Regulation of T helper 17 to regulatory T cell (Th17/Treg) as mediator of stress‐induced psychological impairment and cognitive deterioration

Abstract Background Chronic stress disrupts immune homeostasis while gut microbiota‐derived metabolites attenuate inflammation, thus promoting resilience to stress‐induced immune and behavioral abnormalities. There are both peripheral and brain region‐specific maladaptations of the immune response to chronic stress that produce interrelated mechanistic considerations required for the design of novel therapeutic strategies for prevention of cognitive deterioration in a mouse model of Alzheimer’s disease (AD) type cognitive deterioration Methods Chronic unpredictable stress was performed in wild‐type mice. Mice were treated with a combination of either prebiotics and probiotics (synbiotics) or vehicle. Mice were assessed for behavioral changes including mood and cognitive dysfunction. RNAseq was in performed in the gut and correlative analyses of behavior and inflammatory responses in the brain were conducted. Results Using a model of chronic unpredictable stress, behavioral abnormalities were associated to strong immune cell activation and recruitment in the ileum while inflammasome pathways were implicated in the hippocampus. Chronic stress also upregulated the ratio of activated proinflammatory T helper 17 (Th17) to regulatory T cells (Treg) in the liver and ileum and it was predicted with ingenuity pathway analysis that the aryl hydrocarbon receptor (AHR) could be driving the synbiotic’s effect on the ileum’s inflammatory response to stress. Synbiotic treatment attenuated the stress‐induced immune and behavioral aberrations in both the ileum and the brain while in a gut‐immune co‐culture model, the synbiotic‐specific metabolites promoted anti‐inflammatory activity through the AHR. Overall, this study characterizes a novel synbiotic treatment for chronic‐stress induced behavioral impairments while defining a putative mechanism of gut‐microbiota host interaction for modulating cognitive functions through modulationof of the peripheral and brain immune systems. Conclusion This study shows that a combination of probiotics and polyphenol‐rich prebiotics, a synbiotic, attenuates the chronic‐stress induced inflammatory responses in the ileum and cortical‐hippocampal regions promoting resilience to the consequent cognitive deterioration in male mice.