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Inflammasome signaling affects anxiety- and depressive-like behavior and gut microbiome composition

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dc.contributor.authorWong, M.
dc.contributor.authorInserra, A.
dc.contributor.authorLewis, M.
dc.contributor.authorMastronardi, C.
dc.contributor.authorLeong, L.
dc.contributor.authorChoo, J.
dc.contributor.authorKentish, S.
dc.contributor.authorXie, P.
dc.contributor.authorMorrison, M.
dc.contributor.authorWesselingh, S.
dc.contributor.authorRogers, G.
dc.contributor.authorLicinio, J.
dc.date.issued2016
dc.description.abstractThe inflammasome is hypothesized to be a key mediator of the response to physiological and psychological stressors, and its dysregulation may be implicated in major depressive disorder. Inflammasome activation causes the maturation of caspase-1 and activation of interleukin (IL)-1β and IL-18, two proinflammatory cytokines involved in neuroimmunomodulation, neuroinflammation and neurodegeneration. In this study, C57BL/6 mice with genetic deficiency or pharmacological inhibition of caspase-1 were screened for anxiety- and depressive-like behaviors, and locomotion at baseline and after chronic stress. We found that genetic deficiency of caspase-1 decreased depressive- and anxiety-like behaviors, and conversely increased locomotor activity and skills. Caspase-1 deficiency also prevented the exacerbation of depressive-like behaviors following chronic stress. Furthermore, pharmacological caspase-1 antagonism with minocycline ameliorated stress-induced depressive-like behavior in wild-type mice. Interestingly, chronic stress or pharmacological inhibition of caspase-1 per se altered the fecal microbiome in a very similar manner. When stressed mice were treated with minocycline, the observed gut microbiota changes included increase in relative abundance of Akkermansia spp. and Blautia spp., which are compatible with beneficial effects of attenuated inflammation and rebalance of gut microbiota, respectively, and the increment in Lachnospiracea abundance was consistent with microbiota changes of caspase-1 deficiency. Our results suggest that the protective effect of caspase-1 inhibition involves the modulation of the relationship between stress and gut microbiota composition, and establishes the basis for a gut microbiota–inflammasome–brain axis, whereby the gut microbiota via inflammasome signaling modulate pathways that will alter brain function, and affect depressive- and anxiety-like behaviors. Our data also suggest that further elucidation of the gut microbiota–inflammasome–brain axis may offer novel therapeutic targets for psychiatric disorders.
dc.description.statementofresponsibilityM-L Wong, A Inserra, MD Lewis, CA Mastronardi, L Leong, J Choo, S Kentish, P Xie, M Morrison, SL Wesselingh, GB Rogers, and J Licinio
dc.identifier.citationMolecular Psychiatry, 2016; 21(6):797-805
dc.identifier.doi10.1038/mp.2016.46
dc.identifier.issn1359-4184
dc.identifier.issn1476-5578
dc.identifier.orcidWong, M. [0000-0003-1512-3073]
dc.identifier.orcidLewis, M. [0000-0002-3332-3776]
dc.identifier.orcidKentish, S. [0000-0002-5479-2643]
dc.identifier.orcidLicinio, J. [0000-0001-6905-5884]
dc.identifier.urihttp://hdl.handle.net/2440/100147
dc.language.isoen
dc.publisherNature Publishing Group
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1070935
dc.rights© 2016 Macmillan Publishers Limited All rights reserved
dc.source.urihttps://doi.org/10.1038/mp.2016.46
dc.subjectBrain
dc.subjectAnimals
dc.subjectMice, Inbred C57BL
dc.subjectMice
dc.subjectInflammation
dc.subjectCaspase 1
dc.subjectCytokines
dc.subjectBehavior, Animal
dc.subjectDepression
dc.subjectStress, Psychological
dc.subjectAnxiety
dc.subjectAnxiety Disorders
dc.subjectDepressive Disorder, Major
dc.subjectSignal Transduction
dc.subjectNeuroimmunomodulation
dc.subjectMale
dc.subjectInflammasomes
dc.subjectMicrobiota
dc.subjectGastrointestinal Microbiome
dc.titleInflammasome signaling affects anxiety- and depressive-like behavior and gut microbiome composition
dc.typeJournal article
pubs.publication-statusPublished

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