Dataset Information

Comparison of (R)-ketamine and lanicemine on depression-like phenotype and abnormal composition of gut microbiota in a social defeat stress model.

ABSTRACT: Accumulating evidence suggests a key role of the gut-microbiota-brain axis in the antidepressant actions of certain compounds. Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, showed rapid and sustained antidepressant effects in treatment-resistant depressed patients. In contrast, another NMDAR antagonist, lanicemine, did not exhibit antidepressant effects in such patients. (R)-ketamine, the (R)-enantiomer of ketamine, has rapid-acting and long-lasting antidepressant effects in rodent models of depression. Here we compared the effects of (R)-ketamine and lanicemine on depression-like phenotype and the composition of the gut microbiota in susceptible mice after chronic social defeat stress (CSDS). In behavioral tests, (R)-ketamine showed antidepressant effects in the susceptible mice, whereas lanicemine did not. The 16S ribosomal RNA gene sequencing of feces demonstrated that (R)-ketamine, but not lanicemine, significantly attenuated the altered levels of Bacteroidales, Clostridiales and Ruminococcaceae in the susceptible mice after CSDS. At the genus level, (R)-ketamine significantly attenuated the marked increase of Clostridium in the susceptible mice. In contrast, the effects of lanicemine were less potent than those of (R)-ketamine. This study suggests that the antidepressant effects of (R)-ketamine might be partly mediated by the restoration of altered compositions of the gut microbiota in a CSDS model.

SUBMITTER: Qu Y

PROVIDER: S-EPMC5691133 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Comparison of (R)-ketamine and lanicemine on depression-like phenotype and abnormal composition of gut microbiota in a social defeat stress model.

Qu Youge Y Yang Chun C Ren Qian Q Ma Min M Dong Chao C Hashimoto Kenji K

Scientific reports 20171116 1

Accumulating evidence suggests a key role of the gut-microbiota-brain axis in the antidepressant actions of certain compounds. Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, showed rapid and sustained antidepressant effects in treatment-resistant depressed patients. In contrast, another NMDAR antagonist, lanicemine, did not exhibit antidepressant effects in such patients. (R)-ketamine, the (R)-enantiomer of ketamine, has rapid-acting and long-lasting antidepressant effects in rod ...[more]

PMID: 29147024

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Project description:BackgroundThe gut microbiota (GM) has proven to be essential for both physical health and mental wellbeing, yet the forces that ultimately shape its composition remain opaque. One critical force known to affect the GM is the social environment. Prior work in humans and free-ranging non-human primates has shown that cohabitation and frequent social interaction can lead to changes in GM composition. However, it is difficult to assess the direction of causation in these studies, and interpretations are complicated by the influence of uncontrolled but correlated factors, such as shared diet.ResultsWe performed a 15-month longitudinal investigation wherein we disentangled the impacts of diet and social living conditions on GM composition in a captive cohort of 13 male cynomolgus macaques. The animals were in single housing for the first 3 months of the study initially with a variable diet. After baseline data collection they were placed on a controlled diet for the remainder of the study. Following this diet shift the animals were moved to paired housing for 6 months, enabling enhanced social interaction, and then subsequently returned to single housing at the end of our study. This structured sequencing of diet and housing changes allowed us to assess their distinct impacts on GM composition. We found that the early dietary adjustments led to GM changes in both alpha and beta diversity, whereas changes in social living conditions only altered beta diversity. With respect to the latter, we found that two particular bacterial families - Lactobacillaceae and Clostridiaceae - demonstrated significant shifts in abundance during the transition from single housing to paired housing, which was distinct from the shifts we observed based on a change in diet. Conversely, we found that other bacteria previously associated with sociality were not altered based on changes in social living conditions but rather only by changes in diet.ConclusionsTogether, these findings decouple the influences that diet and social living have on GM composition and reconcile previous observations in the human and animal literatures. Moreover, the results indicate biological alterations of the gut that may, in part, mediate the relationship between sociality and wellbeing.

Project description:ObjectivesDoxorubicin (Dox), a chemotherapeutic anthracycline agent for the treatment of a variety of malignancies, has a limitation in clinical application for dose-dependent cardiotoxicity. The purpose of this study was to explore the relationship between the composition/function of the gut microbiota and Dox-induced cardiotoxicity (DIC).MethodsC57BL/6J mice were injected intraperitoneally with 15 mg/kg of Dox, with or without antibiotics (Abs) administration. The M-mode echocardiograms were performed to assess cardiac function. The histopathological analysis was conducted by H&E staining and TUNEL kit assay. The serum levels of creatine kinase (CK), CK-MB (CK-MB), lactic dehydrogenase (LDH), and cardiac troponin T (cTnT) were analyzed by an automatic biochemical analyzer. 16S rRNA gene and metagenomic sequencing of fecal samples were used to explore the gut microbiota composition and function.Key findingsDox caused left ventricular (LV) dilation and reduced LV contractility. The levels of cardiomyocyte apoptosis and myocardial enzymes were elevated in Dox-treated mice compared with the control (Con) group. 16S rRNA gene sequencing results revealed significant differences in microbial composition between the two groups. In the Dox group, the relative abundances of Allobaculum, Muribaculum, and Lachnoclostridium were significantly decreased, whereas Faecalibaculum, Dubosiella, and Lachnospiraceae were significantly increased compared with the Con group at the genus level. Functional enrichment with Cluster of orthologous groups of proteins (COG) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that the Dox mice displayed different clusters of cellular processes and metabolism from the Con mice. The different species and their functions between the two groups were associated with the clinical factors of cardiac enzymes. Moreover, depletion of the gut microbiota could alleviate Dox-induced myocardial injury and cardiomyocyte apoptosis.ConclusionsThe study here shows that composition imbalance and functional changes of the gut microbiota can be one of the etiological mechanisms underlying DIC. The gut microbiota may serve as new targets for the treatment of cardiotoxicity and cardiovascular diseases.

Dataset Information

Comparison of (R)-ketamine and lanicemine on depression-like phenotype and abnormal composition of gut microbiota in a social defeat stress model.

Publications

Comparison of (R)-ketamine and lanicemine on depression-like phenotype and abnormal composition of gut microbiota in a social defeat stress model.

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