Gait selection of Caenorhabditis elegans is regulated by mechanosensitive DEG/ENaC channels

摘要

Circadian rhythm is an endogenous and entrainable oscillation involved in many physiological processes with approximately 24- hour period driven by a molecular clock which can be affected by the intrinsic and extrinsic state of an animal. The molecular clock in the suprachiasmatic nucleus (SCN), the master clock, and many peripheral tissues has transcriptional-translational feedback loops mediated by the various clock genes including Periods and Bmal1. Recently, gut microbiota, a community of symbiotic microorgan- isms in the host’s gastrointestinal tract, has been known to exert a significant impact on the circadian rhythm of its host, how- ever, how host-gut microbiota interaction affects circadian rhythm remains largely unknown. Thus, we focused on two metabolites, 4-hydroxyl-phenylpropionic acid (4-OH-PPA) and phenylpropi- onic acid (PPA), exclusively produced by Clostridium sporogenes (C. sporogenes) that may function as chemical messengers com- municating with its host, and we examined whether these two metabolites can modulate the oscillation of the mammalian molec- ular clock. By using the real-time bioluminescence recording of the luciferase (Luc) activity driven by the circadian gene promoter in Per2::Luc knock-in and Bmal1:Luc mouse embryonic fibroblasts, we identified that C. sporogenes-produced metabolites increased the amplitude of Per2 and Bmal1 oscillation in a dose-dependent man- ner when treated at the circadian peak or nadir of the expression in each gene. Besides, the transcription levels of Per2 and Bmal1 were changed by the treatment of 4-OH-PPA and PPA. We also exam- ined whether C. sporogenes-produced metabolites can increase the amplitude of circadian oscillation using organotypic culture model. Ex vivo bioluminescence recordings with the SCN, hippocampus, liver and small intestine from Per2::Luc knock-in mice showed the same tendency of increased amplitude by the treatment of 4-OH- PPA with the increase of the basal level of Per2 oscillation in both SCN and hippocampus. In summary, the C. sporogenes-produced.