Circadian rhythm disturbance impairs intestinal mucus barrier and immune microenvironment via sebacic acid-mediated gut dysbiosis
Li Cheng, Xinyuan Wang, Qianqian Wang, Kehan Yin, Bo Wang, Bi-Yu Wu, Ping Xu, Hong-Yi Qiu, Wenjing Ge, Jiali Sun, Qing Shi, Xiu-Juan Yan, Shengliang Chen
Abstract
Circadian rhythm disturbance caused by shift work has become increasingly prevalent, emerging as a risk factor for digestive diseases. Both the host’s and the microbial metabolic pathways and functions might be markedly altered by circadian disruption. However, metabolic changes in the gut during shift work are poorly reported. Here, we demonstrated intestinal metabolome signatures in individuals with shift work disorder and identified sebacic acid as a symptoms-related metabolite. Shift work-related circadian rhythm disturbance leads to enhanced hepatic fatty acid ω-oxidation and a significant increase in dicarboxylic fatty acids in feces. Among these, the increased sebacic acid impaired the intestinal mucus barrier by regulating composition of mucus-related gut bacteria, characterized by an increase in Muribaculaceae and a decrease in Akkermansia abundance, along with activated immune system characterized by increased B cell responses, thereby driving the occurrence of intestinal inflammation. The application of the inhibitor for CYP4A, a key ω-hydroxylase in fatty acid oxidation, effectively improved intestinal dysfunction caused by circadian rhythm disturbance. Our findings provide a deep insight into understanding the role of circadian rhythm in maintaining intestinal homeostasis. • Fecal dicarboxylic acids increased in individuals with circadian disruption. • The level of fecal sebacic acid positively correlated with severity of symptoms. • Sebacic acid caused gut dysbiosis, impaired mucus layer and B cell overactivation. • Elevated sebacic acid originated from enhanced hepatic ω-oxidation of fatty acids. • The CYP4A inhibitor help mitigate metabolic disturbances and gut dysfunction.