Temporal and Spatial Dynamics and Mechanisms of Brain-Gut Axis Injury Induced by Confinement-Like Physical Restraint Stress in Mice.

Abstract

Long-term SIS exposure across aerospace, deep-sea, underground, and quarantine settings increases depression and gut-brain axis dysfunction risk, but long-term nonlinear injury dynamics remain poorly understood. We analyzed GBD 2023 depression burden data in adults aged 15-49, then established a 0-35 day (d) chronic restraint stress mouse model that isolates the core physical confinement and activity-restriction component of SIS. Integrating behavior, histology, biochemistry, 16S sequencing, metabolomics, and formal nonlinear changepoint analysis, we validated picolinic acid (PLA) effects via in vivo intervention, in silico docking, and fecal microbiota transplantation (FMT). Population data showed that the global depression burden during the COVID-19 period followed a rapid rise-partial recovery-persistent disability pattern, providing a temporal reference for the experimental model. In mice, confinement-like restraint stress induced triphasic nonlinear gut-brain injury with changepoints at ~7 and ~21 days: early HPA/inflammatory activation, mid-phase gut barrier disruption and anxiety-like behavior, and late hippocampal damage with despair-like behavior. Microbiota remodeling and tryptophan metabolic shift formed the core signaling cascade, with PLA identified as the key gut-brain metabolite. Exogenous PLA dose-dependently improved depressive phenotypes, repaired barriers, and suppressed HPA hyperactivity and inflammation. FMT provided suggestive evidence that gut microbiota contribute to PLA's protective effects. Chronic confinement-like restraint stress induces triphasic nonlinear gut-brain axis injury rather than linear damage. PLA is a promising candidate target for mental health protection in isolated, confined, extreme environment populations and stress-related depression intervention.

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