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.

法布雷病（Fabry disease, FD）是一种X连锁代谢性疾病，由α-半乳糖苷酶A（α-galactosidase A, α-Gal A）活性缺乏引发。该酶缺陷会导致糖鞘脂（glycosphingolipids），尤其是球三叶糖基神经酰胺（globotriaosylceramide, Gb3）在多种细胞与器官中异常蓄积。神经病理性疼痛及胃肠道（gastrointestinal, GI）症状，包括腹痛、恶心、腹泻、便秘与早饱感，是法布雷病患者最常见的主诉症状，严重降低患者的生活质量。目前公认Gb3与溶血球三叶糖基神经酰胺（lyso-globotriaosylceramide, lyso-Gb3）参与了疾病症状的发生，但此类症状的致病机制复杂且受多因素调控，确切的发病通路至今仍未完全阐明。本研究采用法布雷病小鼠模型——雄性α-Gal A缺陷（α-Gal A (-/0)）小鼠——对其生理功能、行为学特征与微生物组进行系统表征，旨在解析三个不同年龄阶段下的微生物群-肠-脑轴（microbiota-gut-brain axis）调控机制。研究证实，该模型小鼠出现腹泻样表型与内脏痛觉超敏，同时伴随运动能力减退与类焦虑行为。本研究首次发现，疾病症状与肠道微生物群的早期组成及功能失调显著相关，同时伴有粪便短链脂肪酸水平的异常改变，且此类变化在小鼠衰老进程中部分持续存在。值得关注的是，多数肠道菌群失调特征均提示肠道稳态遭到破坏，这可能是导致肠道转运加速、内脏痛觉超敏及肠-脑轴信号传递受损的重要诱因。