阿茲海默症 (Alzheimer’s disease；AD) 係主要的腦神經退化性疾病之一，患者症狀包含記憶缺失及認知與語言能力下降。AD 成因複雜，腦神經細胞中類澱粉前驅蛋白質(Amyloid precursor protein；APP) 經酵素水解後形成乙型類澱粉蛋白(Amyloid beta；Aβ)，Aβ 錯誤摺疊後會異常聚集並自組裝形成寡聚物(Oligomer) 和纖維(Fibril)，最後形成斑塊(Plaque) 並導致神經細胞死亡。腸道微生物的組成及變化與人體健康相關，腸道中分佈複雜的神經系統，腸道與腦之間透過腸腦軸(Gut-brain axis) 互相聯繫與影響，而腸道微生物會產生Aβ 與其它腦神經傳導物質(Neurotransmitters)，影響腸道細胞及免疫細胞，進而影響宿主的行為與情緒表現。胞外泌體(Extracellular vesicles；EV) 為奈米大小之球形脂雙層膜 (Lipid bilayer) 構造，EV 內包覆有核酸及蛋白質等成分，細菌分泌之EV 會與鄰近細菌交互作用，進而調控微生物環境及微生物本身。本研究探討APP knock-in AD 模型APPNL-G-F/NL-G-F 基因轉殖小鼠(Transgenic mice；TG) 腸道微生物組成之變化，以釐清影響AD 病程的關鍵腸道微生物菌種，並探討乳酸菌(Lactic acid bacteria；LAB) Pediococcus acidilactici NCKU-C01 及其分泌之 EV (LAB-EV) 延緩 AD 症狀之潛力。試驗結果顯示，3 月齡 non-TG 及 TG 小鼠之腸道微生物組成具差異性，TG 小鼠腸道益生菌含量於AD 病狀發生前減少，體外試驗將Aβ 寡聚體及 TG 小鼠血清分離之EV (TGEV) 與益生菌共培養，以分析對益生菌生長之影響，結果顯示，Aβ 寡聚體及TGEV 皆會減緩P. acidilactici NCKU-C01 之生長，以口服方式給予TG 小鼠P. acidilactici NCKU-C01 或LAB-EV 4 周後，小鼠短期工作記憶能力提升，腦部海馬迴區域與血清之Aβ 表現量及腸道中APP 與 Aβ 表現量均顯著下降。此外，給予LAB-EV 可以減緩TG 小鼠腸道通透性之增加，提升緊密連結蛋白ZO-1 之表現量。給予P. acidilactici NCKU-C01 或 LAB-EV 可改變 TG 小鼠腸道微生物與代謝物組成，且與non-TG 小鼠腸道微生物組成相似。體外試驗結果顯示，LAB-EV 可促進部分腸道益生菌生長，故P. acidilactici NCKU-C01 可能為AD 病程發展的關鍵微生物。口服48 小時後LAB-EV 會分布於小鼠迷走神經及腦中，而迷走神經切除之小鼠口服LAB-EV 後則無法於腦部觀察到其分布，顯示LAB-EV 可透過腸腦軸傳遞至腦部。綜合上述，P. acidilactici NCKU-C01 及其EV 有效減緩小鼠記憶缺失症狀及Aβ 堆積，改善腸道屏障功能及腸道微生物組成，進而調控腸道微生物代謝物之分泌，促使血清中與神經傳導相關代謝物含量上升，特定益生菌分泌之EV 具有干預AD 病程發展之潛力，且EV 透過迷走神經傳遞至腦部，未來具潛力開發做為治療AD 之新穎藥物。

Alzheimer’s disease (AD) is the most common degenerative brain disease. The gut microbiota homeostasis is associated with human health and affects brain function through gut-brain axis. This study intends to investigate the change of gut microbiota composition in AD transgenic mice and clarify the key gut microbiota that affect AD progression. In addition, amyloid precursor protein (APP) knock-in transgenic (TG) mice were administered with lactic acid bacteria (LAB) Pediococcus acidilactici NCKU-C01 or extracellular vesicles (EV) derived from P. acidilactici NCKU-C01 (LAB-EV) to evaluate the potential of P. acidilactici NCKU-C01 on alleviating the symptoms of AD. The results indicated that both diversity and composition of gut microbiota were difference between 3-month-old TG mice and wild-type (non-TG) ones. Amyloid beta (Aβ) or EV isolated from serum of TG mice treatment inhibited the growth of P. acidilactici NCKU-C01. P. acidilactici NCKU-C01 or LAB-EV treatment reduced Aβ concentration in the brain, colon, and serum when compared to TG mice. Besides, LAB-EV treatment reduced the intestinal permeability of TG mice. The data of sequencing showed that composition of gut microbiota in TG mice was shift after treating with P. acidilactici NCKU-C01 or LAB-EV. Moreover, P. acidilactici NCKU-C01 or LAB-EV treatment alleviated deficits in cognitive behavior. LAB-EV delivered to brain through gut-brain axis after oral administration to mice. In summary, P. acidilactici NCKU-C01 or LAB-EV has potential on AD intervention.

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