Table_2_A Pilot Study Exploring the Association of Entacapone, Gut Microbiota, and the Subsequent Side Effects in Patients With Parkinson’s Disease.xlsx

Background and AimsEntacapone, one of the most common drugs distributed among patients with Parkinson’s disease, is a peripherally acting catechol-O-methyltransferase (COMT) inhibitor that is used in addition to levodopa to control symptoms. However, there have been negative effects reported against entacapone, namely, gastrointestinal (GI) problems and drowsiness. In this pilot study, we aim to examine the hypothesis that the discomfort induced by entacapone might be originated from the shift of microbial composition by adjusting the effect of levodopa.
MethodsThe population in this pilot study consisted of 13 PD patients treated with levodopa only and 11 with both levodopa and entacapone. The 16S rRNA gene sequence data were processed, aligned, and categorized using the DADA2. Alpha diversity indices for Observed, Chao1, Shannon, and Simpson metrics were calculated with Phyloseq 1.32.0. Dissimilarities were calculated using unweighted unique fraction metrics (Unifrac), weighted Unifrac, and Canberra distance. Functional differences were calculated by PICRUSt2 based on the KEGG database.
ResultsResults of 16S rRNA sequencing analysis showed that while entacapone did not influence the species richness, the composition of the microbial community shifted considerably. Relative abundances of bacteria related to constipation and other GI disorders also altered significantly. Functional enrichment analysis revealed changes in the metabolic activity of alanine, aspartate, and glutamate. These amino acids are related to common side effects of entacapone such as auditory hallucinations, fatigue, and nightmare.
ConclusionOur findings provide testable hypothesis on the cause of unpleasant side effects of entacapone, which in the long run could possibly be reduced through gut microbiota manipulation.

背景与目的：恩他卡朋（Entacapone）是帕金森病（Parkinson’s disease）患者常用药物之一，属于外周作用型儿茶酚-O-甲基转移酶（catechol-O-methyltransferase, COMT）抑制剂，常与左旋多巴（levodopa）联用以控制疾病症状。但已有报道指出恩他卡朋存在不良反应，即胃肠道（gastrointestinal, GI）不适与嗜睡。本预实验旨在验证下述假说：恩他卡朋引发的不适症状，可能源于其通过影响左旋多巴的作用而改变了肠道微生物群落组成。
方法：本预实验的研究对象共24名帕金森病患者，其中13名单纯接受左旋多巴治疗，11名同时接受左旋多巴与恩他卡朋联合治疗。采用DADA2工具对16S rRNA基因测序数据进行处理、比对与分类。使用Phyloseq 1.32.0软件计算Observed、Chao1、Shannon及Simpson等α多样性指数。分别采用非加权UniFrac（unweighted Unifrac）、加权UniFrac以及堪培拉距离计算样本间群落差异。基于京都基因与基因组百科全书（KEGG）数据库，通过PICRUSt2工具预测菌群功能组间的差异。
结果：16S rRNA测序分析结果显示，尽管恩他卡朋未对物种丰富度产生影响，但微生物群落组成发生了显著改变。与便秘及其他胃肠道病症相关的细菌类群相对丰度同样出现显著变化。功能富集分析结果表明，丙氨酸、天冬氨酸与谷氨酸的代谢活性发生改变，而这三类氨基酸与恩他卡朋常见不良反应（如幻听、疲劳及梦魇）存在关联。
结论：本研究结果为恩他卡朋不良反应的潜在致病机制提供了可验证的假说，未来或可通过调控肠道微生物群来减轻此类不适症状。