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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)-1? 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.

SUBMITTER: Wong ML

PROVIDER: S-EPMC4879188 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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

Wong M-L ML Inserra A A Lewis M D MD Mastronardi C A CA Leong L L Choo J J Kentish S S Xie P P Morrison M M Wesselingh S L SL Rogers G B GB Licinio J J

Molecular psychiatry 20160419 6

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 ...[more]

PMID: 27090302

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Project description:This study aimed to identify whether early-life conditions in broiler chickens could affect their behavior and welfare, and whether or not this was associated with an altered gut microbiome composition or diversity. Broilers were tested in a 2 x 2 factorial design with hatching conditions [home pen (OH) or at the hatchery (HH)] and enrichment (dark brooder (EE) or no brooder (NE) until 14 days of age) as factors (N = 6 per treatment combination). Microbiota composition was measured in the jejunum on days (d) 7, 14, and 35 and in pooled fecal samples on day 14. A novel environment test (NET) was performed on days 1 and 11, and the behavior was observed on days 6, 13, and 33. On day 35, composite asymmetry was determined and footpad dermatitis and hock burn were scored. In their home pen, HH showed more locomotion than OH (P = 0.05), and NE were sitting more and showed more comfort behavior than EE at all ages (P <0.001 and P = 0.001, respectively). On days 6 and 13 NE showed more eating and litter pecking while sitting, but on day 33 the opposite was found (age*enrichment: P = 0.05 and P <0.01, respectively). On days 1 and 11, HH showed more social reinstatement in the NET than OH, and EE showed more social reinstatement than NE (P <0.05). Composite asymmetry scores were lower for EE than NE (P <0.05). EE also had less footpad dermatitis and hock burn than NE (P <0.001). Within OH, NE had a more diverse fecal and jejunal microbiome compared to EE on day 14 (feces: observed richness: P = 0.052; jejunum: observed richness and Shannon: P <0.05); the principal component analysis (PCA) showed differences between NE and EE within both HH and OH in fecal samples on day 14, as well as significant differences in bacterial genera such as Lactobacillus and Lachnospiraceae (P <0.05). On day 35, PCA in jejunal samples only showed a trend (P = 0.068) for differences between NE vs. EE within the OH. In conclusion, these results suggest that especially the dark brooder affected the behavior and had a positive effect on welfare as well as affected the composition and diversity of the microbiome. Whether or not the behavior was modulated by the microbiome or vice versa remains to be investigated.

Project description:Background - Prepregnancy overweight and obesity promote deleterious health impacts on both mothers during pregnancy and the offspring. Significant changes in the maternal peripheral blood mononuclear cells (PBMCs) gene expression due to obesity are well-known. However, during pregnancy the impact of overweight on immune cell gene expression and its association with maternal and infant outcomes is not well explored. Methods – Blood samples were collected from healthy normal weight (NW, BMI 18.5-24.9) or overweight (OW, BMI 25-29.9) 2nd parity pregnant women at 12, 24 and 36 weeks of pregnancy. PBMCs were isolated from the blood and subjected to mRNA sequencing. Maternal and infant microbiota were analyzed by 16S rRNA gene sequencing. Integrative multi-omics data analysis was performed to evaluate the association of gene expression with maternal diet, gut microbiota, milk composition, and infant gut microbiota. Results - Gene expression analysis revealed that 453 genes were differentially expressed in the OW women compared to NW women at 12 weeks of pregnancy, out of which 354 were upregulated and 99 were downregulated. Several up-regulated genes in the OW group were enriched in inflammatory, chemokine-mediated signaling and regulation of interleukin-8 production-related pathways. At 36 weeks of pregnancy healthy eating index score was positively associated with several genes that include, DTD1, ELOC, GALNT8, ITGA6-AS1, KRT17P2, NPW, POT1-AS1 and RPL26. In addition, at 36 weeks of pregnancy, genes involved in adipocyte functions, such as NG2 and SMTNL1, were negatively correlated to human milk 2’FL and total fucosylated oligosaccharides content collected at 1 month postnatally. Furthermore, infant Akkermansia was positively associated with maternal PBMC anti-inflammatory genes that include CPS1 and RAB7B, at 12 and 36 weeks of pregnancy. Conclusions – These findings suggest that prepregnancy overweight impacts the immune cell gene expression profile, particularly at 12 weeks of pregnancy. Further, deciphering the complex association of PBMC’s gene expression levels with maternal gut microbiome and milk composition and infant gut microbiome may aid in developing strategies to mitigate obesity-mediated effects.

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Dataset Information

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

Publications

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

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