Inflammasome Signaling Affects Anxiety-and Depressive-Like Behaviors and Gut Microbiome Composition

Antonio Inserra, Martin Lewis, Claudio A. Mastronardi, Geraint Rogers, Lex Leong, Jocelyn Choo, Ma-Li Wong, Julio Licinio

Research output: Contribution to conferencePoster

Abstract

Background: The inflammasome is hypothesised to be a key mediator of the response to physiological and psychological stressors, and its dysregulation could be implicated in the
development of major depressive disorder. Inflammasome activation causes the maturation of caspase-1 and activation of interleukin (IL)-1b and IL-18, two pro-inflammatory cytokines involved in neuroimmunomodulation, neuroinflammation, and neurodegeneration. In this study, mice
with genetic deficiency or pharmacological inhibition of caspase-1 (casp1) were screened for anxiety-like, depressive-like and locomotor activity at baseline and after chronic stress. The microbiota-gut-brain (MGB) axis is a complex multi-organ bidirectional signaling system between
the microbiota and the brain that plays a fundamental role in host physiology, homeostasis, development, metabolism and behavior. A growing body of work shows reproducible and consistent effects of microbial states on mice behavior, supporting a role for microbiota in
modulating behavior.

Methods: Mice with genetic deficiency or pharmacological inhibition of caspase 1 (casp1) were screened for anxiety-like, depressive-like and locomotor activity at baseline and after
chronic stress. Fecal pellets were collected and gut microbiota was evaluated in wild-type mice after stress with pharmacological inhibition of casp1 and compared to controls.

Results: Genetic deficiency of casp1 decreased depressive and anxiety-like behaviors, and increased locomotor activity and skills. Moreover, casp1 deficiency prevented the exacerbation of anxiety-like behaviors following chronic stress; furthermore, pharmacological casp1 antagonism
prevented stress-induced increase in depressive-like behavior. Restraint stress or pharmacological inhibition of casp1 affected fecal microbiome composition and were both
associated with a dysbiotic state. Analysis of individual bacterial taxon relative abundance provided evidence of both synergistic and antagonistic effects of chronic restraint
and casp1 inhibition.

Conclusions: Casp1 inhibition has a protective effect modulating the relationship between stress and microbiota composition, which support the concept of a microbiota-gut-inflammasome-brain (MGIB) axis, in which the gut microbiota via the inflammasome signaling platform modulates inflammatory pathways that will alter brain function and affect anxiety- and depressive-like behaviors. Our data suggest that the MGIB
LanguageEnglish
Publication statusPublished - Dec 2015
Event54th Annual Meeting of the American College of Neuropsychopharmacology (ACNP) - Hollywood, United States
Duration: 6 Dec 201510 Dec 2015

Conference

Conference54th Annual Meeting of the American College of Neuropsychopharmacology (ACNP)
CountryUnited States
CityHollywood
Period6/12/1510/12/15

Cite this

Inserra, A., Lewis, M., Mastronardi, C. A., Rogers, G., Leong, L., Choo, J., ... Licinio, J. (2015). Inflammasome Signaling Affects Anxiety-and Depressive-Like Behaviors and Gut Microbiome Composition. Poster session presented at 54th Annual Meeting of the American College of Neuropsychopharmacology (ACNP), Hollywood, United States.