細胞間藉由分泌奈米大小之胞外泌體 (extracellular vesicles，EVs) 中所攜帶之訊息分子來相互溝通，微生物亦會分泌胞外泌體，然目前少有研究探討微生物胞外泌體之功能性及其於微生物之間所扮演的角色。有文獻顯示，一些益生菌所分泌之胞外泌體可改善腸道發炎相關疾病並調整免疫功能。人類腸道中的困難梭狀芽孢桿菌 (Clostridioides difficile) 過度生長會造成困難梭狀芽孢桿菌感染症 (C. difficile infection，CDI)，CDI 是被關注之重大院內感染之一，主要的治療方式為抗生素治療，然患者於治療後可能再次復發，另一治療選擇為糞便菌群移植 (fecal microbiota transplantation，FMT)，雖然 FMT 可治療復發性 CDI，但其作用機制尚不明確並且存在一些限制，因此，開發其它可能的治療方法就顯得重要。有研究顯示，益生菌具治療 CDI 疾病之潛力，但詳細作用未知。本研究探討益生菌胞外泌體對 C. difficile 等腸道致病菌以及食品病原菌生長之抑制能力並釐清益生菌胞外泌體抑制腸道致病菌生長可能的分子機制，以瞭解細菌與細菌之間的交互作用及溝通方式。本研究建置益生菌胞外泌體之分離方法，分析其特性與組成分，結果顯示，數種益生菌分泌之胞外泌體可有效抑制 C. difficile 之生長，然對其它致病菌如具核梭狀桿菌 (Fusobacterium nucleatum subsp. nucleatum)、食品病原菌如金黃色葡萄球菌 (Staphylococcus aureus) 及腸炎弧菌 (Vibrio parahaemolyticus) 之生長則不具影響。試驗證明，對 C. difficile 之生長具顯著抑制效果的益生菌胞外泌體能夠選擇性進入 C. difficile 菌體內；以脂質體學分析益生菌胞外泌體膜上之脂質組成，發現不同菌種所含的脂質種類皆不同，並證實特定脂質組成之益生菌胞外泌體決定其進入 C. difficile 之能力。益生菌胞外泌體中的小片段 RNAs (small RNAs) 經定序及進行 C. difficile 基因之靶向預測後發現，胞外泌體中具有能與 C. difficile 特定基因序列相對應的小片段 RNAs，推測胞外泌體中的小片段 RNAs 應能透過抑制C. difficile 當中的目標基因達到抑制其生長之效果。進一步將經益生菌胞外泌體處理之 C. difficile 進行轉錄體分析，並以定量即時聚合酶連鎖反應進行驗證，結果顯示，益生菌胞外泌體可調節 C. difficile 的基因表現，經益生菌胞外泌體處理後，fusA、rpoC、secA2、tcdA、tcdB、txeR 與 luxS 等基因的表現均下降，顯示益生菌胞外泌體所包覆的小片段 RNAs 可藉由抑制 C. difficile 之繁殖或致毒相關基因表現，進而抑制其生長與毒素。本研究證明，不同來源的益生菌胞外泌體抑制微生物生長之能力具特異性，益生菌胞外泌體透過其雙層膜上的特定脂質使之可選擇性進入 C. difficile 菌體中，並透過胞外泌體所包覆的特定小片段 RNAs 抑制 C. difficile 之生長及毒素基因表現，進而抑制其繁殖與致病性。因此，益生菌胞外泌體中所含的功能性成分，如本研究中的小片段 RNAs，未來或可應用於 RNAs 藥物開發，以作為 CDI 的新穎治療方針。

Cells communicate with each other via secreting extracellular vesicles (EVs). The study showed that probiotics have a positive effect on the prevention of initial Clostridioides difficile infection (CDI), and EVs may be an important factor in regulation. This study explored the inhibitory effect of probiotics-derived EVs on the growth of C. difficile and other pathogens. In addition, this study further clarified the possible molecular mechanisms of probiotics-derived EVs on inhibiting the growth of pathogens. The lactic acid bacteria-derived EVs were added to the culture medium of pathogens and measured the growth curve. In the experiment of fluorescence staining, EVs were stained with fluorescent dye and then incubated with pathogens. After interacting with EVs, the pathogens were stained and observed with confocal laser scanning microscope. Besides, lipidomic analysis was used to analyze the lipid composition on the membrane of EVs. Pathogens were treated with EVs and then analyzed by transcriptome sequencing. Finally, quantitative real-time polymerase chain reaction was used for verification. The results showed that probiotics-derived EVs treatment effectively inhibited the growth of C. difficile, whereas the EVs did not affect the growth of other pathogens such as Fusobacterium nucleatum, Staphylococcus aureus, and Vibrio parahaemolyticus. It was shown that EVs from different probiotics have different abilities on regulating the intestinal microorganisms. The probiotics-derived EVs selectively entered C. difficile through specific lipids on the bilayer membrane, and EVs carried specific small RNAs to inhibit the expression of growth and toxicity associated genes of C. difficile, thereby inhibiting its reproduction and pathogenicity.

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