Circadian rhythm disruption modulates enteric neural precursor cells differentiation leading to gastrointestinal motility dysfunction via the NR1D1/NF-κB axis.

Abstract

Objectives: Circadian rhythm disruption (CRD) is implicated with numerous gastrointestinal motility diseases, with the enteric nervous system (ENS) taking main responsibility for the coordination of gastrointestinal motility. The purpose of this study is to explore the role of circadian rhythms in ENS remodeling and to further elucidate the underlying mechanisms.

Methods: First, we established a jet-lagged mice model by advancing the light/dark phase shift by six hours every three days for eight weeks. Subsequent changes in gastrointestinal motility and the ENS were then assessed. Additionally, a triple-transgenic mouse strain (Nestin-creER^T2 × Ngfr-DreER^T2: DTRGFP) was utilized to track the effects of CRD on the differentiation of enteric neural precursor cells (ENPCs). RNA sequencing was also performed to elucidate the underlying mechanism.

Results: Compared to the control group, CRD significantly accelerated gastrointestinal motility, evidenced by faster intestinal peristalsis (P < 0.01), increased fecal output (P < 0.01), and elevated fecal water content (P < 0.05), as well as enhanced electrical field stimulation induced contractions (P < 0.05). These effects were associated with an increase in the number of glial cells and nitrergic neurons in the colonic myenteric plexus. Additionally, ENPCs in the colon showed a heightened differentiation into glial cells and nitrergic neurons. Notably, the NR1D1/nuclear factor-kappaB (NF-κB) axis played a crucial role in the CRD-mediated changes in ENPCs differentiation. Supplementation with NR1D1 agonist or NF-κB antagonist was able to restore gastrointestinal motility and normalize the ENS in jet-lagged mice.

Conclusions: CRD regulates the differentiation of ENPCs through the NR1D1/NF-κB axis, resulting in dysfunction of the ENS and impaired gastrointestinal motility in mice.