Prebiotics chronotherapy alleviates depression-like behaviors in FMT mice through enhancing short-chain fatty acids receptors and intestinal barrier.

Background: Prebiotics interventions to restore microbiome homeostasis may have long-lasting benefits for mental health especially in adolescence. However, the anti-depressants of prebiotics, particularly in prebiotics chronotherapy, orchestrated remain unknown. We aimed to elucidate the underlying mechanisms of prebiotics in light of maximum antidepressant effects by appropriate dosing timing.

Methods: Adolescent depression mouse model was made by fecal microbiota transplantation (FMT) from major depressive disorder (MDD) adolescent patients. Sodium Butyrate (SB), one of SCFAs, was intragastrically administrated to mice at Zeitgeber time 4 (ZT4: the highest short-chain fatty acids (SCFAs) receptor-activated timing) or ZT16 (the lowest SCFA receptor-activated timing) for the last 2 weeks within 4-week-FMT exposure. The success of modeling and antidepressant effects of SB chronotherapy were determined by changes in depression-like behaviors, inflammation, neurotrophy, neuron functions, circadian rhythm, and barrier systems.

Results: SB alleviated depressive symptoms at ZT4 with better efficacy over ZT16. SB decreased inflammation, upregulated neurotrophy, restored functions, and re-established circadian rhythm. Notably, SB increased the expressions of SCFAs receptors to repair the intestinal barrier and blood-brain barrier, thereby alleviating depressive symptoms.

Limitation: Only one prebiotic with one disease was involved.

Conclusion: SB supplementation could be a promising therapeutic tactic for restoring the integrity of barrier systems by enhancing the intestinal SCFAs receptors. Alignment SB supplementation with circadian clocks might help to obtain better antidepressant efficacy, which may generate novel insights into diseases related to diseases with barrier system impairment and optimize interventions to improve health and human well-being.