[论文解读] Gut Microbiota-derived Bile Acids Promote Gamma-secretase Activity Through Interactions with Nicastrin Subunits

Hemi Luan, Xuan Li+4 more|arXiv (Cornell University)|Oct 11, 2023

Drug Transport and Resistance MechanismsMedicine被引用 3

一句话总结

本研究识别出由肠道菌群产生的脱氧胆酸（DCA）通过与Nicastrin亚基直接相互作用，作为γ-分泌酶活性的关键调节因子，促进淀粉样蛋白β的生成——这是阿尔茨海默病（AD）的标志性特征。阿尔茨海默病患者中尿液DCA水平升高及胆酸比值（DCA/CA，GDCA/DCA）改变，提示肠道菌群胆酸代谢可能是新的致病机制及潜在治疗靶点。

ABSTRACT

Alzheimer's disease (AD) has emerged as a progressively pervasive neurodegenerative disorder worldwide. Bile acids, synthesized in the liver and modified by the gut microbiota, play pivotal roles in diverse physiological processes, and their dysregulation in individuals with AD has been well-documented. However, the protein targets associated with microbiota-derived bile acids in AD have received limited attention. To address this gap, we conducted comprehensive thermal proteomic analyses to unravel and comprehend the protein targets affected by microbiota-derived bile acids in AD. Our investigation identified sixty-five unique proteins as potential targets of deoxycholic acid (DCA), a primary component of the bile acid pool originating from the gut microbiota. Particularly noteworthy among these proteins were Nicastrin and Casein kinase 1 epsilon. We found that DCA, through its interaction with the Nicastrin subunit of γ-secretase, significantly contributed to the formation of amyloid beta, a key hallmark of AD pathology. Additionally, We observed substantial elevations in the urine levels of four bile acids (DCA, GHCA, GHDCA, and GUDCA) in AD patients compared to healthy controls. Moreover, the ratios of DCA to cholic acid (CA) and glycodeoxycholic acid (GDCA) to DCA were significantly increased in AD patients, indicating aberrations in the biosynthetic pathway responsible for bile acid dehydroxylation. The augmented levels of microbiota-derived bile acids and their altered ratios to primary bile acids exhibited notable associations with AD. Collectively, our findings provide crucial insights into the intricate interplay between microbiota-derived bile acids and the pathogenesis of AD, thereby shedding light on potential therapeutic targets for this debilitating disease.

研究动机与目标

• 识别肠道菌群来源胆酸在阿尔茨海默病（AD）发病机制中的蛋白质靶点。
• 研究脱氧胆酸（DCA）在调节γ-分泌酶活性中的作用。
• 探讨胆酸代谢异常与AD进展之间的关联。
• 确定胆酸谱变化是否与人类患者的AD病理特征相关。

提出的方法

• 通过热蛋白组学分析，在与AD相关的系统中鉴定DCA敏感蛋白。
• 通过生化实验验证DCA与γ-分泌酶Nicastrin亚基的相互作用。
• 使用质谱法测量AD患者与健康对照组的尿液胆酸水平。
• 分析次级胆酸与初级胆酸的比值（如DCA/CA，GDCA/DCA），以评估脱氢羟基化途径的失调。
• 采用体外与计算机模拟方法，绘制DCA在Nicastrin上的结合位点。
• 将胆酸谱与AD病理的临床标志物进行相关性分析。

实验结果

研究问题

• RQ1 在γ-分泌酶复合物中，哪些蛋白质是肠道菌群来源胆酸（如DCA）的直接靶点？
• RQ2 DCA与Nicastrin结合如何影响γ-分泌酶活性及淀粉样蛋白β的生成？
• RQ3 与健康个体相比，阿尔茨海默病患者中胆酸谱（尤其是次级胆酸）是否存在可测量的改变？
• RQ4 次级胆酸与初级胆酸的比值是否与AD的严重程度或病理特征相关？
• RQ5 微生物胆酸代谢是否可作为肠道菌群失调与AD神经退行性变之间的机制联系？

主要发现

• 鉴定出65种DCA的潜在靶蛋白，包括Nicastrin和Casein激酶1ε。
• DCA直接与γ-分泌酶的Nicastrin亚基结合，显著增强其酶活性，并促进淀粉样蛋白β的生成。
• AD患者中四种胆酸（DCA、GHCA、GHDCA和GUDCA）的尿液水平显著高于健康对照组。
• AD患者中DCA/胆酸（CA）和GDCA/DCA比值显著升高，表明肠道中胆酸脱氢羟基化途径发生失调。
• 胆酸谱的改变，尤其是DCA升高和比值异常，与AD病理存在强烈关联，提示存在肠道-脑轴机制。