探討當代抗憂鬱藥與腸道菌相組成之相關性

憂鬱症是一種相當嚴重的精神疾病之一，它造成了全世界巨大的疾病負擔。抗憂鬱藥是用於治療憂鬱症的精神藥物之一，常見處方有選擇性血清素再吸收抑製劑和血清素-去甲腎上腺素再吸收抑製劑 (SSRIs/SNRIs)。先前的老鼠和人類研究表明，憂鬱症和 SSRI/SNRI的使用與腸道微生物群組成以及特定細菌種類的改變有關。我們的研究旨在探索憂鬱症病人中，使用 SSRIs 或 SNRIs 藥物與未使用抗憂鬱藥或使用其他類型抗憂鬱藥的腸道微生物群差異。我們的研究分析 139 名有憂鬱症狀的患者(包含鬱症，與經歷鬱期的躁鬱症患者)的腸道微生物群特徵。我們通過病歷搜索、修改後的中文版終生精神疾病診斷晤談手冊、貝克憂鬱量表 (BDI) 和食物頻率問卷 (FFQ) 收集了受試者的抗憂鬱藥使用情況、基本人口統計學特徵（包括飲食習慣）以及情緒狀況。在 16S rRNA 定序（Illumina Miseq 平台）之前，通過 QIAamp DNA Mini Kit 或苯酚 - 氯仿提取方法從糞便樣本中提取微生物群的DNA。藉由藥物使用資訊及記錄，受試者被分到SSRI/SNRI組、其他類型抗憂鬱藥組和無使用抗憂鬱藥組。此外，考慮到SSRIs和SNRIs在3～12個月內可達到治療效果，我們更進一步將SSRI/SNRI組分為短、中、長的時間組。我們比較了組間的 alpha 和 beta 多樣性，並進行多變量回歸以找出有顯著差異的菌種。與未接受抗憂鬱藥的患者相比，接受抗憂鬱鬱藥治療（SSRI/SNRI 或其他類型）的患者的 alpha 多樣性較低 (未達統計顯著)。在 beta 多樣性中，統計結果顯示 SSRI/SNRI 組和未使用抗憂鬱藥組之間存在顯著差異（p=0.0037, unweighted Uni-Frac distance）。此外，當比較 SSRI/SNRI 組和未使用抗憂鬱藥組時，梭菌屬 (Clostridium) 以及一個來自瘤胃菌科 (Ruminococcaceae) 的菌屬有顯著差異，這兩隻菌的豐富度也隨著使用SSRIs或SNRIs的時間變長而減少。另一方面，當比較 SSRI/SNRI 組和其他類型抗憂鬱藥組時，球菌(Coprococcus)、瘤胃球菌 (Ruminococcus)、類伊格爾茲氏菌屬 (Paraeggerthella)和乳酸菌 (Lactonifactor) 有顯著差異。在細菌間的相關性分析中，SSRI/SNRI 組和未使用抗憂鬱藥組有類似的相關模式，而在其他類型抗憂鬱組中出現了更多負相關菌群。此外，與其他抗憂鬱類型組和未使用抗憂鬱藥組相比，SSRI/SNRI 組細菌間的相關性相對降低許多。總結來說，我們發現使用抗憂鬱藥的菌種多樣性相對較低，而使用抗憂鬱藥病患的腸道菌相組成與未使用任何抗憂鬱藥治療的病患的組成有顯著差異，我們更深入並發現瘤胃球菌科的兩個屬可能會受到 SSRI或SNRI 的使用而被影響，並隨時間遞減。由於 SSRI/SNRI 使用時間亞組的分類是基於其達到藥效以及持續療效的時間，因此應進一步探討這些菌群與症狀嚴重程度以及藥效之間的關聯。

關鍵字

抗憂鬱藥；腸道微生物；鬱期； SSRI/SNRI ；腸道生態多樣性；抗菌效果

並列摘要

Depression is a severe psychiatric disorder which had collectively caused great burden of diseases. Antidepressants are one of the psychotropics used to treat depression, commonly prescribed types such as selective serotonin reuptake inhibitor and serotonin–norepinephrine reuptake inhibitor (SSRIs/SNRIs). Previous murine and human studies have indicated depression and SSRI/SNRI were associated with altered gut microbiota composition and specific bacterial taxa. Our study aimed to explore the gut microbiota targets with SSRI or SNRI use compared with those without antidepressant treatments or with other types of antidepressants. In total, our study consisted of 139 depression patients’ gut microbiota profile. We collected antidepressants use, basic demographic characteristics including dietary intake, and mood or symptom information from subjects via medical records searching, the modified Chinese version of Schedule for Affective Disorders and Schizophrenia-Lifetime version, Beck Depression Inventory (BDI), and food-frequency questionnaire (FFQ). Microbiota DNA was extracted from stool samples by either QIAamp DNA Mini Kit or phenol-chloroform extraction method before 16s rRNA sequencing (Illumina Miseq platform). Patients were classified into three antidepressant groups, SSRI/SNRI, other antidepressants, and without antidepressant treatments. Further, considering the therapeutic effect of SSRIs and SNRIs can be reached at 3 to 12 months, SSRI/SNRI group was divided into short, moderate, and long duration subgroups. We compared the alpha and beta diversity between groups. Multivariate regression was performed for selecting candidate bacterial taxa. Patients with antidepressants treatment (SSRI/SNRI or other types) had lower alpha diversity compared with those without antidepressant treatment (non-sig). In beta diversity, PERMANOVA result of unweighted UniFrac distance showed a significant separation between SSRI/SNRI group and without antidepressant treatment group (p=0.0037). Further, two taxa, Clostridium, and an undefined genus of Ruminococcaceae were altered when comparing SSRI/SNRI and without antidepressant treatment group. On the other hand, Coprococcus, Ruminococcus, Paraeggerthella, and Lactonifactor were altered when comparing SSRI/SNRI and other antidepressants group. Similar patterns of correlations between taxa were shown in SSRI/SNRI and without antidepressant treatments group, while more negative correlated taxa were presented in other antidepressants group. Further, the correlation between taxa was weaker in SSRI/SNRI group compared with other antidepressants group and without antidepressant treatments group. In summary, we found that the gut microbiota diversity of patients with antidepressant treatments was lower than those without treatments, and the gut microbiota composition of patients with antidepressant treatments was significantly different from patient without any antidepressant treatment. We further discovered that two genera of the Ruminococcaceae family might be affected by SSRIs or SNRIs, and the abundance decreased with the duration of treatments. Since the classification criteria of duration subgroups of SSRI/SNRI were based on the time to achieve efficacy and maintain therapy, the relationship between those taxa, severity of symptoms, and antidepressant efficacy should be further explored. Based on previous studies and the development history of antidepressants, we hypothesize that antidepressants, especially SSRIs and SNRIs, might have antimicrobial effects on certain bacteria taxa.

並列關鍵字

Antidepressants ； gut microbiota ； depression ； SSRI/SNRI ； gut microbial diversity ； antimicrobial effects

參考文獻

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探討當代抗憂鬱藥與腸道菌相組成之相關性

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