Simulated spaceflight disrupts the immune-gut-brain axis and drives sex-dependent neuroinflammation, axonal injury, and behavioral deficits

Apr 27, 2026bioRxiv : the preprint server for biology

Simulated spaceflight disrupts immune, gut, and brain interactions and causes sex-linked brain inflammation, nerve damage, and behavior problems

AI simplified

Gut-Brain Axis on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

Hindlimb unloading combined with 100cGy of ionizing radiation resulted in significant neurodegenerative changes in mice.

Region-selective neurodegenerative changes consistent with axonal injury were observed in the cortex and major white-matter tracts.
In the somatosensory cortex, reductions in MAP-2+ neurons and increases in axonal injury were noted, lowering the intact-to-dystrophic axonal area ratio.
Combined exposure to hindlimb unloading and radiation resulted in robust axonal damage and gliosis, as indicated by elevated microglia and astrocytes.
Sex-dependent changes in peripheral immune profiles included an increase in inflammatory myeloid cells and altered T-cell activation.
Intestinal barrier integrity was compromised, with changes in cellular architecture and increased leukocyte infiltration across the gut.
Behavioral assessments indicated deficits in anxiety, depression, motor skills, and cognitive functions, which were also sex-dependent.

AI simplified

Simulated spaceflight perturbs multiple organ systems, yet the integrated impact of spaceflight-relevant stressors on the immune-gut-brain axis remains poorly defined. We used a ground-based model combining hindlimb unloading (HU) with low-dose ionizing radiation (IR; 50 or 100cGy) to quantify neuropathology, peripheral immune phenotypes, intestinal barrier integrity, and behavioral performance in male and female C57BL/6 mice. HU and/or IR induced region-selective neurodegenerative changes consistent with axonal injury across the cortex and major white-matter tracts. In the somatosensory cortex, MAP-2+ neurons were reduced and SMI-312-labeled axonal injury increased, lowering the intact-to-dystrophic axonal area ratio. Long-range fiber pathways (corpus callosum, cingulate gyrus, external capsule) showed robust axonal damage accompanied by gliosis, with elevated Iba-1+ microglia and GFAP+ astrocytes most prominent after HU+IR (100cGy). Peripheral immunophenotyping revealed a sustained, sex-dependent innate inflammatory bias, with expanded CD11b+ myeloid cells and increased TNF-α+ myeloid activation after IR and IR+HU, alongside maladaptive T-cell polarization despite largely unchanged total CD8+ and CD4+ frequencies. In parallel, the gut exhibited architectural remodeling and barrier failure, including altered mucin profiles, reduced ZO-1 tight-junction labeling, and increased CD45+ leukocyte infiltration across the jejunum, ileum, and colon. Behavioral assays demonstrated sex-dependent deficits spanning affective, motor, and cognitive domains, including increased anxiety- and depressive-like behaviors, impaired rotarod performance, reduced recognition memory, and less efficient spatial strategies. Overall, these findings identify a sex-dependent immune-gut-brain vulnerability in which combined HU and low-dose IR drive gut barrier breakdown and immune imbalance that coincide with neuroinflammatory axonopathy and measurable neurobehavioral dysfunction.