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

Wong, M-L, Inserra, A., Lewis, M. D., Mastronardi, C. A., Leong, L., Choo, J., Kentish, S., Xie, P., Morrison, M., Wesselingh, S. L., Rogers, G. B. and Licinio, J. (2016) Inflammasome signaling affects anxiety- and depressive-like behavior and gut microbiome composition. Molecular Psychiatry, 21 6: 797-805. doi:10.1038/mp.2016.46

Author Wong, M-L
Inserra, A.
Lewis, M. D.
Mastronardi, C. A.
Leong, L.
Choo, J.
Kentish, S.
Xie, P.
Morrison, M.
Wesselingh, S. L.
Rogers, G. B.
Licinio, J.
Title Inflammasome signaling affects anxiety- and depressive-like behavior and gut microbiome composition
Journal name Molecular Psychiatry   Check publisher's open access policy
ISSN 1476-5578
Publication date 2016-06-01
Year available 2016
Sub-type Article (original research)
DOI 10.1038/mp.2016.46
Open Access Status DOI
Volume 21
Issue 6
Start page 797
End page 805
Total pages 9
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Collection year 2017
Language eng
Formatted abstract
The 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.
Keyword Major depressive disorder (MDD)
Antidepressant response
Physiological and psychological stressors
Psychiatric disorders
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
UQ Diamantina Institute Publications
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