Leng Hui, Thijs Theo, Desmet Louis, Vanotti Guillaume, Farhadipour Mona, Depoortere Inge
Translational Research Center in Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.
Translational Research Center in Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.
Cell Mol Gastroenterol Hepatol. 2025;19(4):101440. doi: 10.1016/j.jcmgh.2024.101440. Epub 2024 Dec 10.
BACKGROUND & AIMS: Circadian disturbances result in adverse health effects, including gastrointestinal symptoms. We investigated which physiological pathways in jejunal mucosa were disrupted during chronic jetlag and prevented during time-restricted feeding (TRF). Enteroids from Bmal1 and Bmal1 mice were used to replicate the processes that were affected by chronic jetlag and rescued by TRF.
C57BL/6J male mice were subjected to chronic jetlag or night-TRF for 4 weeks. An around-the-clock bulk-RNA sequencing study was performed on the jejunal mucosa. Bmal1 and Bmal1 mouse enteroids were generated to study the jejunal epithelial clock dependency of rhythmic jejunal processes.
Chronic jetlag disrupted the rhythmicity of jejunal clock genes and the jejunal transcriptome, which was partially rescued by TRF. Genes whose rhythm was altered by chronic jetlag but prevented by TRF were primarily associated with nutrient transport, lipid metabolism, ketogenesis, and cellular organization. In vivo, chronic jetlag caused a phase shift in the rhythmic accumulation of neutral lipids and induced a diurnal rhythm in the number of crypt epithelial cells, both of which were prevented by TRF. In vitro, enteroids replicated the in vivo rhythmic accumulation of neutral lipids in a clock-dependent manner, whereas the rhythm of S phase proliferation was ultradian in both genotypes of enteroids.
This pioneering transcriptomic study demonstrates that TRF acts as a robust entrainer during chronic jetlag, realigning disturbances in the circadian clock and the transcriptome involved in metabolic functions in the jejunal mucosa. Enteroids can replicate the rhythmic accumulation of neutral lipids dependent on the jejunal epithelial clock, enabling these functions to be studied in vitro.
昼夜节律紊乱会导致包括胃肠道症状在内的不良健康影响。我们研究了慢性时差反应期间空肠黏膜中的哪些生理途径受到破坏，以及限时进食（TRF）期间哪些途径得到了预防。利用Bmal1基因敲除小鼠和野生型小鼠的肠类器官来复制受慢性时差反应影响并通过TRF得到挽救的过程。
将C57BL/6J雄性小鼠进行4周的慢性时差反应或夜间TRF处理。对空肠黏膜进行全基因组RNA测序研究。构建Bmal1基因敲除小鼠和野生型小鼠的肠类器官，以研究空肠节律性过程对空肠上皮生物钟的依赖性。
慢性时差反应破坏了空肠生物钟基因的节律性和空肠转录组，而TRF可部分挽救这种破坏。其节律因慢性时差反应而改变但被TRF预防的基因主要与营养物质转运、脂质代谢、生酮作用和细胞组织有关。在体内，慢性时差反应导致中性脂质节律性积累出现相位偏移，并诱导隐窝上皮细胞数量出现昼夜节律，而这两种情况都可被TRF预防。在体外，肠类器官以生物钟依赖的方式复制了体内中性脂质的节律性积累，而在两种基因型的肠类器官中，S期增殖的节律都是超日节律。
这项开创性的转录组学研究表明，TRF在慢性时差反应期间起到了强大的同步器作用，重新调整了昼夜生物钟和空肠黏膜中参与代谢功能的转录组的紊乱。肠类器官可以复制依赖于空肠上皮生物钟的中性脂质节律性积累，从而能够在体外研究这些功能。
