{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T20:23:13Z","timestamp":1769458993155,"version":"3.49.0"},"reference-count":73,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T00:00:00Z","timestamp":1753401600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health","award":["RC2024-2025"],"award-info":[{"award-number":["RC2024-2025"]}]},{"name":"5x1000 tax","award":["RC2024-2025"],"award-info":[{"award-number":["RC2024-2025"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Neuronal ceroid lipofuscinoses (NCLs) are paediatric neurodegenerative disorders that primarily affect the central nervous system (CNS). The high prevalence of gastrointestinal (GI) symptoms has prompted researchers and clinicians to move beyond an exclusively \u201cbrain-centric\u201d perspective. At the molecular level, mutations in CLN genes lead to lysosomal dysfunction and impaired autophagy, resulting in intracellular accumulation of storage material that disrupts both central and enteric neuronal homeostasis. To systematically examine current clinical and preclinical knowledge on gut involvement in NCLs, with a focus on recent findings related to the enteric nervous system and gut microbiota. We conducted a systematic review following the PRISMA guidelines using PubMed as the sole database. Both clinical (human) and preclinical (animal) studies were included. A total of 18 studies met the inclusion criteria, focusing on gastrointestinal dysfunction, nervous system involvement, and gut microbiota. We found that the nature of GI symptoms was multifactorial in NCLs, involving not only the CNS but also the autonomic and enteric nervous systems, which were affected early by lysosomal deposits and enteric neuron degeneration. Of note, preclinical studies showed that gene therapy could improve not only CNS manifestations but also GI ones, which may have beneficial implications for patient care. While the role of the ENS seems to be clearer, that of gut microbiota needs to be further clarified. Current evidence from preclinical models highlighted alterations in the composition of the microbiota and suggested a possible influence on the progression and modulation of neurological symptoms. However, these results need to be confirmed by further studies demonstrating the causality of this relationship. GI involvement is a key feature of NCLs, with early impact on the enteric nervous system and possible links to gut microbiota. Although preclinical findings\u2014particularly on gene therapy\u2014are encouraging due to their dual impact on both CNS and GI manifestations, the causal role of the gut microbiota remains to be fully elucidated. In this context, the development of sensitive and specific outcome measures to assess GI symptoms in clinical trials is crucial for evaluating the efficacy of future therapeutic interventions.<\/jats:p>","DOI":"10.3390\/ijms26157192","type":"journal-article","created":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T11:38:41Z","timestamp":1753443521000},"page":"7192","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Gut\u2013Brain Interactions in Neuronal Ceroid Lipofuscinoses: A Systematic Review Beyond the Brain in Paediatric Dementias"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2066-2162","authenticated-orcid":false,"given":"Stefania","family":"Della Vecchia","sequence":"first","affiliation":[{"name":"Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Viale Pieraccini, 6, 50139 Florence, Italy"},{"name":"Neurobiology and Molecular Medicine Unit, IRCCS Fondazione Stella Maris, Calambrone, Via dei Giacinti 2, 56128 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0194-0702","authenticated-orcid":false,"given":"Maria","family":"Marchese","sequence":"additional","affiliation":[{"name":"Neurobiology and Molecular Medicine Unit, IRCCS Fondazione Stella Maris, Calambrone, Via dei Giacinti 2, 56128 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6908-5418","authenticated-orcid":false,"given":"Alessandro","family":"Simonati","sequence":"additional","affiliation":[{"name":"Department of Surgery, Dentistry, Paediatrics and Gynaecology, University of Verona, 37134 Verona, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1359-9062","authenticated-orcid":false,"given":"Filippo Maria","family":"Santorelli","sequence":"additional","affiliation":[{"name":"Neurobiology and Molecular Medicine Unit, IRCCS Fondazione Stella Maris, Calambrone, Via dei Giacinti 2, 56128 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Mole, S.E., Williams, R.E., and Goebel, H.H. 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