Genomic stress in diseases stemming from defects in the second brain

• Published in: Neurogastroenterology and motility Vol. 37; no. 8; pp. e14860 - n/a
• Main Authors: Mombeek, Lobke Marie M., Boesmans, Werend, Wilson, David M.
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.08.2025; John Wiley and Sons Inc
• Subjects: Animals; Central nervous system; Cockayne syndrome; Contaminants; Digestive system; DNA Damage; DNA Repair; Dysbacteriosis; Enteric nervous system; Enteric Nervous System - metabolism; Enteric Nervous System - physiopathology; enteric neuropathies; Gastrointestinal Diseases - genetics; gastrointestinal motility; Gastrointestinal tract; genomic instability; Genotoxicity; Humans; Mini Review; Nervous system; Neuropathy; Oxidative stress; Phenotypes; gastrointestinal motility; enteric neuropathies; enteric nervous system; genomic instability; DNA repair; DNA damage
• DOI: 10.1111/nmo.14860
• ISSN: 1350-1925; 1365-2982

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. The enteric nervous system, a.k.a., second brain, is subject to a range of genotoxic exposures that include intrinsic oxidative stress and extrinsic agents associated with ingested foods, inflammation, and dysbiosis. Resulting DNA damage, if left unrepaired, can induce cell dysfunction or death, resulting in gut abnormalities and enteric neuropathy.