Disruption of the microbiota-gut-brain axis is a defining characteristic of the α-Gal A (-/0) mouse model of Fabry disease
C. Delprete,
R. Rimondini Giorgini,
E. Lucarini,
T.F.S. Bastiaanssen,
D. Scicchitano,
N. Interino,
F. Formaggio,
F. Uhlig,
C. Ghelardini,
N.P. Hyland,
J.F. Cryan,
R. Liguori,
M. Candela,
J. Fiori,
S. Turroni,
L. Di Cesare Mannelli,
M. Caprini
Affiliations
C. Delprete
Laboratory of Human and General Physiology, Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Bologna, Italy
R. Rimondini Giorgini
Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
E. Lucarini
Department of Neuroscience, Psychology, Drug Research and Child Health, Neurofarba, Pharmacology and ToxicoKGMI_A_2256045logy Section, University of Florence, Florence, Italy
T.F.S. Bastiaanssen
APC Microbiome Ireland, University College Cork, Cork, Ireland
D. Scicchitano
Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Bologna, Italy
N. Interino
Complex Operational Unit Clinica Neurologica, IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy
F. Formaggio
Laboratory of Human and General Physiology, Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Bologna, Italy
F. Uhlig
APC Microbiome Ireland, University College Cork, Cork, Ireland
C. Ghelardini
Department of Neuroscience, Psychology, Drug Research and Child Health, Neurofarba, Pharmacology and ToxicoKGMI_A_2256045logy Section, University of Florence, Florence, Italy
N.P. Hyland
APC Microbiome Ireland, University College Cork, Cork, Ireland
J.F. Cryan
APC Microbiome Ireland, University College Cork, Cork, Ireland
R. Liguori
Complex Operational Unit Clinica Neurologica, IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy
M. Candela
Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Bologna, Italy
J. Fiori
Complex Operational Unit Clinica Neurologica, IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy
S. Turroni
Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Bologna, Italy
L. Di Cesare Mannelli
Department of Neuroscience, Psychology, Drug Research and Child Health, Neurofarba, Pharmacology and ToxicoKGMI_A_2256045logy Section, University of Florence, Florence, Italy
M. Caprini
Laboratory of Human and General Physiology, Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Bologna, Italy
ABSTRACTFabry disease (FD) is an X-linked metabolic disease caused by a deficiency in α-galactosidase A (α-Gal A) activity. This causes 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 their quality of life. It is generally accepted that Gb3 and lyso-Gb3 are involved in the symptoms; nevertheless, the origin of these symptoms is complex and multifactorial, and the exact mechanisms of pathogenesis are still poorly understood. Here, we used a murine model of FD, the male α-Gal A (-/0) mouse, to characterize functionality, behavior, and microbiota 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 anxiety-like behavior. We also showed for the first time that symptomology was associated with early compositional and functional dysbiosis of the gut microbiota, paralleled by alterations in fecal short-chain fatty acid 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.
