Dataset Information

Fto Deficiency Reduces Anxiety- and Depression-Like Behaviors in Mice via Alterations in Gut Microbiota.

ABSTRACT: Depression and obesity have high concurrence within individuals, which may be explained by sharing the same risk factors, including disruption of the intestinal microbiota. However, evidence that delineated the causal connections is extremely scarce. Methods: Mice lacking fat mass- and obesity-associated gene (Fto) were generated. Fto-deficient and wild-type control mice were subjected to novel conditions with or without chronic unpredictable mild stress (CUMS) for 6 weeks. Some mice were treated with antibiotics via their drinking water for 6 weeks in order to deplete their microbiota. Behavioral tests were performed to evaluate anxiety- and depression-like behaviors. 16S rRNA amplicon and metagenomic sequencing were employed to analyse fecal microbiota. Plasma levels of inflammatory cytokines and lipopolysaccharides (LPS) were also compared. Results: Deletion of Fto led to lower body weight and decreased anxiety- and depression-like behaviors, Fto+/- mice were also less susceptible to stress stimulation, highlighting the essential role of Fto in pathogenesis of depression. With regard to gut microbiota, Fto deficiency mice harbored specific bacterial signature of suppressing inflammation, characterized with higher abundance of Lactobacillus, lower Porphyromonadaceae and Helicobacter. Critically, behavioral alterations of Fto +/- mice are mediated by shift in gut microbiota, as such changes can be partially attenuated using antibiotics. Exposure to CUMS increased serum IL-6 level while Fto deficiency reduced its level, which may be explained by a lower LPS concentration. Conclusion: Together, our findings uncover the roles of Fto on depression and provide insights into microbiota-related biological mechanisms underlying the association between obesity and depression.

SUBMITTER: Sun L

PROVIDER: S-EPMC6376469 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Fto Deficiency Reduces Anxiety- and Depression-Like Behaviors in Mice via Alterations in Gut Microbiota.

Sun Lijuan L Ma Lanjing L Zhang Haohao H Cao Ying Y Wang Chenchen C Hou Nannan N Huang Niu N von Deneen Karen M KM Zhao Changhai C Shi Yupeng Y Pan Yan Y Wang Meixia M Ji Gang G Nie Yongzhan Y

Theranostics 20190124 3

Depression and obesity have high concurrence within individuals, which may be explained by sharing the same risk factors, including disruption of the intestinal microbiota. However, evidence that delineated the causal connections is extremely scarce. Methods: Mice lacking fat mass- and obesity-associated gene (Fto) were generated. Fto-deficient and wild-type control mice were subjected to novel conditions with or without chronic unpredictable mild stress (CUMS) for 6 weeks. ...[more]

PMID: 30809304

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Project description:Gut microbiota regulate the neurodevelopmental processes and brain functions through the regulation of the microbiota-gut interaction and gut-brain communication. Buspirone, an agonist for serotonin 5-HT1A receptors, is used for the treatment of anxiety/depression. Therefore, to understand the gut microbiota-mediated mechanism of buspirone on anxiety/depression, we examined its effect on the immobilization stress (IS) or Escherichia coli K1 (EC)-induced anxiety/depression in mice. Oral or intraperitoneal administration of buspirone significantly suppressed stressor-induced anxiety/depression-like behaviors in the elevated plus maze, light/dark transition, tail suspension, and forced swimming tasks. Their treatments also reduced TNF-α expression and NF-κB+/Iba1+ cell population in the hippocampus and myeloperoxidase activity and NF-κB+/CD11c+ cell population in the colon. Buspirone treatments partially restored IS- or EC-induced gut microbiota perturbation such as β-diversity to those of normal control mice: they reduced the IS- or EC-induced gut Proteobacteria population. In particular, the anxiolytic activity of buspirone was positively correlated with the populations of Bacteroides and PAC001066_g in EC- or IS-exposed mice, while the populations of Lachnospiraceae, KE159660_g, LLKB_g, Helicobacter, and PAC001228_g were negatively correlated. The anti-depressant effect of buspirone was positively correlated with the Roseburia population. The fecal microbiota transplantations from buspirone-treated mice with IS-induced anxiety/depression or normal control mice suppressed IS-induced anxiety/depression-like behaviors and reduced hippocampal NF-κB+/Iba1+ and colonic NF-κB+/CD11c+ cell populations in the transplanted mice. Furthermore, they modified IS-induced perturbation of gut microbiota composition, particularly Proteobacteria, in the transplanted mice. In conclusion, buspirone alleviates IS as well as EC-induced anxiety/depression and colitis. It also suppresses associated neuroinflammation and modulates gut microbiota. Future studies can help to explain the relationship, if any, in the central and peripheral effects of buspirone.

Project description:Introduction: Major depressive disorder is a mental disease with complex pathogenesis and treatment mechanisms involving changes in both the gut microbiota and neuroinflammation. Cuscutae Semen (CS), also known as Chinese Dodder seed, is a medicinal herb that exerts several pharmacological effects. These include neuroprotection, anti-neuroinflammation, the repair of synaptic damage, and the alleviation of oxidative stress. However, whether CuscutaeSemen exerts an antidepressant effect remains unknown. Methods: In this study, we evaluated the effect of CS on chronic unpredictable stress (CUS)-induced depression-like behaviors in mice by observing changes in several inflammatory markers, including proinflammatory cytokines, inflammatory proteins, and gliocyte activation. Meanwhile, changes in the gut microbiota were analyzed based on 16 S rRNA sequencing results. Moreover, the effect of CS on the synaptic ultrastructure was detected by transmission electron microscopy. Results: We found that the CS extract was rich in chlorogenic acid and hypericin. And CS relieved depression-like behaviors in mice exposed to CUS. Increased levels of cytokines (IL-1β and TNF-α) and inflammatory proteins (NLRP3, NF-κB, and COX-2) induced by CUS were reversed after CS administration. The number of astrocytes and microglia increased after CUS exposure, whereas they decreased after CS treatment. Meanwhile, CS could change the structure of the gut microbiota and increase the relative abundance of Lactobacillus. Moreover, there was a significant relationship between several Lactobacilli and indicators of depression-like behaviors and inflammation. There was a decrease in postsynaptic density after exposure to CUS, and this change was alleviated after CS treatme. Conclusion: This study found that CS treatment ameliorated CUS-induced depression-like behaviors and synaptic structural defects in mice via the gut microbiota-neuroinflammation axis. And chlorogenic acid and hypericin may be the main active substances for CS to exert antidepressant effects.

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Fto Deficiency Reduces Anxiety- and Depression-Like Behaviors in Mice via Alterations in Gut Microbiota.

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<i>Fto</i> Deficiency Reduces Anxiety- and Depression-Like Behaviors in Mice via Alterations in Gut Microbiota.

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