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The microbiota-gut-inflammasome-brain (MGIB) axis

Antonio Inserra1, 2*, Ma-Li Wong1, 2, Martin D. Lewis1, Claudio A. Mastronardi3, Lex Leong4, 5, Jocelyn Choo4, 5, Stephen Kentish6, P Xie7, 8, Mark Morrison9, Steve Wesselingh4, Geraint Rogers4, 5 and Julio Licinio1, 2
  • 1 South Australian Health and Medical Research Institute, Mind and Brain Theme, Australia
  • 2 Flinders Medical Centre, Department of Psychiatry, Australia
  • 3 The John Curtin School of Medical Research, Genomics and Predictive Medicine, Australia
  • 4 South Australian Health and Medical Research Institute, Infection and Immunity Theme, Australia
  • 5 Flinders University School of Medicine and Flinders Medical Centre, Department of Microbiology and Infectious Diseases, Australia
  • 6 The University of Adelaide, Gastrointestinal Vagal Afferent Research Group, Australia
  • 7 The First Affiliated Hospital of Chongqing Medical University, Department of Neurology, China
  • 8 Chongqing Medical University, Institute of Neuroscience Collaborative Innovation Center for Brain Science, China
  • 9 The University of Queensland Diamantine Institute, Translational Research Institute, Australia

Increasing evidence suggests the involvement of neuroinflammatory pathways and gut microbiota in major depressive disorder and in antidepressant response. Inflammasome activation triggered by psychosocial stress results in the maturation of caspase-1 and activation of interleukin (IL)-1ß and IL-18, two pro-inflammatory cytokines involved in HPA axis activation and stress-coping pathways. The microbiota-gut-brain (MGB) axis is a multi-organ bidirectional signaling system between the gut microbiota and the CNS that plays fundamental roles in host homeostasis, behavior and stress response. Caspase-1 KO and minocycline-treated mice were screened for anxiety-like, depressive-like and locomotor activity at baseline and following chronic stress. Moreover, gut microbiota was studied through 16S sequencing in chronically stressed and control wild-type mice with or without pharmacological inhibition of caspase-1. Caspase-1 deficiency decreased depressive- and anxiety-like behaviours at baseline, and increased locomotor activity and locomotor skills. Moreover, caspase-1 genetic deletion decreased the exacerbation of anxiety- and depressive- like behaviours following stress. Furthermore, caspase-1 antagonism with minocycline decreased stress-induced rise in depressive-like behaviour. Gut microbiota composition of stressed mice showed alterations of the Firmicutes/Bacteroidetes ratio, decreased Bifidobacterium spp. as well as increased Lactobacillus spp., changes associated with increased inflammasome activation and increased NF-kB activity. When restrained mice were treated with minocycline, evidence of both synergistic and antagonistic effects on microbiota composition was detected. For example, Blautia, Akkermansia and a member of the Lachnospiraceae family were increased. This effect is relevant to stress-responses given that Akkermansia attenuates inflammation in adipose tissue via induction of Foxp3 regulatory T-cells, and suppression of IL-6- and IL-1ß-mediated pathways. Caspase-1 inhibition exerts protective effects via modulating the interface between stress response and microbiota composition. We propose the novel concept of a “microbiota-gut-inflammasome-brain (MGIB) axis”, in which the gut microbiota through inflammasome signalling modulates inflammatory pathways that modulate brain function and affect anxiety- and depressive-like behaviours.

Keywords: Pathway, in vivo, Neuroinflammation, Gut Microbiota, major depression

Conference: 14th Meeting of the Asian-Pacific Society for Neurochemistry, Kuala Lumpur, Malaysia, 27 Aug - 30 Aug, 2016.

Presentation Type: Poster Presentation Session

Topic: 14th Meeting of the Asian-Pacific Society for Neurochemistry

Citation: Inserra A, Wong M, Lewis MD, Mastronardi CA, Leong L, Choo J, Kentish S, Xie P, Morrison M, Wesselingh S, Rogers G and Licinio J (2016). The microbiota-gut-inflammasome-brain (MGIB) axis. Conference Abstract: 14th Meeting of the Asian-Pacific Society for Neurochemistry. doi: 10.3389/conf.fncel.2016.36.00163

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Received: 04 Aug 2016; Published Online: 11 Aug 2016.

* Correspondence: Mr. Antonio Inserra, South Australian Health and Medical Research Institute, Mind and Brain Theme, Adelaide, SA, Australia, antonio.inserra@sahmri.com