Gut microbiota dysbiosis and disturbed tryptophan metabolism mediate cognitive impairment in mice with circadian rhythm disruption

Circadian rhythm disorder (CRD) is a risk factor for cognitive deficits, yet its mechanisms remain unclear. We previously found CRD model mice developed cognitive impairment mediated through gut microbiota disturbance, intestinal barrier damage, and microglia activation, but the signaling pathway was undefined. Here, we show CRD induces cognitive deficits and gut microbiota disturbance in mice. Fecal microbiota transplantation (FMT) from CRD mice to normal mice reproduced intestinal barrier damage, microglia activation, neuronal damage, and cognitive deficits. Notably, gut metabolite analysis revealed significant alterations, with tryptophan metabolism being particularly affected: tryptophan decreased by 26.9 % and 5-hydroxytryptophan (5-HTP) by 30.7 % (both P < 0.05). Dietary tryptophan supplementation restored serum tryptophan and 5-HTP levels, ameliorating the neuronal damage and cognitive deficits caused by CRD gut microbiota. Collectively, these findings indicate that disturbances in gut microbiota and metabolites play a key role in CRD-induced neurological damage in mice, suggesting targeting the gut microbiota or tryptophan metabolism may prevent CRD-induced cognitive dysfunction. ● CRD induces gut microbiota dysbiosis and cognitive deficit in mice. ● CRD gut microbiota mediates gut barrier damage, neuroinflammation and cognitive impairment. ● Tryptophan supplementation effectively reverses CRD-induced cognitive deficit.