Gut microbiota from NLRP3-deficient mice ameliorates depressive-like behaviors by regulating astrocyte dysfunction via circHIPK2

Yuan Zhang,Peng Zheng,Peng Xie,Zhijun Zhang,Mengjing Cheng,Rongrong Huang,Lirui Wang,Honghong Yao,Jie Chao,Junxu Li

doi:10.1186/s40168-019-0733-3

Abstract

BackgroundInflammasomes have been found to interact with the gut microbiota, and this effect is associated with depression, but the mechanisms underlying this interaction have not been elucidated in detail.ResultsThe locomotor activity of NLRP3 KO mice was significantly greater than that of their WT littermates, while cohousing and transplantation of the NLRP3 KO gut microbiota avoid the effects of NLRP3 KO on the general locomotor activity at baseline. Meanwhile, transplantation of the NLRP3 KO microbiota alleviated the CUS-induced depressive-like behaviors. The compositions of the gut microbiota in NLRP3 KO mice and WT mice were significantly different in terms of the relative abundance of Firmicutes, Proteobacteria, and Bacteroidetes. Fecal microbiota transplantation (FMT) from NLRP3 KO mice significantly ameliorated the depressive-like behavior induced by chronic unpredictable stress (CUS) in recipient mice. Given the correlation between circular RNA HIPK2 (circHIPK2) and depression and the observation that the level of circHIPK2 expression was significantly increased in CUS-treated mice compared with that in the control group, further experiments were performed. FMT significantly ameliorated astrocyte dysfunction in recipient mice treated with CUS via inhibition of circHIPK2 expression.ConclusionsOur study illustrates the involvement of the gut microbiota-circHIPK2-astrocyte axis in depression, providing translational evidence that transplantation of the gut microbiota from NLRP3 KO mice may serve as a novel therapeutic strategy for depression.

Highlights

Inflammasomes have been found to interact with the gut microbiota, and this effect is associated with depression, but the mechanisms underlying this interaction have not been elucidated in detail
We found that cohousing prevented the effects of NLRP3 inflammasome deficiency on locomotor activity at baseline (Additional file 1: Figure S3A) but reduced the significant differences in depressive and anxiety-like behaviors between WT and NLRP3 KO littermates as demonstrated by the immobility time in the TST and forced swim test (FST) (Fig. 1d, e), and the time and distance spent exploring the central region in the open field test (OFT) (Additional file 1: Figure S3B, C)
Transplantation of the gut microbiota from NLRP3 KO mice alleviated astrocyte dysfunction in chronic unpredictable stress (CUS) mice Since astrocyte dysfunction was found to be involved in depression and antibiotic cocktail treatment did not influence on astrocyte activation (Additional file 1: Figure S7), we examined the effect of transplantation of the gut microbiota from NLRP3 KO mice on astrocyte function

Summary

Introduction

Inflammasomes have been found to interact with the gut microbiota, and this effect is associated with depression, but the mechanisms underlying this interaction have not been elucidated in detail. Caspase-1 and NLRP3 mRNA levels are increased in the blood cells of depressed patients [19], suggesting that inflammasomes are a key mediator in the development of depression [20]. Caspase-1 KO resulted in decreased depressive-like behavior, and administration of the caspase-1 inhibitor minocycline ameliorated depressive-like behavior by modulating the relationship between stress and the gut microbiota composition [18]. Despite these findings, a detailed understanding of the interactions between the inflammasome and the gut microbiota is still lacking

Methods

Results

Discussion

Conclusion