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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/102145完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 張嘉銓 | zh_TW |
| dc.contributor.advisor | Chia-Chuan Chang | en |
| dc.contributor.author | 柯岱岑 | zh_TW |
| dc.contributor.author | Tai-Tsen Ko | en |
| dc.date.accessioned | 2026-03-13T16:47:27Z | - |
| dc.date.available | 2026-03-14 | - |
| dc.date.copyright | 2026-03-13 | - |
| dc.date.issued | 2025 | - |
| dc.date.submitted | 2025-10-30 | - |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/102145 | - |
| dc.description.abstract | 近年來研究顯示，腸道菌群的多樣性和穩定性與宿主的健康或疾病息息相關。腸–腦軸 (gut-brain axis) 在重度憂鬱症、自閉症譜系障礙 (簡稱自閉症) 等多種精神疾患中扮演關鍵角色。先前研究表明， Lactiplantibacillus plantarum PS128有助於改善部分自閉症兒童的行為問題，並具潛在抗憂鬱效果。
為釐清L. plantarum PS128之代謝物之化學成分，本研究將L. plantarum PS128於MRS肉湯培養基中培養16小時後的上清液，以液-液分配法進行極性分割，得到正己烷、乙酸乙酯、正丁醇及水可溶部分，以固相萃取進行初步分離與富集，並利用LC-MS進行分析，最終鎖定具未知代謝物的乙酸乙酯層，其LC-ESI-MS 分析結果顯示[M+Na]^+偽分子峰為m/z 1,278.7，推估分子量為 1,256 Da。以逆相管柱層析技術進一步分離與純化，並使用NMR技術進行結構鑑定，結果顯示該代謝物為非核糖體多肽類似物，由三種胺基酸組成並連接一條長碳鏈，顯示該代謝物為一種脂肽。然儘管嘗試調整流動相之沖提比例及變更固定相之材質，仍未能完全去除其中之雜質。 此外，本研究同時針對L. plantarum PS128菌體內代謝物之萃取方法進行優化比較，比較不同的胞內代謝物萃取及淬滅方法。碘化丙啶染色及ATP含量測定結果顯示，常見之預冷有機溶劑萃滅法會破壞細胞膜，導致大量胞內代謝物的外洩，因此進行非靶向代謝體學時應採用不淬滅的處理方式，以最大化胞內代謝物的保留效果；此外，採用甲醇/乙腈/水混合溶劑萃取具有較廣泛的代謝物覆蓋範圍與更佳的整體再現性，更適合作為非靶向代謝體學研究的首選方法。同時，本研究嘗試解決MRS肉湯培養基內之Tween 80對LC-MS分析所造成的離子化競爭問題，發現油酸取代之MRS肉湯培養基能成功支持L. plantarum PS128生長，為後續相關研究提供新方向。 綜合上述，本研究對L. plantarum PS128的菌體外代謝物進行分離和鑑定並初步建立利用資訊技術及搭配低解析質譜儀以更有效率的尋找微生物產的次級代謝物，同時對L. plantarum PS128的菌體內代謝物的萃取進行方法優化。 | zh_TW |
| dc.description.abstract | Recent studies have demonstrated that the diversity and stability of the gut microbiota are closely associated with host health and disease. The gut-brain axis plays a critical role in various psychiatric disorders, including major depressive disorder (MDD) and autism spectrum disorder (ASD). Previous research has shown that Lactiplantibacillus plantarum PS128 can alleviate behavioral problems in some children with ASD and exhibits potential antidepressant effects.
To elucidate the chemical composition of metabolites produced by L. plantarum PS128, the culture supernatant obtained after 16 h of cultivation in MRS broth was subjected to liquid-liquid extraction to fractionate into Hexanes, EtOAc, n-Butanol, and "H" _"2" "O" fractions. Preliminary enrichment was performed using solid-phase extraction (SPE), followed by LC-MS analysis, which identified the EtOAc fraction as containing unknown metabolites of interest. LC-ESI-MS analysis revealed a pseudomolecular ion peak at m/z 1,278.7 [M+Na]^+, corresponding to a calculated molecular weight of 1,256 Da. Further purification was achieved by reversed-phase column chromatography, and the structure was elucidated using NMR spectroscopy. The results indicate that this metabolite is a nonribosomal peptide-like compound composed of three amino acids linked to a long carbon chain, suggesting that it is a lipopeptide. However, despite attempts to adjust the mobile phase composition and the stationary phase, the co-eluting impurities could not be removed. In parallel, the extraction methods for intracellular metabolites were systematically optimized and compared. Propidium iodide staining and ATP quantification indicated that conventional cold organic solvent quenching disrupted the cell membrane, leading to extensive intracellular metabolite leakage. Thus, non-quenching approaches should be adopted in untargeted metabolomics to maximize the intracellular metabolite retention. Moreover, extraction with a MeOH/ACN/ "H" _"2" "O" mixture provided broader metabolite coverage and superior reproducibility, making it the preferred method for untargeted metabolomics studies. This study also addressed the ionization competition caused by Tween 80 in MRS broth. Replacing Tween 80 with oleic acid successfully supported the growth of L. plantarum PS128, thereby offering a new direction for future investigations. In conclusion, this work reports the isolation and structural elucidation of extracellular metabolites of L. plantarum PS128, and preliminary establishes an efficient strategy combining informatics with low-resolution mass spectrometry for the discovery of microbial secondary metabolites. In addition, optimized methodologies for the extraction of intracellular metabolites of L. plantarum PS128 were developed. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2026-03-13T16:47:27Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2026-03-13T16:47:27Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 口試委員會審定書 I
中文摘要 II Abstract III 目次 IV 圖次 VIII 表次 X 流程圖次 X 附圖次 XI 略語表 XIII 1. 緒論 1 1.1 腸-腦軸簡介 1 1.2 植物乳桿菌簡介 3 1.2.1 L. plantarum之發現與主要特性 3 1.2.2 L. plantarum與健康或疾病的關係 4 1.2.2.1 L. plantarum維護腸道屏障的多重調控機制 7 1.2.2.2 L. plantarum 對神經、內分泌、情緒及免疫調控 8 1.2.2.3 腸道菌群間的相互作用 10 1.2.3 L. plantarum之次級代謝物與細胞外分泌物 11 1.2.3.1 色胺酸代謝物 12 1.2.3.2 細菌素 15 1.2.3.3 L. plantarum 的細胞外多醣 17 1.2.3.4 γ-氨基丁酸 18 1.2.3.5 乳酸 18 1.2.3.6 細胞外囊泡 19 1.3 兩種精神相關疾病 (自閉症與憂鬱症) 之治療與植物乳桿菌 20 1.3.1 自閉症簡介 20 1.3.1.1 自閉症與腸道菌關聯 20 1.3.1.2 L. plantarum的自閉症治療潛力 21 1.3.2 憂鬱症簡介 23 1.3.2.1 憂鬱症與腸道菌之關聯 24 1.3.2.2 L. plantarum治療憂鬱症之潛力 24 1.4 腸道菌次級代謝物研究方法的文獻回顧 26 1.4.1 基因體學之應用 28 1.4.2 代謝體學之應用 30 1.4.2.1 光譜處理及數據分析 31 1.4.2.2 代謝物鑑別 32 1.5 研究目的 35 2. 實驗材料與方法 36 2.1 實驗儀器與材料 36 2.1.1 理化性質測定儀器 36 2.1.2 分離及分析之儀器與材料 36 2.1.3 生化性質分析儀器與材料 37 2.1.4 LC-MS數據、核磁共振圖譜處理軟體 37 2.1.5 試劑與溶媒 37 2.2 L. plantarum PS128的基本培養條件 39 2.2.1 細菌培養液配製 39 2.2.2 L. plantarum PS128培養及凍存方法 40 2.2.3 L. plantarum PS128大量培養方法 40 2.3 L. plantarum PS128菌體內代謝物分析過程 41 2.3.1 菌體外代謝物液相–液相分配 41 2.3.2 樣品分析前前處理：降低Tween 80 干擾方法 42 2.3.2.1 降低Tween 80 干擾方法一 42 2.3.2.2 降低Tween 80 干擾方法二 42 2.3.2.3 降低Tween 80 干擾方法三 43 2.3.3 樣品分析前前處理：低豐度代謝物的富集 44 2.3.3.1 富集方法一 44 2.3.3.2 富集方法二 44 2.3.3.3 富集方法三 45 2.3.3.4 富集方法四 45 2.3.3.5 富集方法五 45 2.4 L. plantarum PS128菌體外代謝物之分離 47 2.4.1 分離方法一 (Scheme 3) 47 2.4.2 分離方法二 (Scheme 4) 48 2.4.3 分離方法三 (Scheme 5) 50 2.5 L. plantarum PS128菌體內代謝物之分析 51 2.5.1 菌體淬滅效果評估(外膜完整性評估、代謝終止法)與菌體代謝物之萃取 51 2.5.1.1 淬滅效果評估一：菌體膜完整性評估 51 2.5.1.2 淬滅效果評估二：ATP含量測定 53 2.5.1.3 菌體內代謝物萃取 54 2.5.2 代謝物活性分析 56 2.5.2.1 類升糖素胜肽-1活性分析 56 2.5.2.2 二肽基酶活性分析 58 2.5.2.3 ABTS 自由基清除活性分析 59 2.5.3 高效液相層析串聯質譜 (HPLC-MS) 分析方法 60 2.5.4 LC-MS數據處理與分析 61 2.5.4.1 MZmine 波峰辨識 62 2.5.4.2 Pandas數據處理 65 2.6 L. plantarum代謝物生合成基因簇預測與分析：antiSMASH 67 2.6.1 搜尋L. plantarum WCFS1全基因組 67 2.6.2 利用L. plantarum的全基因組預測代謝物 68 3. 實驗結果 69 3.1 菌體外代謝物三種溶媒Hexanes、MeOH、n-BuOH與"H2O" 可溶層之活性測試結果 69 3.1.1 GLP-1分泌刺激活性 69 3.1.2 DPP-4之抑制活性結果 70 3.1.3 ABTS 自由基清除活性 71 3.1.4 以LC-MS分析L. plantarum PS128之代謝物與基質成分利用 72 3.1.4.1 代謝物分析 72 3.1.4.2 L. plantarum PS128於培養過程中對基質成分之利用分析 75 3.2 菌體內代謝物 79 3.2.1 菌體之淬滅結果分析 79 3.2.1.1 細胞膜破裂分析 79 3.2.1.2 活性終止分析 80 3.2.2 以LC-MS評估菌體內代謝物之萃取方式 81 3.2.2.1 正離子模式 81 3.2.2.2 負離子模式 84 3.3 M3-4-2之結構解析 87 3.4 M3-4-2之生合成基因簇分析結果: antiSMASH 91 4. 討論 92 4.1 M3-4-2之未知結構探討 92 4.2 M3-4-2之生物活性探討 93 4.3 M3-4-2 產量影響因素之探討 93 4.4 M3-4-2分離效果不佳之原因探討 95 4.5 與既有代謝體學流程之比較 96 5. 結論 97 參考文獻 98 | - |
| dc.language.iso | zh_TW | - |
| dc.subject | 植物乳桿菌 PS128 | - |
| dc.subject | 代謝物組學 | - |
| dc.subject | 脂肽 | - |
| dc.subject | 憂鬱症 | - |
| dc.subject | Lactiplantibacillus plantarum PS128 | - |
| dc.subject | metabolomics | - |
| dc.subject | lipopeptide | - |
| dc.subject | depression | - |
| dc.title | 精神益生菌植物乳桿菌 PS128 所產次級代謝物探索 | zh_TW |
| dc.title | Exploration of Secondary Metabolites from the psychobiotic Lactiplantibacillus plantarum PS128 | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 114-1 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 李水盛;林玉麒 | zh_TW |
| dc.contributor.oralexamcommittee | Shoei-Sheng Lee ;Yu-Chi Lin | en |
| dc.subject.keyword | 植物乳桿菌 PS128,代謝物組學脂肽憂鬱症 | zh_TW |
| dc.subject.keyword | Lactiplantibacillus plantarum PS128,metabolomicslipopeptidedepression | en |
| dc.relation.page | 143 | - |
| dc.identifier.doi | 10.6342/NTU202504624 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2025-10-30 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 藥學研究所 | - |
| dc.date.embargo-lift | N/A | - |
| 顯示於系所單位： | 藥學系 | |
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| ntu-114-1.pdf 未授權公開取用 | 9.03 MB | Adobe PDF |
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