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Characterization of Fabry disease-associated lyso-Gb3 on mouse colonic ion transport and motility
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Date
2024
Authors
Delprete, Cecilia
Uhlig, Friederike
Caprini, Marco
Hyland, Niall P.
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Publisher
American Physiological Society
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Abstract
Fabry 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.
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Keywords
Fabry disease , Lyso-Gb3 , Biomarker , Ussing chamber , Gastrointestinal
Citation
Delprete, 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.00220.2024
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© 2024, American Journal of Physiology-Gastrointestinal and Liver Physiology.