Intermittent fasting protects against stress-induced depression and demyelination via the gut microbiota-brain axis

Chronic stress is a major risk factor for depression and disrupts myelin integrity in brain regions involved in emotional regulation. Although intermittent fasting (IF) improves metabolic and inflammatory states, its effects on stress-induced depression and demyelination remain unclear. Here, we investigated whether IF alleviates depression-like behaviors and myelin deficits in mice exposed to chronic restraint stress (CRS) and whether these effects involve modulation of the gut microbiota. Adult male C57BL/6 J mice underwent 14 days of CRS while maintained on either an ad libitum (AL) diet or an IF regimen. CRS induced robust depression-like phenotypes-characterized by increased immobility in the forced swimming test and reduced sucrose preference-without affecting locomotor activity, whereas IF significantly attenuated these behavioral abnormalities. Black-Gold II staining and myelin basic protein (MBP) immunofluorescence revealed marked demyelination in the corpus callosum, medial prefrontal cortex, and hippocampus of CRS mice, which was substantially reversed by IF. 16S rRNA sequencing demonstrated that IF reshaped gut microbial diversity and community composition under stress. Species-level analyses identified Prevotellamassilia timonensis and Muricoprocola aceti as positively associated with myelin integrity and behavioral improvement, whereas Anaeroplasma abactoclasticum showed negative associations. Functional pathway prediction further indicated that IF partially normalized stress-induced alterations in microbial metabolic functions. Collectively, these findings demonstrate that IF mitigates depression-like behaviors and preserves myelin integrity in CRS-exposed mice, potentially through gut microbiota-mediated mechanisms. IF may therefore represent a promising non-pharmacological strategy for alleviating stress-related neurobiological dysfunction.