A Peripheral Mechanism of Depression: Disturbed Intestinal Epithelial Per2 Gene Expression Causes Depressive Behaviors in Mice with Circadian Rhythm Disruption via Gut Barrier Damage and Microbiota Dysbiosis

Abstract Circadian rhythm disruption (CRD) is a potential risk factor for the development of depression. However, the underlying mechanisms remain unclarified. Here, it is found that in CRD model mice showing significant depressive‐like behaviors, the expression rhythm of Period 2 ( Per2 ), an important rhythm gene, is disrupted in intestinal epithelium, which results in defect of gut barrier integrity and gut microbiota disturbance, accompanied by peripheral and neuroinflammation, deficit in hippocampal neurogenesis, and impairment of excitatory neurotransmission. Specific knockdown of Per2 gene in intestinal epithelial cells prevents the development of depression‐like phenotype induced by CRD, with a reverse of these pathologic changes. Metabonomic analysis reveals that both CRD and CRD gut microbiota‐transplanted mice have downregulated tryptophan metabolism and reduced tryptophan levels both in serum and brain, and tryptophan supplementation is sufficient to prevent CRD‐induced depression, reduce systemic and neuronal inflammatory response, and rescue neurogenesis and synaptic function. These data suggest that the disturbed expression of intestinal epithelial Per2 gene plays a critical role in CRD‐induced neurological damage and depression in mice, which is mediated by gut microbiota and metabolites. Therefore, specific targeting on intestinal epithelial Per2 or tryptophan metabolism is a promising strategy to prevent CRD‐induced depression.