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

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by a deficiency in a-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 (I_sc). This increase in I_sc was insensitive to inhibition of the cystic fibrosis transmembrane conductance regulator and Na-K-Cl cotransporter 1, suggesting that the increase in I_sc is Cl^- ion independent. This response was also insensitive to inhibition by the neurotoxin, tetrodotoxin. In addition, 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 prerequisite for the more pronounced disturbances in GI physiology characteristic of FD. NEW & NOTEWORTHY Fabry disease-associated lyso-Gb₃ significantly influences mouse colonic ion transport in a Cl^- ion-independent manner.