From the Gut to the Mind: Elucidating the Microbiome-chronobiology Axis in the Context of Depressive Illness

INTRODUCTION: Depression is a highly prevalent mood disorder and is often comorbid with gastrointestinal dysfunction and circadian disturbances. Many studies suggest that gut microbiota (GM) dysbiosis and circadian rhythm disruption may contribute to depressive pathophysiology; however, the mechanistic interactions between these systems remain incompletely defined. Deciphering these interactions may provide insights into prospective therapeutic targets or biomarkers for depression, although further mechanistic studies are needed to validate these findings. METHODS: The PubMed, Web of Science, Embase, and the Cochrane Library for articles published between January 2000 and December 2024 served as the basis of this review for analyzing, which covers original research, meta-analyses, high-impact reviews published in English, and excluding conference abstracts, case reports, and studies focusing solely on animal models without potential translational implications. After independently screening all retrieved articles and resolving discrepancies, a narrative synthesis approach was adopted to integrate data on mechanistic pathways, clinical associations, and translational potential. RESULTS: In this review, we focused on the dynamic interaction network between the GM and circadian rhythms, considering a new pathway by which they participate in the occurrence and development of depressive symptoms through bidirectional regulation: significant abnormalities in the GM structure of depressed patients are specifically associated with disruption of the circadian rhythm, and this association is dysbiosis-misalignment. DISCUSSION: Deciphering the molecular mechanisms of the regulatory loop may provide valuable information that can help screen specific therapeutic targets and biomarkers for depression, which may promote the transformation of depression diagnosis and treatment models from symptomatic treatment to precision-targeted intervention. CONCLUSION: Studies have confirmed dysbiosis-misalignment between the GM and circadian rhythms: dysbiosis can reshape the regulatory system underlying circadian rhythm, and disruption of the circadian rhythm in turn exacerbates dysbiosis. This interaction imbalance may drive the pathophysiological processes of depression. In this review, we highlighted that a comprehensive assessment of the interaction mechanism of the microbiome-chronobiology axis may help overcome the current bottleneck in treating depression and may provide a theoretical basis for developing novel intervention strategies with both timeliness and targeting.