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

Publisher: BioMed Central Country of Publication: England NLM ID: 101190741 Publication Model: Electronic Cited Medium: Internet ISSN: 1479-5876 (Electronic) Linking ISSN: 14795876 NLM ISO Abbreviation: J Transl Med Subsets: MEDLINE

Original Publication: [London] : BioMed Central, 2003-

Gastrointestinal Motility* ; Cell Differentiation* ; Enteric Nervous System*/pathology ; Enteric Nervous System*/physiopathology ; Neural Stem Cells*/metabolism ; NF-kappa B*/metabolism ; Circadian Rhythm*/physiology ; Nuclear Receptor Subfamily 1, Group D, Member 1*/metabolism; Animals ; Mice, Transgenic ; Signal Transduction ; Mice, Inbred C57BL ; Male ; Mice

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.
(© 2024. The Author(s).)

J Gastroenterol Hepatol. 2018 Feb;33(2):443-452. (PMID: 28573746)
Nat Rev Gastroenterol Hepatol. 2021 Aug;18(8):571-587. (PMID: 33731961)
Am J Physiol. 1999 Aug;277(2):G275-9. (PMID: 10444440)
J Clin Invest. 2021 Aug 2;131(15):. (PMID: 34338232)
J Clin Invest. 2021 Oct 1;131(19):. (PMID: 34596053)
J Clin Invest. 2024 Jul 15;134(14):. (PMID: 39007272)
Mol Psychiatry. 2023 Apr;28(4):1451-1465. (PMID: 36732586)
Front Immunol. 2019 May 09;10:1043. (PMID: 31143184)
Prog Neurobiol. 2019 Feb;173:41-53. (PMID: 29886147)
J Neuroinflammation. 2018 Feb 20;15(1):49. (PMID: 29463313)
Nat Commun. 2019 Apr 3;10(1):1523. (PMID: 30944313)
J Physiol. 2017 Jun 1;595(11):3409-3424. (PMID: 28066889)
Cell. 2021 Feb 4;184(3):709-722.e13. (PMID: 33482084)
Ann N Y Acad Sci. 2020 Dec;1482(1):85-94. (PMID: 33140485)
Cells. 2021 Apr 08;10(4):. (PMID: 33917855)
Nat Rev Endocrinol. 2020 Dec;16(12):731-739. (PMID: 33106657)
Cell. 2020 Sep 17;182(6):1606-1622.e23. (PMID: 32888429)
Ind Health. 2021 Mar 24;59(2):66-77. (PMID: 33408309)
Am J Gastroenterol. 2010 Apr;105(4):842-7. (PMID: 20160712)
Gut. 2006 May;55(5):630-7. (PMID: 16236773)
Physiol Rev. 2023 Apr 1;103(2):1487-1564. (PMID: 36521049)
Cell Mol Life Sci. 2021 May;78(10):4713-4733. (PMID: 33770200)
Acta Pharmacol Sin. 2019 Jan;40(1):26-34. (PMID: 29950615)
Nat Commun. 2018 Oct 12;9(1):4246. (PMID: 30315268)
Cell Rep. 2023 Jun 27;42(6):112590. (PMID: 37261952)
Proc Natl Acad Sci U S A. 2017 May 2;114(18):E3709-E3718. (PMID: 28420791)
Nat Rev Gastroenterol Hepatol. 2020 Jun;17(6):338-351. (PMID: 32152479)
Cell. 2014 Oct 23;159(3):514-29. (PMID: 25417104)
Signal Transduct Target Ther. 2022 Feb 8;7(1):41. (PMID: 35136018)
Nature. 2002 May 16;417(6886):329-35. (PMID: 12015613)
Front Public Health. 2022 Nov 25;10:980603. (PMID: 36504996)
Neurogastroenterol Motil. 2023 Dec;35(12):e14687. (PMID: 37815021)
Gastroenterology. 2020 Jul;159(1):200-213.e8. (PMID: 32234538)
Cell Mol Gastroenterol Hepatol. 2016 May;2(3):328-339. (PMID: 27446985)
Cell Stem Cell. 2020 Jun 4;26(6):817-831. (PMID: 32502402)
Cell Mol Gastroenterol Hepatol. 2023;15(2):511-531. (PMID: 36343901)
Proc Natl Acad Sci U S A. 2024 Feb 20;121(8):e2318030121. (PMID: 38346182)
Cell Mol Gastroenterol Hepatol. 2015 Nov 1;1(6):631-645. (PMID: 26693173)

82100569 National Natural Science Foundation of China; 82300616 National Natural Science Foundation of China; 81974068 National Natural Science Foundation of China; 81770539 National Natural Science Foundation of China; 2023AFB301 Natural Science Foundation of Hubei Province

Keywords: Circadian rhythm; Enteric nervous system; Enteric neural precursor cells; Gastrointestinal motility; NF-κB signaling

0 (NF-kappa B)
0 (Nuclear Receptor Subfamily 1, Group D, Member 1)
0 (Nr1d1 protein, mouse)

Date Created: 20241029 Date Completed: 20241029 Latest Revision: 20241105

20241106

PMC11520590

10.1186/s12967-024-05766-8

39468593