Gut dysbiosis impairs intestinal renewal and lipid absorption in Scarb2 deficiency-associated neurodegeneration

Scavenger receptor class B, member 2 (SCARB2) is related to Gaucher disease (GD) and Parkinson's disease (PD). Deficiency in the SCARB2 gene causes progressive myoclonus epilepsy (PME), a rare group of inherited neurodegenerative diseases characterized by myoclonus. We found that Scarb2 deficiency in mice leads to age-dependent dietary lipid malabsorption, accompanied with vitamin E deficiency. Our investigation revealed that Scarb2 deficiency is associated with gut dysbiosis and an altered bile acid pool, leading to hyperactivation of FXR in intestine. Hyperactivation of FXR impaired epithelium renewal and lipid absorption. Patients with SCARB2 mutations had a severe reduction in their vitamin E levels and cannot absorb dietary vitamin E. Finally, supplementing vitamin E ameliorates the neuromotor impairment and neuropathy in Scarb2 knockout mice. These data indicate gastrointestinal dysfunction is associated with SCARB2 deficiency-related neurodegeneration, and SCARB2-associated neurodegeneration can be improved by addressing the nutrition deficits and gastrointestinal issues.

B类清道夫受体成员2（Scavenger receptor class B, member 2，SCARB2）与戈谢病（Gaucher disease，GD）及帕金森病（Parkinson's disease，PD）密切相关。SCARB2基因缺陷可引发进行性肌阵挛癫痫（progressive myoclonus epilepsy，PME）——一类以肌阵挛为核心特征的罕见遗传性神经退行性疾病群。本研究发现，小鼠体内Scarb2缺陷会导致年龄依赖性的膳食脂质吸收不良，并伴随维生素E缺乏。进一步研究揭示，Scarb2缺陷与肠道菌群失调及胆汁酸池改变相关，进而引发肠道内法尼醇X受体（Farnesoid X receptor，FXR）过度激活。FXR过度激活会损害上皮更新与脂质吸收功能。携带SCARB2突变的患者体内维生素E水平显著降低，且无法吸收膳食来源的维生素E。最终，补充维生素E可改善Scarb2基因敲除小鼠的神经运动功能障碍与神经病变。上述数据表明，胃肠功能紊乱与SCARB2缺陷相关的神经退行性变存在关联，且通过纠正营养缺陷与改善胃肠道问题，可改善SCARB2相关神经退行性疾病。