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http://dx.doi.org/10.14348/molcells.2020.2309

Gut Microbial Metabolites Induce Changes in Circadian Oscillation of Clock Gene Expression in the Mouse Embryonic Fibroblasts  

Ku, Kyojin (Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST))
Park, Inah (Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST))
Kim, Doyeon (Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST))
Kim, Jeongah (Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST))
Jang, Sangwon (Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST))
Choi, Mijung (Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST))
Choe, Han Kyoung (Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST))
Kim, Kyungjin (Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST))
Publication Information
Molecules and Cells / v.43, no.3, 2020 , pp. 276-285 More about this Journal
Abstract
Circadian rhythm is an endogenous oscillation of about 24-h period in many physiological processes and behaviors. This daily oscillation is maintained by the molecular clock machinery with transcriptional-translational feedback loops mediated by clock genes including Period2 (Per2) and Bmal1. Recently, it was revealed that gut microbiome exerts a significant impact on the circadian physiology and behavior of its host; however, the mechanism through which it regulates the molecular clock has remained elusive. 3-(4-hydroxyphenyl)propionic acid (4-OH-PPA) and 3-phenylpropionic acid (PPA) are major metabolites exclusively produced by Clostridium sporogenes and may function as unique chemical messengers communicating with its host. In the present study, we examined if two C. sporogenes-derived metabolites can modulate the oscillation of mammalian molecular clock. Interestingly, 4-OH-PPA and PPA increased the amplitude of both PER2 and Bmal1 oscillation in a dose-dependent manner following their administration immediately after the nadir or the peak of their rhythm. The phase of PER2 oscillation responded differently depending on the mode of administration of the metabolites. In addition, using an organotypic slice culture ex vivo, treatment with 4-OH-PPA increased the amplitude and lengthened the period of PER2 oscillation in the suprachiasmatic nucleus and other tissues. In summary, two C. sporogenes-derived metabolites are involved in the regulation of circadian oscillation of Per2 and Bmal1 clock genes in the host's peripheral and central clock machineries.
Keywords
3-(4-hydroxyphenyl)propionic acid; 3-phenylpropionic acid; Bmal1; circadian rhythm; gut microbiome; Per2; real-time bioluminescence recording;
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