Caffeic Acid Alleviates Chronic Sleep Deprivation-Induced Intestinal Damage by Inhibiting the IMD Pathway in Drosophila

Dan Yang,1,* Minghui Xiu,2,* Xiaolin Jiang,1 Qian Kang,1 Jinyu Fu,1 Shihong Zhou,2 Yongqi Liu,1,2 Jianzheng He1– 3 1Provincial-Level Key Laboratory for Molecular Medicine of Major Diseases and The Prevention and Treatment with Traditional Chinese Medicine Research in Gansu Colleges and University, Gansu University of Chinese Medicine, Lanzhou, 730000, People’s Republic of China; 2College of Public Health, Gansu University of Chinese Medicine, Lanzhou, 730000, People’s Republic of China; 3Scientific Research and Experimental Center, Gansu University of Chinese Medicine, Lanzhou, 730000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianzheng He, Email [email protected]: Sleep is vital for maintaining the health of the organism. Chronic sleep deprivation (CSD) is a key contributor to significant health risks, including the induction of gastrointestinal disorders. However, the mechanism of CSD caused intestinal damage remains unclear.Methods: Drosophila melanogaster as an in vivo model was used to investigate the mechanism of CSD-induced intestinal injury, as well as the ameliorative effect of caffeic acid.Results: CSD resulted in reduced survival and severely affected intestinal homeostasis in flies, as evidenced by disruption of intestinal acid-base homeostasis, increased feeding, increased intestinal permeability and shortened intestinal length. Meanwhile, the expressions of the immune deficiency (IMD) pathway-related genes PGRP-SB1, Dpt, AttA, AttB and Mtk were significantly up-regulated in the intestine of CSD flies. On the other hand, Caffeic acid supplementation restored intestinal acid-base homeostasis and intake, while improving intestinal barrier permeability and intestinal length, and effectively reducing intestinal damage. In addition, administration of caffeic acid decreased the expressions of PGRP-SB1, Dpt, AttA and Mtk genes in the CSD flies gut.Discussion: These results suggested that CSD could disrupt gut homeostasis in adult flies by overactivating the IMD pathway, while Caffeic acid has an obvious protective role on the gut homeostasis. Keywords: thermogenetic CSD, intestine, Immune signaling, polyphenolic compounds, Drosophila melanogaster