Disruption of the Microbiota-Gut-Brain Axis is a Defining Characteristic of the a-Gal A (-/0) Mouse Model of Fabry Disease
Fabry disease (FD) is an X-linked metabolic disease due to a deficiency in a-galactosidase A (a-Gal A) activity. This causes the accumulation of glycosphingolipids, especially globotriaosylceramide (Gb3), in different cells and organs. Neuropathic pain and gastrointestinal (GI) symptoms, such as abdominal pain, nausea, diarrhea, constipation and early satiety, are the most frequent symptoms reported by FD patients and severely affect patients' quality of life. It is generally accepted that Gb3 and lyso-Gb3 are involved in symptoms, nevertheless, the origin of these is complex and multifactorial and the exact mechanisms of pathogenesis are still poorly understood. Here we used a murine model of FD, the male a-Gal A (-/0) mouse, to characterize functionality, behavior and microbiome in an attempt to elucidate the microbiota-gut-brain axis at three different ages.  We provided evidence of a diarrhea-like phenotype and visceral hypersensitivity in our FD model, together with reduced locomotor activity and an anxiety like behavior. We also showed for the first time that symptomology was associated with an early compositional and functional dysbiosis of the gut microbiota, paralleled by alterations in fecal short-chain fatty acids levels, which partly persisted with advancing age. Interestingly, most of the dysbiotic features suggested a disruption of gut homeostasis, possibly contributing to accelerated intestinal transit, visceral hypersensitivity and impaired communication along the gut-brain axis.