Lobke Marie M Mombeek, Werend Boesmans, David M Wilson
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引用次数: 0
Abstract
This review discusses the less-explored realm of DNA damage and repair within the enteric nervous system (ENS), often referred to as the "second brain." While the central nervous system has been extensively studied for its DNA repair mechanisms and associated neuropathologies, the ENS, which can autonomously coordinate gastrointestinal function, experiences unique challenges and vulnerabilities related to its genome integrity. The susceptibility of the ENS to DNA damage is exacerbated by its limited protective barriers, resulting in not only endogenous genotoxic exposures, such as oxidative stress, but also exogenous threats, such as ingested environmental contaminants, local inflammatory responses, and gut dysbiosis. Here, we discuss the evidence for DNA repair defects in enteric neuropathies, most notably, the reported relationship between inherited mutations in RAD21 and LIG3 with chronic intestinal pseudo-obstruction and mitochondrial gastrointestinal encephalomyopathy disorders, respectively. We also introduce the lesser-recognized gastrointestinal complications in DNA repair syndromes, including conditions like Cockayne syndrome. The review concludes by pointing out the potential role of DNA repair defects in not only congenital disorders but also aging-related gut dysfunction, as well as the crucial need for further research to establish direct causal links between DNA damage accumulation and ENS-specific pathologic phenotypes.
这篇综述讨论了肠道神经系统(ENS)(通常被称为 "第二大脑")中较少被探索的 DNA 损伤和修复领域。中枢神经系统的 DNA 修复机制和相关神经病理学已被广泛研究,而能自主协调胃肠功能的 ENS 则在其基因组完整性方面面临着独特的挑战和脆弱性。ENS 的保护屏障有限,不仅会导致内源性基因毒性暴露(如氧化应激),还会导致外源性威胁(如摄入的环境污染物、局部炎症反应和肠道菌群失调),从而加剧了 ENS 对 DNA 损伤的易感性。在此,我们讨论了肠道神经病中 DNA 修复缺陷的证据,最值得注意的是,据报道 RAD21 和 LIG3 的遗传突变分别与慢性肠假性梗阻和线粒体胃肠道脑肌病之间的关系。我们还介绍了 DNA 修复综合征中较少被认识到的胃肠道并发症,包括 Cockayne 综合征等疾病。综述最后指出,DNA 修复缺陷不仅在先天性疾病中具有潜在作用,而且在与衰老相关的肠道功能障碍中也具有潜在作用,因此亟需开展进一步研究,以确定 DNA 损伤积累与 ENS 特异性病理表型之间的直接因果关系。
期刊介绍:
Neurogastroenterology & Motility (NMO) is the official Journal of the European Society of Neurogastroenterology & Motility (ESNM) and the American Neurogastroenterology and Motility Society (ANMS). It is edited by James Galligan, Albert Bredenoord, and Stephen Vanner. The editorial and peer review process is independent of the societies affiliated to the journal and publisher: Neither the ANMS, the ESNM or the Publisher have editorial decision-making power. Whenever these are relevant to the content being considered or published, the editors, journal management committee and editorial board declare their interests and affiliations.