Abstract
Fabry disease is a rare X-linked lysosomal storage disorder resulting from deficient activity of α-galactosidase A, leading to the accumulation of glycosphingolipids such as globotriaosylsphingosine (lyso-Gb3). The gastrointestinal symptoms of this disease may be disabling, and the life expectancy of affected patients is shortened by kidney and heart disease. Our hypothesis was that lyso-Gb3 may modify the gut microbiota. The impact of a clinically relevant concentration of lyso-Gb3 on mono- or multispecies bacterial biofilms were evaluated. A complex bacterial community from the simulated transverse colon microbiota was studied using quantitative PCR to estimate different bacterial group concentrations and a HPLC was used to estimate short-chain fatty acids concentrations. We found that lyso-Gb3 increased the biofilm-forming capacity of several individual bacteria, including Bacteroides fragilis and significantly increased the growth of B. fragilis in a multispecies biofilm. Lyso-Gb3 also modified the bacterial composition of the human colon microbiota suspension, increasing bacterial counts of B. fragilis, among others. Finally, lyso-Gb3 modified the formation of short-chain fatty acids, leading to a striking decrease in butyrate concentration. Lyso-Gb3 modifies the biology of gut bacteria, favoring the production of biofilms and altering the composition and short-chain fatty-acid profile of the gut microbiota.
Highlights
Fabry disease is a rare X-linked lysosomal storage disorder resulting from deficient activity of α-galactosidase A, leading to the accumulation of glycosphingolipids such as globotriaosylsphingosine
The most consistent results were obtained for E. coli and B. fragilis, in which all three strains tested significantly increased the biofilm formation for each species
The pathophysiology of gastrointestinal symptoms in Fabry disease is complex and multifactorial, though the fact that these symptoms stem from Gb3 and lyso-Gb3 accumulation within intestinal tissues is widely accepted[15]
Summary
Fabry disease is a rare X-linked lysosomal storage disorder resulting from deficient activity of α-galactosidase A, leading to the accumulation of glycosphingolipids such as globotriaosylsphingosine (lyso-Gb3). There are two dominant hypotheses as to the mechanisms of the gastrointestinal symptoms reported in Fabry disease: dysfunction of autonomic neurons controlling gut motility[13] on the one hand and vascular dysfunction and/or ischemia due to intestinal smooth-muscle or endothelial cell injury[14] on the other. These mechanisms lead to a rapid gut transit time, impaired peristalsis, gastroparesis and intestinal stasis, bacterial overgrowth, and nutrient malabsorption[15]. An altered microbiota may release uremic toxins or their precursors, which accelerate the progression of chronic kidney disease and cardiovascular disease, both key consequences of Fabry disease[20,21,22], or may impair the release of protective molecules that modulate the inflammatory and immune responses, among others[23]
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