The microbiota-gut-inflammasome-brain (MGIB) axis

Increasing evidence suggests the involvement of neuroinflammatory pathways and gut microbiota in major depressive disorder and in antidepressant response. Inflammasome activation triggered by psychosocial stress results in the maturation of caspase-1 and activation of interleukin (IL)-1ß and IL-18, two pro-inflammatory cytokines involved in HPA axis activation and stress-coping pathways. The microbiota-gut-brain (MGB) axis is a multi-organ bidirectional signaling system between the gut microbiota and the CNS that plays fundamental roles in host homeostasis, behavior and stress response. Caspase-1 KO and minocycline-treated mice were screened for anxiety-like, depressive-like and locomotor activity at baseline and following chronic stress. Moreover, gut microbiota was studied through 16S sequencing in chronically stressed and control wild-type mice with or without pharmacological inhibition of caspase-1. Caspase-1 deficiency decreased depressive- and anxiety-like behaviours at baseline, and increased locomotor activity and locomotor skills. Moreover, caspase-1 genetic deletion decreased the exacerbation of anxiety- and depressive- like behaviours following stress. Furthermore, caspase-1 antagonism with minocycline decreased stress-induced rise in depressive-like behaviour. Gut microbiota composition of stressed mice showed alterations of the Firmicutes/Bacteroidetes ratio, decreased Bifidobacterium spp. as well as increased Lactobacillus spp., changes associated with increased inflammasome activation and increased NF-kB activity. When restrained mice were treated with minocycline, evidence of both synergistic and antagonistic effects on microbiota composition was detected. For example, Blautia, Akkermansia and a member of the Lachnospiraceae family were increased. This effect is relevant to stress-responses given that Akkermansia attenuates inflammation in adipose tissue via induction of Foxp3 regulatory T-cells, and suppression of IL-6- and IL-1ß-mediated pathways. Caspase-1 inhibition exerts protective effects via modulating the interface between stress response and microbiota composition. We propose the novel concept of a “microbiota-gut-inflammasome-brain (MGIB) axis”, in which the gut microbiota through inflammasome signalling modulates inflammatory pathways that modulate brain function and affect anxiety- and depressive-like behaviours.