Targeting the gut-brain axis: probiotic intervention alleviates depressive-like behaviors and social deficit after cranial irradiation.

Cranial radiotherapy adversely impacts mental health, often leading to neuropsychiatric sequelae such as depressive-like behaviors and social impairment. Although the hippocampus and the gut-brain axis are critically involved in this process, the specific mechanisms are not yet fully elucidated. Therefore, this study focused on the gut-brain axis to elucidate the role and mechanisms of probiotic intervention in cranial irradiation-induced depressive-like behaviors and social deficits. We first established a radiation-induced brain injury (RBI) model in mice using a cranial X-ray hypofractionation regimen (5 Gy × 4 fractions). Then we verified that acute neuroinflammation, hippocampal damage, and systemic metabolic disruption contributed to behavioral alterations. Subsequently, probiotic intervention demonstrated significant restorative effects on gut-brain axis disruptions. Targeted metabolomics identified key neurotransmitter pathways, particularly the noradrenergic system, as closely associated with the probiotic-mediated recovery. Furthermore, probiotic supplementation ameliorated both intestinal barrier and hippocampal structural damage. The intervention mitigated depressive-like behaviors and social deficits by alleviating neuroinflammation and promoting hippocampal neurogenesis. These findings highlight the critical role of gut-brain axis disruption in neuropsychiatric changes following cranial irradiation and suggest that probiotics can modulate neurochemical homeostasis and behavioral outcomes through this axis.