PDF(Pubmed)
Abstract：
Intestinal peristalsis is vital for gastrointestinal physiology and host homeostasis and is frequently dysregulated in intestinal disorders. Gut microbiota can regulate gut motility, especially through the tryptophan metabolism pathway. However, the role of indoles as microbial tryptophan metabolites in colonic function requires further exploration. Here, we show that the delivery of indole acetic acid (IAA) targeting the colon can improve gut motility by activating the aryl hydrocarbon receptor (AHR). To achieve colon-targeted delivery, Eudragit S-100 (ES) and chitosan (CS) were used as drug carriers. After optimisation, IAA-loaded ES-coated CS nanoparticles exhibited an encapsulation efficiency of 83% and a drug-loading capacity of 16%. These nanoparticles exhibited pH-dependent characteristics and remained stable in acidic conditions and the upper intestine. In simulated intestinal fluid (pH 7.4) and colonic lumen, considerable amounts of IAA were released after approximately 4 h. Compared with free IAA, the nanoparticles exerted enhanced therapeutic effects on gut movement disorders induced by loperamide. The efficacy of IAA treatment was attributable to the activation of the AHR signalling pathway and increased levels of AHR agonists. Furthermore, the oral administration of IAA-loaded nanoparticles promoted serotonin secretion and maintained the intestinal barrier function. The experimental outcomes demonstrate the efficiency of the proposed colon-specific delivery system and highlight the role of IAA, produced by gut microbiota metabolism, in regulating gut peristalsis through AHR activation.
摘要：
肠蠕动对于胃肠生理学和宿主稳态至关重要,并且在肠道疾病中经常失调。肠道菌群可以调节肠道运动，特别是通过色氨酸代谢途径。然而,吲哚作为微生物色氨酸代谢产物在结肠功能中的作用需要进一步探索。这里,我们表明，靶向结肠的吲哚乙酸（IAA）的递送可以通过激活芳烃受体（AHR）来改善肠道运动。为了实现结肠靶向给药，使用EudragitS-100（ES）和壳聚糖（CS）作为药物载体。优化后,负载IAA的ES包被的CS纳米颗粒表现出83％的封装效率和16％的药物负载能力。这些纳米颗粒表现出pH依赖性特征,并且在酸性条件和上肠中保持稳定。在模拟肠液（pH7.4）和结肠腔中，大约4小时后释放了大量的IAA。与游离IAA相比，纳米颗粒对洛哌丁胺诱导的肠道运动障碍具有增强的治疗作用。IAA治疗的功效归因于AHR信号传导途径的激活和AHR激动剂水平的增加。此外，口服负载IAA的纳米粒促进5-羟色胺分泌并维持肠屏障功能。实验结果证明了所提出的结肠特异性递送系统的效率，并强调了IAA的作用。由肠道微生物群代谢产生，通过AHR激活调节肠道蠕动。
