Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
J Neurochem. 2022 Dec;163(5):406-418. doi: 10.1111/jnc.15701. Epub 2022 Oct 13.
Circadian rhythm disruption (CRD) is a potential risk factor for developing Alzheimer's disease (AD). However, the mechanistic link between CRD and AD is still not fully understood. CRD may lead to intestinal barrier impairment. Several studies in animals and humans suggest a connection between gut microbiota disturbance, intestinal barrier damage and neurodegenerative diseases. In this study, we investigated the effect of CRD on cognition in mice and explored the role of intestinal barrier and inflammatory responses in this process. CRD modulates the composition of gut microbiota, impairs intestinal barrier integrity, and induces both peripheral and central inflammation and cognitive impairment in mice. Rifaximin, a non-absorbable antibiotic which modulates the gut microbial composition and increases intestinal barrier integrity, effectively suppresses inflammatory responses, and rescues cognitive impairment induced by CRD. Furthermore, the impairment in hippocampal neurogenesis, tau hyperphosphorylation, and loss in synaptic proteins in CRD mice is also reversed by Rifaximin. These data identify that the impaired intestinal barrier integrity related to gut microbiota disturbance plays a key role in CRD-induced inflammatory responses and cognitive impairments in mice, and Rifaximin is effective in preventing CRD-induced cognitive deficit through protecting the gut barrier and ameliorating neuroinflammation.
昼夜节律紊乱（CRD）是阿尔茨海默病（AD）发病的潜在危险因素。然而，CRD 与 AD 之间的机制联系仍不完全清楚。CRD 可能导致肠道屏障损伤。一些动物和人类研究表明，肠道微生物群紊乱、肠道屏障损伤与神经退行性疾病之间存在关联。在本研究中，我们研究了 CRD 对小鼠认知的影响，并探讨了肠道屏障和炎症反应在此过程中的作用。CRD 调节肠道微生物群的组成，损害肠道屏障的完整性，并在小鼠中引起外周和中枢炎症以及认知障碍。利福昔明是一种不被吸收的抗生素，可调节肠道微生物组成并增加肠道屏障的完整性，它能有效抑制炎症反应，并挽救 CRD 引起的认知障碍。此外，CRD 小鼠海马神经发生受损、tau 过度磷酸化以及突触蛋白丢失也被利福昔明逆转。这些数据表明，与肠道微生物群紊乱相关的肠道屏障完整性受损在 CRD 诱导的炎症反应和认知障碍中起关键作用，利福昔明通过保护肠道屏障和改善神经炎症来有效预防 CRD 引起的认知障碍。
