Study on the efficacy and mechanism of fecal microbiota transplantation for depression based on circadian rhythm

Nov 20, 2025Brain, behavior, and immunity

How Gut Bacteria Transplant Can Help Fight Depression Related to Sleep Patterns

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Abstract

Health-FMT significantly alleviated depressive-like behaviors, with superior efficacy at ZT4.

Fecal microbiota transplantation (FMT) from healthy mice improved symptoms of depression in a mouse model.
Optimal timing for FMT was identified as ZT4, where it effectively restored circadian gene expressions.
Health-FMT reduced neuroinflammation in the hippocampus and prefrontal cortex.
Increased abundance of the genus Alistipes was linked to tryptophan availability and was significantly reduced by Health-FMT.
Tryptophan supplementation influenced circadian gene expressions and inflammatory factors through the ERK signaling pathway.

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BACKGROUND: Depression is closely associated with disruptions in circadian rhythms, and emerging evidence highlights critical roles of gut dysbiosis in its pathogenesis. However, the mechanisms by which FMT chronotherapy influences circadian gene in depression-via gut microbiota-remain poorly understood.

METHODS: In this study, we established a chronic unpredictable mild stress (CUMS) mouse model and performed fecal microbiota transplantation (FMT) using donor microbiota from healthy mice at two distinct circadian time points-zeitgeber time (ZT) 4 or ZT16 to identify the optimal timing for FMT based on behavioral assessments. Integrating omics dependent mechanisms of antidepressant effects mediated by these key functional bacteria.

RESULTS: Health-FMT significantly alleviated depressive-like behaviors, with superior efficacy at ZT4. It restored circadian gene expressions and attenuated neuroinflammation expression in the hippocampus and prefrontal cortex. 16S rRNA sequencing revealed that Health-FMT reduced uncultured_bacterium_g_Alistipes abundance, a genus linked to tryptophan availability. Tryptophan supplementation regulated circadian gene expressions, inflammatory factors, brain-derived neurotrophic factors (BDNF), microglial and astrocytic activation, and exerted antidepressant effects via the ERK signaling pathway.

CONCLUSIONS: These findings suggest that Health-FMT exerts antidepressant effects by restoring gut homeostasis, particularly by reducing Alistipes, thereby rebalancing tryptophan metabolic and circadian gene expressions. These findings offer a new possible mechanism and novel insights into the microbiota-gut-brain axis in depression, and underscore the importance of chronotherapy in FMT-based therapeutic strategies.

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Study on the efficacy and mechanism of fecal microbiota transplantation for depression based on circadian rhythm

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