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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 <jats:italic>RAD21<\/jats:italic> and <jats:italic>LIG3<\/jats:italic> with chronic intestinal pseudo\u2010obstruction and mitochondrial gastrointestinal encephalomyopathy disorders, respectively. We also introduce the lesser\u2010recognized 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\u2010related gut dysfunction, as well as the crucial need for further research to establish direct causal links between DNA damage accumulation and ENS\u2010specific pathologic phenotypes.<\/jats:p>","DOI":"10.1111\/nmo.14860","type":"journal-article","created":{"date-parts":[[2024,7,15]],"date-time":"2024-07-15T02:24:41Z","timestamp":1721010281000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Genomic stress in diseases stemming from defects in the second brain"],"prefix":"10.1111","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4188-7771","authenticated-orcid":false,"given":"Lobke Marie M.","family":"Mombeek","sequence":"first","affiliation":[{"name":"Faculty of Medicine and Life Sciences, Biomedical Research Institute Hasselt University  Diepenbeek 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