Glia-mediated gut–brain cytokine signaling couples sleep to intestinal inflammatory responses induced by oxidative stress

作者：Alina Malita, Anne H Skakkebaek, Olga Kubrak, Xiaokang Chen, Takashi Koyama, Elizabeth C Connolly, Nadja Ahrentløv, Ditte S. Andersen, Michael J. Texada, Kenneth A. Halberg, Kim Rewitz · 发表于：eLife · 年份：2024 · DOI：10.7554/elife.99999 · 被引用次数：8 · 研究领域：Circadian rhythm and melatonin、Neurobiology and Insect Physiology Research、Invertebrate Immune Response Mechanisms

gut to brain glial cells regulates sleep. Under healthy conditions, this pathway promotes wakefulness. However, elevated gut cytokine signaling in response to oxidative stress - triggered by immune and inflammatory responses in the intestine - induces sleep. The cytokines Unpaired 2 and -3 are upregulated by oxidative stress in enteroendocrine cells and activate JAK-STAT signaling in glial cells, including those of the blood-brain barrier (BBB). This activity maintains elevated sleep during oxidative-stress-induced intestinal disturbances, suggesting that the JAK-STAT pathway in glia inhibits wake-promoting signaling to facilitate sleep-dependent restoration under these conditions. We find that the enteric peptide Allatostatin A (AstA) enhances wakefulness, and during intestinal oxidative stress, gut-derived Unpaired 2/3 inhibits AstA receptor expression in BBB glia, thereby sustaining an elevated sleep state during gut inflammation or illness. Taken together, our work identifies a gut-to-glial communication pathway that couples sleep with intestinal homeostasis and disease, enhancing sleep during intestinal sickness, and contributing to our understanding of how sleep disturbances arise from gastrointestinal disturbances.