Characterization of Fabry disease-associated lyso-Gb3 on mouse colonic ion transport and motility

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dc.check.date2025-10-17en
dc.check.infoAccess to this article is restricted until 12 months after publication by request of the publisheren
dc.contributor.authorDelprete, Ceciliaen
dc.contributor.authorUhlig, Friederikeen
dc.contributor.authorCaprini, Marcoen
dc.contributor.authorHyland, Niall P.en
dc.contributor.funderScience Foundation Irelanden
dc.contributor.funderFondazione Cassa di Risparmio in Bolognaen
dc.contributor.funderUniversità di Bolognaen
dc.contributor.funderHorizon 2020en
dc.date.accessioned2024-10-17T14:17:54Z
dc.date.available2024-10-17T14:17:54Z
dc.date.issued2024en
dc.description.abstractFabry disease (FD) is a rare X-linked lysosomal storage disorder caused by a deficiency in α-galactosidase A leading to the accumulation of globotriaosylceramide (Gb3) and subsequent increase in globotriaosylsphingosine (lyso-Gb3) in different cells and organs, including the gastrointestinal (GI) tract. GI symptoms represent some of the earliest manifestations of FD and significantly impact quality of life. The origin of these symptoms is complex, and the exact mechanisms remain poorly understood. Here, we sought to determine whether lyso-Gb3 contributes to the pathophysiology of GI symptoms associated with FD by examining its effects on mouse colonic ion transport and motility ex vivo using Ussing chambers and organ baths respectively. Lyso-Gb3 significantly increased colonic baseline short-circuit current (ISC). This increase in ISC was insensitive to inhibition of the cystic fibrosis transmembrane conductance regulator and Na-K-Cl cotransporter 1 suggesting that the increase in ISC is Cl- ion independent. This response was also insensitive to inhibition with the neurotoxin, tetrodotoxin. Additionally, pretreatment with lyso-Gb3 did not significantly influence subsequent responses to either veratridine or capsaicin implying that the response to lyso-Gb3 does not involve the enteric nervous system. In terms of colonic motility, lyso-Gb3 did not significantly influence colonic tone, spontaneous contractility or cholinergic-induced contractions. These data suggest that lyso-Gb3, significantly influences ion transport in mouse colon, but that accumulation of Gb3 may be a pre-requisite for the more pronounced disturbances in GI physiology characteristic of FD.en
dc.description.sponsorshipScience Foundation Ireland (12/RC/2273_P2); Fondazione Cassa di Risparmio in Bologna (2020.0404)en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationDelprete, C., Uhlig, F., Caprini, M. and Hyland, N. P. (2024) 'Characterization of Fabry disease-associated lyso-Gb3 on mouse colonic ion transport and motility', American Journal of Physiology-Gastrointestinal and Liver Physiology. https://doi.org/10.1152/ajpgi.00220.2024en
dc.identifier.doihttps://doi.org/10.1152/ajpgi.00220.2024en
dc.identifier.eissn1522-1547en
dc.identifier.issn0193-1857en
dc.identifier.journaltitleAmerican Journal of Physiology-Gastrointestinal and Liver Physiologyen
dc.identifier.urihttps://hdl.handle.net/10468/16584
dc.language.isoenen
dc.publisherAmerican Physiological Societyen
dc.relation.project12/RC/2273_P2en
dc.relation.projectinfo:eu-repo/grantAgreement/EC/H2020::MSCA-COFUND-FP/754535/EU/APC Postdoctoral EXcellence Programme/APEXen
dc.rights© 2024, American Journal of Physiology-Gastrointestinal and Liver Physiology.en
dc.subjectFabry diseaseen
dc.subjectLyso-Gb3en
dc.subjectBiomarkeren
dc.subjectUssing chamberen
dc.subjectGastrointestinalen
dc.titleCharacterization of Fabry disease-associated lyso-Gb3 on mouse colonic ion transport and motilityen
dc.typeArticle (peer-reviewed)en
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