helped stabilize the Enterobacteriales root.
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                Author and article information

                Contributors
                yangchuntz@sina.com
                anesthesia3143@163.com
                Journal
                CNS Neurosci Ther
                CNS Neurosci Ther
                10.1111/(ISSN)1755-5949
                CNS
                CNS Neuroscience & Therapeutics
                John Wiley and Sons Inc. (Hoboken )
                1755-5930
                1755-5949
                24 January 2019
                June 2019
                : 25
                : 6 ( doiID: 10.1111/cns.2019.25.issue-6 )
                : 685-696
                Affiliations
                [ 1 ] Department of Anesthesiology, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China
                [ 2 ] Department of Hand Surgery, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China
                [ 3 ] Department of Cardiology and Critical Care Medicine The Third Affiliated Hospital of Soochow University Changzhou China
                [ 4 ] Division of Clinical Neuroscience Chiba University Center for Forensic Mental Health Chiba Japan
                Author notes
                [*] [* ] Correspondence

                Chun Yang or Ai‐Lin Luo, Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

                Emails: chunyang@ 123456tjh.tjmu.edu.cn (CY); alluo@ 123456tjh.tjmu.edu.cn (A‐LL)

                Author information
                http://orcid.org/0000-0003-1540-4385
                Article
                CNS13103
                10.1111/cns.13103
                6515708
                30680947
                eaf7084c-a762-4e00-b09c-8ba25b087df0
                © 2019 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 09 August 2018
                : 02 December 2018
                : 22 December 2018
                Page count
                Figures: 9, Tables: 0, Pages: 12, Words: 6166
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 81500931
                Award ID: 81571047
                Award ID: 81703482
                Award ID: 81771159
                Funded by: Bureau of Science and Technology Foundation of Changzhou
                Award ID: CJ20159022
                Award ID: CJ20160030
                Funded by: Major Science and Technology Projects of Changzhou Municipal Committee of Health and Family Planning
                Award ID: ZD201505
                Award ID: ZD201407
                Funded by: Japan Agency for Medical Research and Development
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                cns13103
                June 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.2.1 mode:remove_FC converted:14.05.2019

                Neurosciences
                abdominal surgery,gut microbiota,gut‐brain axis,microbiota transplant,postoperative delirium

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