Mice lacking Casp1, Ifngr and Nos2 genes exhibit altered depressive- and anxiety-like behaviour, and gut microbiome composition

Antonio Inserra,Julio Licinio,Geraint B Rogers,Ma-Li Wong,Jocelyn M Choo,Martin D Lewis

doi:10.1038/s41598-018-38055-8

Abstract

Converging evidence supports the involvement of pro-inflammatory pathways and the gut microbiome in major depressive disorder (MDD). Pre-clinical and clinical studies suggest that decreasing pro-inflammatory signaling may provide clinical benefit in MDD. In this study, we used the chronic unpredictable stress (CUS) paradigm to assess whether mice lacking the pro-inflammatory caspase 1, interferon gamma-receptor, and nitric oxide synthase (Casp1, Ifngr, Nos2)−/− present altered depressive- and anxiety-like behaviour at baseline and in response to CUS. In comparison to wild-type (wt) mice, (Casp1, Ifngr, Nos2)−/− mice displayed decreased depressive- and anxiety-like behaviour, and increased hedonic-like behaviour and locomotor activity at baseline, and resistance to developing anhedonic-like behaviour and a heightened emotional state following stress. Plasma levels of ACTH and CORT did not differ between the triple knockout and wt mice following stress. The faecal microbiome of (Casp1, Ifngr, Nos2)−/− mice differed from that of wt mice at baseline and displayed reduced changes in response to chronic stress. Our results demonstrate that simultaneous deficit in multiple pro-inflammatory pathways has antidepressant-like effects at baseline, and confers resilience to stress-induced anhedonic-like behaviour. Moreover, accompanying changes in the gut microbiome composition suggest that CASP1, IFNGR and NOS2 play a role in maintaining microbiome homeostasis.

Highlights

Increasing evidence implicates neuroinflammatory pathways in the development, treatment response, and remission of MDD1,2
We further assessed whether: 1) the (Casp[1], Ifngr, Nos2)−/− model is associated with an altered basal gut microbiota composition compared with wt, and 2) (Casp[1], Ifngr, Nos2)−/− mice are protected from stress-induced shifts in gut microbiome composition, due to deficits on mediating inflammatory pathways
Preference for a 1% sucrose solution in the sucrose preference test was increased in the (Casp[1], Ifngr, Nos2)−/− genotype compared to wt mice (F1,34 = 23.331, P < 0.001) (Fig. 1d)

Summary

Introduction

Increasing evidence implicates neuroinflammatory pathways in the development, treatment response, and remission of MDD1,2. Dysregulation of three major inflammatory systems is evident in those patients: (a) increased oxidative stress by means of nitric oxide (NO) overproduction, driven by NOS2 (NO synthase 2 or inducible NOS)[3,4], (b) low-grade chronic pro-inflammatory status driven by CASP1 overproduction[5,6], and (c) INFG over production driven by Th1 lymphocytes[7,8,9]. Each of these pathways has been investigated in isolation as an antidepressant-like strategy for MDD10–12. We further assessed whether: 1) the (Casp[1], Ifngr, Nos2)−/− model is associated with an altered basal gut microbiota composition compared with wt, and 2) (Casp[1], Ifngr, Nos2)−/− mice are protected from stress-induced shifts in gut microbiome composition, due to deficits on mediating inflammatory pathways

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