Neuroinflammation contributes to neurodegenerative disorders, including Alzheimer's disease (AD). Gut microbes are involved in regulating systemic inflammation. Short-chain fatty acids (SCFAs), which are among the many metabolites released by gut microbes, can cross the blood-brain barrier (BBB) and interact with microglia. High concentrations of individual SCFAs decrease the inflammatory responses of peripheral monocytes; therefore, we hypothesized that SCFAs act on their own or in combinations to reduce the inflammatory response of microglia. Cultured human THP-1 monocytic cells and differentiated human HL-60 myelomonocytic cells were used to model select immune functions of human microglia. Acetate, propionate, butyrate, formate, and valerate were added to cells alone or as a mixture containing SCFAs at an approximate physiological concentration ratio. The SCFA mixture, as well as several individual SCFAs at the highest concentrations used in the mixture (15-236 μM), decreased the secretion of interleukin (IL)-1β, monocyte chemoattractant protein (MCP)-1, tumor necrosis factor (TNF)-α, and cytotoxins by immune-stimulated THP-1 cells. GLPG 0974, a free fatty acid receptor (FFAR) 2/3 antagonist, did not block the inhibitory effect of the SCFA mixture on IL-1β secretion by THP-1 cells while blocking the inhibitory effect of formate alone. We demonstrated that formate and valerate alone reduced the phagocytic activity of immune-stimulated THP-1 cells. Formate, but not valerate, alone also inhibited the N-formylmethionine-leucyl-phenylalanine (fMLP)-induced respiratory burst of HL-60 cells, reducing the production of reactive oxygen species (ROS). Our data indicate that SCFAs could regulate select microglial functions that are disrupted in AD.

中文翻译：

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短链脂肪酸（SCFA）单独或组合使用可调节小胶质细胞样细胞的选择免疫功能。

神经炎症会导致神经退行性疾病，包括阿尔茨海默氏病（AD）。肠道微生物参与调节全身性炎症。肠道微生物释放的许多代谢产物中的短链脂肪酸（SCFA）可以穿过血脑屏障（BBB）并与小胶质细胞相互作用。高浓度的单个SCFA会降低外周单核细胞的炎症反应；因此，我们假设SCFA单独或联合作用可减少小胶质细胞的炎症反应。培养的人类THP-1单核细胞和分化的人类HL-60骨髓单核细胞被用于模拟人类小胶质细胞的选择免疫功能。醋酸，丙酸，丁酸，甲酸盐，将戊二酸和戊酸酯以大约生理浓度比单独或以含有SCFA的混合物形式加入细胞中。SCFA混合物以及混合物中使用的最高浓度的几种单个SCFA（15-236μM）减少了白介素（IL）-1β，单核细胞趋化蛋白（MCP）-1，肿瘤坏死因子（TNF）的分泌）-α和免疫刺激的THP-1细胞产生的细胞毒素。GLPG 0974，一种游离脂肪酸受体（FFAR）2/3拮抗剂，没有阻断SCFA混合物对THP-1细胞分泌IL-1β的抑制作用，而仅阻断了甲酸盐的抑制作用。我们证明，单独的甲酸酯和戊酸酯会降低免疫刺激的THP-1细胞的吞噬活性。格式化，但不要英勇，单独使用还可以抑制N-甲酰基甲硫氨酸-亮氨酰-苯丙氨酸（fMLP）诱导的HL-60细胞呼吸爆发，从而减少活性氧（ROS）的产生。我们的数据表明，SCFA可以调节在AD中受到干扰的小胶质细胞功能。