title: Inflammasome signaling affects anxiety- and depressive-like behavior and gut microbiome composition.
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.
authors.affiliation: Mind and Brain Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia.|Department of Psychiatry, Flinders Medical Centre, Adelaide, SA, Australia.
authors.forename: M-L
authors.initials: ML
authors.lastname: Wong
authors.affiliation: Mind and Brain Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia.|Department of Psychiatry, Flinders Medical Centre, Adelaide, SA, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Inserra
authors.affiliation: Mind and Brain Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia.|Department of Psychiatry, Flinders Medical Centre, Adelaide, SA, Australia.
authors.forename: M D
authors.initials: MD
authors.lastname: Lewis
authors.affiliation: Genomics and Predictive Medicine, The John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.
authors.forename: C A
authors.initials: CA
authors.lastname: Mastronardi
authors.affiliation: Infection and Immunity Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia.|Department of Microbiology and Infectious Diseases, Flinders University School of Medicine and Flinders Medical Centre, Adelaide, SA, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Leong
authors.affiliation: Infection and Immunity Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia.|Department of Microbiology and Infectious Diseases, Flinders University School of Medicine and Flinders Medical Centre, Adelaide, SA, Australia.
authors.forename: J
authors.identifier: 0000-0001-9500-8360
authors.initials: J
authors.lastname: Choo
authors.affiliation: Gastrointestinal Vagal Afferent Research Group, The University of Adelaide, Adelaide, SA, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Kentish
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurobiology, and Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, China.
authors.forename: P
authors.initials: P
authors.lastname: Xie
authors.affiliation: Translational Research Institute, The University of Queensland Diamantine Institute, Wooloongabba, QLD, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Morrison
authors.affiliation: Infection and Immunity Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia.|Department of Microbiology and Infectious Diseases, Flinders University School of Medicine and Flinders Medical Centre, Adelaide, SA, Australia.
authors.forename: S L
authors.initials: SL
authors.lastname: Wesselingh
authors.affiliation: Infection and Immunity Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia.|Department of Microbiology and Infectious Diseases, Flinders University School of Medicine and Flinders Medical Centre, Adelaide, SA, Australia.
authors.forename: G B
authors.initials: GB
authors.lastname: Rogers
authors.affiliation: Mind and Brain Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia.|Department of Psychiatry, Flinders Medical Centre, Adelaide, SA, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Licinio
mesh_terms: D000818:Animals; D001007:Anxiety / Q000378:metabolism*; D001008:Anxiety Disorders / Q000150:complications; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000378:metabolism; D020170:Caspase 1; D016207:Cytokines / Q000378:metabolism; D003863:Depression / Q000378:metabolism*; D003865:Major Depressive Disorder / Q000378:metabolism; D000069196:Gastrointestinal Microbiome / Q000276:immunology / Q000502:physiology*; D058847:Inflammasomes / Q000378:metabolism* / Q000502:physiology; D007249:Inflammation / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D064307:Microbiota; D015213:Neuroimmunomodulation / Q000502:physiology; D015398:Signal Transduction; D013315:Stress, Psychological / Q000382:microbiology
chemical_list: D016207:Cytokines; D058847:Inflammasomes; D020170:Caspase 1