Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, 32816, USA.
Sci Rep. 2019 Jun 19;9(1):8824. doi: 10.1038/s41598-019-45348-z.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by glia over-proliferation, neuro-inflammation, perturbed neural circuitry, and gastrointestinal symptoms. The role of gut dys-biosis in ASD is intriguing and should be elucidated. We investigated the effect of Propionic acid (PPA), a short-chain fatty acid (SCFA) and a product of dys-biotic ASD gut, on human neural stem cells (hNSCs) proliferation, differentiation and inflammation. hNSCs proliferated to 66 neuropsheres when exposed to PPA versus 45 in control. The neurosphere diameter also increased at day 10 post PPA treatment to (Mean: 193.47 um ± SEM: 6.673 um) versus (154.16 um ± 9.95 um) in control, p < 0.001. Pre-treatment with β-HB, SCFA receptor inhibitor, hindered neurosphere expansion (p < 0.001). While hNSCs spontaneously differentiated to (48.38% ± 6.08%) neurons (Tubulin-IIIβ positive) and (46.63% ± 2.5%) glia (GFAP positive), PPA treatment drastically shifted differentiation to 80% GFAP cells (p < 0.05). Following 2 mM PPA exposure, TNF-α transcription increased 4.98 fold and the cytokine increased 3.29 fold compared to control (P < 0.001). Likewise, GPR41 (PPA receptor) and pro-survival p-Akt protein were elevated (p < 0.001). PTEN (Akt inhibitor) level decreased to (0.42 ug/ul ± 0.04 ug/ul) at 2 mM PPA compared to (0.83 ug/ul ± 0.09 ug/ul) in control (p < 0.001). PPA at 2 mM decreased neurite outgrowth to (80.70 um ± 5.5 um) compared to (194.93 um ± 19.7 um) in control. Clearly, the data supports a significant role for PPA in modulating hNSC patterning leading to gliosis, disturbed neuro-circuitry, and inflammatory response as seen in ASD.
自闭症谱系障碍 (ASD) 是一种神经发育障碍，其特征是神经胶质细胞过度增殖、神经炎症、神经回路紊乱和胃肠道症状。肠道菌群失调在 ASD 中的作用令人着迷，应该加以阐明。我们研究了丙酸（PPA）对人神经干细胞（hNSC）增殖、分化和炎症的影响，PPA 是一种短链脂肪酸（SCFA），也是失调的 ASD 肠道的产物。与对照组的 45 个相比，暴露于 PPA 的 hNSC 增殖到 66 个神经球。PPA 处理后第 10 天，神经球直径也增加到（均值：193.47±SEM：6.673μm），而对照组为 154.16μm±9.95μm，p<0.001。用β-HB（SCFA 受体抑制剂）预处理会阻碍神经球的扩张（p<0.001）。虽然 hNSC 会自发分化为（48.38%±6.08%）神经元（Tubulin-IIIβ 阳性）和（46.63%±2.5%）神经胶质细胞（GFAP 阳性），但 PPA 处理会将分化率急剧转变为 80%的 GFAP 细胞（p<0.05）。在暴露于 2mM PPA 后，TNF-α 的转录增加了 4.98 倍，细胞因子增加了 3.29 倍，与对照组相比（p<0.001）。同样，PPA 受体 GPR41 和生存相关的 p-Akt 蛋白水平升高（p<0.001）。与对照组相比（0.83±0.09μg/ul），2mM PPA 时的 PTEN（Akt 抑制剂）水平降低至（0.42±0.04μg/ul）（p<0.001）。与对照组相比（194.93±19.7μm），2mM PPA 时的神经突生长减少至（80.70±5.5μm）。显然，这些数据支持 PPA 在调节 hNSC 模式形成中发挥重要作用，导致神经胶质增生、神经回路紊乱和炎症反应，这些都是 ASD 的特征。
