Sensitization to Chronic Stress-Induced Depression and Anxiety Modulated by Gut-Brain-Axis Immunity

Abstract

ObjectivesChronic stress manifests as depressive- and anxiety-like impairments while recurrent stress elicits disproportionate psychiatric responses linked to stress-induced immunological priming. The microbiota-gut-brain-axis is a promising therapeutic target for stress-induced behavioral impairment as it simultaneous alters the immunological landscape of the periphery and brain by modulating innate and adaptive immune cells’ activity at barrier sites. MethodsImmunophenotyping of the ileum, spleen and PBMCs verified that the synbiotic’s impact on ileal barrier immunity, and not inflammatory or microglial activation in limbic brain regions, best associated to stress- and synbiotic-induced behavioral responses via the microbiota-ILC3-Treg axis. A multivariate adaptive regression splines (MARS) analysis predicted that immune responses in the brain and periphery create a cross-tissue biological signature of stress-induced behavior. Ileal and splenic IL-1 and IL-6 release and the ileal Treg/Th17 cell ratio associated to limbic chemotactic chemokine and prefrontal cortex IL-1 release, which associated to behavioral deficits. ResultsIn this study, a combination of probiotics and prebiotics (i.e., synbiotic) promoted behavioral resilience to chronic and recurrent stress by promoting regulatory T cell (Treg) activation and reducing the T helper (Th)17 to Treg ratio by modulating ileal innate lymphoid cell (ILC)3 activity. Synbiotics also normalized gut microbiome diversity and composition in response to stress while interactions of the genera Lactobacillus with Faecalibaculum, Blautia or Bifidobacterium spp. best associated to depressive-like behavior during the stress protocol. ConclusionsThis analysis shows how resilience to stress-induced behavioral impairment depends on the gut-brain-axis and that synbiotics indiscriminately attenuate peripheral- and neuro-inflammation associated with chronic and recurrent stress-induced depression and anxiety. Funding SourcesGrant AT008661 from the NIH’s ODS and the NCCIH.