JP2022028794A - モルガネラ属細菌由来ナノ小胞およびその用途 - Google Patents
モルガネラ属細菌由来ナノ小胞およびその用途 Download PDFInfo
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Abstract
Description
(a)正常ヒトおよび被検者のサンプルから分離した小胞からDNAを抽出する段階;
(b)前記抽出したDNAに対して16S rDNAに存在する遺伝子配列に基づいて作製したプライマーペアを用いてPCRを行って、それぞれのPCR産物を収得する段階;および
(c)前記PCR産物の定量分析を通して正常ヒトに比べてモルガネラ属細菌由来小胞の含量が低い場合、胃癌、大腸癌、すい臓癌、胆管癌、乳癌、卵巣癌、膀胱癌、前立腺癌、リンパ腫、心筋梗塞、心筋症、心房細動、異型狭心症、脳卒中、糖尿病、またはパーキンソン病と判定する段階。
(a)正常ヒトおよび被検者のサンプルから分離した小胞からDNAを抽出する段階;
(b)前記抽出したDNAに対して16S rDNAに存在する遺伝子配列に基づいて作製したプライマーペアを用いてPCRを行って、それぞれのPCR産物を収得する段階;および
(c)前記PCR産物の定量分析を通して正常ヒトに比べてモルガネラ属細菌由来小胞の含量が低い場合、胃癌、大腸癌、すい臓癌、胆管癌、乳癌、卵巣癌、膀胱癌、前立腺癌、リンパ腫、心筋梗塞、心筋症、心房細動、異型狭心症、脳卒中、糖尿病、またはパーキンソン病と判定する段階。
(a)正常ヒトおよび被検者のサンプルから分離した小胞からDNAを抽出する段階;
(b)前記抽出したDNAに対して16S rDNAに存在する遺伝子配列に基づいて作製したプライマーペアを用いてPCRを行って、それぞれのPCR産物を収得する段階;および
(c)前記PCR産物の定量分析を通して正常ヒトに比べてモルガネラ属細菌由来小胞の含量が低い場合、胃癌、大腸癌、すい臓癌、胆管癌、乳癌、卵巣癌、膀胱癌、前立腺癌、リンパ腫、心筋梗塞、心筋症、心房細動、異型狭心症、脳卒中、糖尿病、またはパーキンソン病と判定する段階。
腸内細菌と細菌由来小胞が胃腸管を通じて全身的に吸収されるかを評価するために、次のような方法で実験を行った。マウスの胃腸に蛍光で標識した腸内細菌と腸内細菌由来小胞をそれぞれ50μgの用量で胃腸管に投与し、0分、5分、3時間、6時間、12時間後に蛍光を測定した。マウス全体像を観察した結果、図1aに示されたように、細菌である場合には、腸粘膜を通じて全身的に吸収されないが、細菌由来小胞である場合には、投与後5分に全身的に吸収され、投与30分には、膀胱に蛍光が濃く観察されて、小胞が泌尿器系に排泄されることが分かった。また、小胞は、投与12時間まで体内に存在することが分かった(図1a参照)。
血液、尿、便などの臨床サンプルをまず10mlチューブに入れて遠心分離法(3,500xg、10min、4℃)で浮遊物を沈め、上澄み液だけを新しい10mlチューブに移した。0.22μmのフィルターを使用して細菌および異物を除去した後、セントリプレップチューブ(Centriprep centrifugal filters 50kD)に移して1500×g、4℃で15分間遠心分離して、50kDより小さい物質は捨てて、10mlまで濃縮させた。さらに0.22μmのフィルターを使用してバクテリアおよび異物を除去した後、Type 90tiローターで150,000×g、4℃で3時間の間超高速遠心分離方法を使用して上澄み液を捨てて、固まったペレットを生理食塩水(PBS)で溶かした。
実施例2の方法で胃癌患者63人および、年齢と性別をマッチングした正常ヒト126人の便を対象に、便内に存在する小胞から遺伝子を抽出してメタゲノム分析を行った後、モルガネラ属細菌由来小胞の分布を評価した。その結果、正常ヒトの便に比べて胃癌患者の便にモルガネラ属細菌由来小胞が有意に減少していることを確認した(表2および図2a参照)。
実施例2の方法で大腸癌患者38人および、年齢と性別をマッチングした正常ヒト38人の尿を対象に、尿内に存在する小胞から遺伝子を抽出してメタゲノム分析を行った後、モルガネラ属細菌由来小胞の分布を評価した。その結果、正常ヒトの尿に比べて大腸癌患者の尿にモルガネラ属細菌由来小胞が有意に減少していることを確認した(表5および図3参照)。
実施例2の方法ですい臓癌患者176人および、年齢と性別をマッチングした正常ヒト271人の血液を対象に、血液内に存在する小胞から遺伝子を抽出してメタゲノム分析を行った後、モルガネラ属細菌由来小胞の分布を評価した。その結果、正常ヒトの血液に比べてすい臓癌患者の血液にモルガネラ属細菌由来小胞が有意に減少していることを確認した(表6および図4参照)。
実施例2の方法で胆管癌患者79人および、年齢と性別をマッチングした正常ヒト259人の血液を対象に、血液内に存在する小胞から遺伝子を抽出してメタゲノム分析を行った後、モルガネラ属細菌由来小胞の分布を評価した。その結果、正常ヒトの血液に比べて胆管癌患者の血液にモルガネラ属細菌由来小胞が有意に減少していることを確認した(表7および図5参照)。
実施例2の方法で乳癌患者127人の尿および、性別と年齢をマッチングした正常対照群220人の尿を対象に、尿内に存在する小胞から遺伝子を抽出してメタゲノム分析を行った後、モルガネラ属細菌由来小胞の分布を評価した。その結果、正常ヒトの尿に比べて乳癌患者の尿にモルガネラ属細菌由来小胞が有意に減少していることを確認した(表8および図6参照)。
実施例2の方法で卵巣癌患者137人および、年齢と性別をマッチングした正常ヒト139人の血液を対象に、血液内に存在する小胞から遺伝子を抽出してメタゲノム分析を行った後、モルガネラ属細菌由来小胞の分布を評価した。その結果、正常ヒトの血液に比べて卵巣癌患者の血液にモルガネラ属細菌由来小胞が有意に減少していることを確認した(表9および図7a参照)。
実施例2の方法で膀胱癌患者96人の血液および、性別と年齢をマッチングした正常対照群184人の血液を対象に、血液内に存在する小胞から遺伝子を抽出してメタゲノム分析を行った後、モルガネラ属細菌由来小胞の分布を評価した。その結果、正常ヒトの血液に比べて膀胱癌患者の血液にモルガネラ属細菌由来小胞が有意に減少していることを確認した(表11および図8a参照)。
実施例2の方法で前立腺癌患者53人の尿および、性別と年齢をマッチングした正常対照群159人の尿を対象に、尿内に存在する小胞から遺伝子を抽出してメタゲノム分析を行った後、モルガネラ属細菌由来小胞の分布を評価した。その結果、正常ヒトの尿に比べて前立腺癌患者の尿にモルガネラ属細菌由来小胞が有意に減少していることを確認した(表13および図9参照)。
実施例2の方法でリンパ腫患者63人および、年齢と性別をマッチングした正常ヒト53人の血液を対象に、血液内に存在する小胞から遺伝子を抽出してメタゲノム分析を行った後、モルガネラ属細菌由来小胞の分布を評価した。その結果、正常ヒトの血液に比べてリンパ腫患者の血液にモルガネラ属細菌由来小胞が有意に減少していることを確認した(表14および図10参照)。
実施例2の方法で心筋梗塞患者57人の血液および、性別と年齢をマッチングした正常対照群163人の血液を対象に、血液内に存在する小胞から遺伝子を抽出してメタゲノム分析を行った後、モルガネラ属細菌由来小胞の分布を評価した。その結果、正常ヒトの血液に比べて心筋梗塞患者の血液にモルガネラ属細菌由来小胞が有意に減少していることを確認した(表15および図11参照)。
実施例2の方法で脳卒中患者115人および、年齢と性別をマッチングした正常ヒト109人の血液を対象に、血液内に存在する小胞から遺伝子を抽出してメタゲノム分析を行った後、モルガネラ属細菌由来小胞の分布を評価した。その結果、正常ヒトの血液に比べて脳卒中患者の血液にモルガネラ属細菌由来小胞が有意に減少していることを確認した(表19および図15参照)。
実施例2の方法で糖尿病患者73人の血液および、性別と年齢をマッチングした正常対照群146人の血液を対象に、血液内に存在する小胞から遺伝子を抽出してメタゲノム分析を行った後、モルガネラ属細菌由来小胞の分布を評価した。その結果、正常ヒトの血液に比べて糖尿病患者の血液にモルガネラ属細菌由来小胞が有意に減少していることを確認した(表20および図16a参照)。
実施例2の方法でパーキンソン病患者39人の尿および、性別と年齢をマッチングした正常対照群79人の尿を対象に、尿内に存在する小胞から遺伝子を抽出してメタゲノム分析を行った後、モルガネラ属細菌由来小胞の分布を評価した。その結果、正常ヒトの尿に比べてパーキンソン病患者の尿にモルガネラ属細菌由来小胞が有意に減少していることを確認した(表22および図17参照)。
前記実施例に基づいて、モルガネラ・モルガニイ(M.morganii)菌株は、韓国微生物保存センター(KCCM)で標準菌株1種(MMR101)およびヒトから分離した2種の分離菌株(MMR201、MMR202)を培養した後、培養液から小胞を分離して特性を分析した。モルガネラ菌株(M.morganii)を37℃培養器で吸光度(OD600)が1.0~1.5になるまでLB(Luria-Bertani)培地で培養した後、サブカルチャーした。以後、菌株が含まれている培養液を回収して10,000g、4℃で20分間遠心分離して菌株を除去し、0.22μmのフィルターに濾過した。濾過した上澄み液を100kDa Pellicon 2 Cassetteフィルターメンブレイン(Merck Millipore,US)でMasterFlex pump system(Cole-Parmer,US)を用いてマイクロフィルター濾過を通じて50ml以下の体積に濃縮した。濃縮させた上澄み液をさらに0.22μmのフィルターで濾過した。以後、BCAアッセイを用いてタンパク質を定量し、得られた小胞に対して下記実験を実施した。
炎症細胞でモルガネラ・モルガニイ由来小胞(M.morganii EV)の細胞死滅効果を評価するために、マウスマクロファージ細胞株であるRaw 264.7細胞にモルガネラ・モルガニイ(MMR101、MMR201、MMR202)由来小胞を多様な濃度(0.1、1、10μg/ml)で処理した後、細胞死滅程度を評価した。より具体的に、48ウェル細胞培養プレート内に5×104個ずつ分注したRaw 264.7細胞にDMEM無血清培地で希釈した多様な濃度のモルガネラ・モルガニイ(MMR101、MMR201、MMR202)由来小胞を処理して12時間の間培養した。以後、細胞死滅は、EZ-CYTOX(Dogen,Korea)を用いて測定した。その結果、モルガネラ・モルガニイ(MMR101、MMR201、MMR202)由来小胞の処理時に細胞死滅は観察されなかった(図18参照)。
モルガネラ・モルガニイ由来小胞が、炎症細胞で炎症メディエーターの分泌に対する影響を調べてみるために、マウスマクロファージ細胞株であるRaw 264.7細胞にモルガネラ・モルガニイ(MMR101)由来小胞を多様な濃度(0.1、1、10μg/ml)で処理した後、炎症疾患病原性小胞である大腸菌由来小胞(E.coli EV)を処理して炎症メディエーター(IL-6、TNF-αなど)の分泌量を測定した。より具体的に、Raw 264.7細胞を1x105個ずつ24ウェル細胞培養プレートに分注した後、24時間の間DMEM完全培地で培養させた。以後、培養上澄み液を1.5mlのチューブに集めて3000gで5分間遠心分離して上澄み液を集めて4℃に保管しておいて、ELISA分析を進めた。その結果、モルガネラ・モルガニイ由来小胞を前処理した場合、大腸菌由来小胞によるIL-6およびTNF-αの分泌が顕著に抑制されることを確認した(図19aおよび19b参照)。特に、モルガネラ・モルガニイ由来小胞を前処理した場合に、マクロファージでTNF-αの分泌がラクトバチルスプランタルム小胞に比べて抑制程度が顕著に高かった(図19b参照)。
前記実施例18を通じてモルガネラ・モルガニイ標準菌株(MMR101)および分離菌株(MMR201)由来小胞の抗炎症効果を確認し、ひいては、前記小胞の安定性および有効物質の特性を具体的に調べてみようとした。このために、100℃で10分間煮沸、又は10分間酸処理(pH2.0)をした2種のモルガネラ・モルガニイ由来小胞(MMR101、MMR201)をマクロファージ(Raw 264.7)に前処理して抗炎症効果を評価した。その結果、小胞を100℃の煮沸処理や、酸処理をしても、モルガネラ・モルガニイ由来小胞の抗炎症効果が維持されることを確認した(図21参照)。これは、モルガネラ・モルガニイ由来小胞の抗炎症作用は、温度と酸に対して安定であることを意味する。
前記実施例に基づいて、ひいては、モルガネラ・モルガニイ由来小胞の抗癌効果を調べてみようとした。このために、図22に示されたように、モルガネラ・モルガニイ分離菌株(MMR201)由来小胞を6週齢C57BL/6雄性マウスに腹腔注射または経口で投与し、投与4日目に癌細胞株(CT26 cell)を皮下で注射して癌モデルを作成した。癌細胞株を投与した後、モルガネラ・モルガニイ分離菌株由来小胞を腹腔注射または経口で毎日投与し、24日目まで癌組織の大きさを測定した(図22参照)。その結果、癌組織の大きさは、対照群である生理食塩水経口投与群に比べて、前記小胞を腹腔注射で投与したマウスと経口で投与したマウスにおいて癌組織の大きさが減少し、特に、経口で投与した場合に大きさがさらに減少した(図23参照)。これは、モルガネラ・モルガニイ由来小胞を投与したとき、癌組織の成長を効率的に抑制することができることを意味する。
Claims (13)
- モルガネラ(Morganella)属細菌由来小胞を有効成分として含む、胃癌、大腸癌、すい臓癌、胆管癌、乳癌、卵巣癌、膀胱癌、前立腺癌、リンパ腫、心筋梗塞、心筋症、心房細動、異型狭心症、脳卒中、糖尿病、パーキンソン病、および炎症性疾患よりなる群から選ばれる1つ以上の疾病の予防または治療用薬学的組成物。
- 前記炎症性疾患は、アトピー皮膚炎、にきび、乾癬、副鼻腔炎、鼻炎、結膜炎、喘息、皮膚炎、炎症性コラーゲン血管疾患、糸球体腎炎、脳炎、炎症性腸炎、慢性閉鎖性肺疾患、敗血症、敗血症性ショック、肺線維症、未分化脊椎関節症、未分化関節症、関節炎、炎症性骨溶解、ウイルスまたはバクテリア感染による慢性炎症疾患、大腸炎、潰瘍性大腸炎、炎症性腸疾患、関節炎、関節リウマチ、反応性関節炎、骨関節炎、鞏皮症、骨粗しょう症、アテローム性動脈硬化症、心筋炎、心内膜炎、心嚢炎、嚢胞性線維症、橋本甲状腺炎、グレーブス病、ハンセン病、梅毒、ライム病(Lyme disease)、ボレリア症(Borreliosis)、神経性ボレリア症、結核、サルコイドーシス(Sarcoidosis)、ループス、凍瘡状ループス、結核性ループス、ループス腎炎、全身性エリテマトーデス、黄斑変性、ブドウ膜炎、過敏性腸症候群、クローン病、シェーグレン症候群、線維筋痛、慢性疲労症候群、慢性疲労免疫不全症候群、筋痛性脳脊髄炎、筋萎縮性側索硬化症、パーキンソン病、および多発性硬化症よりなる群から選ばれる1つ以上であることを特徴とする、請求項1に記載の薬学的組成物。
- 前記炎症性疾患は、インターロイキン-6(Interleukin-6;IL-6)または腫瘍壊死因子-アルファ(Tumor necrosis factor-alpha;TNF-α)により媒介される疾患であることを特徴とする、請求項1又は2に記載の薬学的組成物。
- 前記小胞は、平均直径が10~200nmであることを特徴とする、請求項1~3のいずれか一項に記載の薬学的組成物。
- 前記小胞は、モルガネラ(Morganella)属細菌から自然的または人工的に分泌されることを特徴とする、請求項1~4のいずれか一項に記載の薬学的組成物。
- 前記モルガネラ(Morganella)属細菌由来小胞は、モルガネラ・モルガニイ(Morganella morganii)から分泌されることを特徴とする、請求項1~5のいずれか一項に記載の薬学的組成物。
- モルガネラ(Morganella)属細菌由来小胞を有効成分として含む、胃癌、大腸癌、すい臓癌、胆管癌、乳癌、卵巣癌、膀胱癌、前立腺癌、リンパ腫、心筋梗塞、心筋症、心房細動、異型狭心症、脳卒中、糖尿病、パーキンソン病、および炎症性疾患よりなる群から選ばれる1つ以上の疾病の予防または改善用食品組成物。
- 前記炎症性疾患は、アトピー皮膚炎、にきび、乾癬、副鼻腔炎、鼻炎、結膜炎、喘息、皮膚炎、炎症性コラーゲン血管疾患、糸球体腎炎、脳炎、炎症性腸炎、慢性閉鎖性肺疾患、敗血症、敗血症性ショック、肺線維症、未分化脊椎関節症、未分化関節症、関節炎、炎症性骨溶解、ウイルスまたはバクテリア感染による慢性炎症疾患、大腸炎、潰瘍性大腸炎、炎症性腸疾患、関節炎、関節リウマチ、反応性関節炎、骨関節炎、鞏皮症、骨粗しょう症、アテローム性動脈硬化症、心筋炎、心内膜炎、心嚢炎、嚢胞性線維症、橋本甲状腺炎、グレーブス病、ハンセン病、梅毒、ライム病(Lyme disease)、ボレリア症(Borreliosis)、神経性ボレリア症、結核、サルコイドーシス(Sarcoidosis)、ループス、凍瘡状ループス、結核性ループス、ループス腎炎、全身性エリテマトーデス、黄斑変性、ブドウ膜炎、過敏性腸症候群、クローン病、シェーグレン症候群、線維筋痛、慢性疲労症候群、慢性疲労免疫不全症候群、筋痛性脳脊髄炎、筋萎縮性側索硬化症、パーキンソン病、および多発性硬化症よりなる群から選ばれる1つ以上であることを特徴とする、請求項7に記載の食品組成物。
- 前記炎症性疾患は、インターロイキン-6(Interleukin-6;IL-6または腫瘍壊死因子-アルファ(Tumor necrosis factor-alpha;TNF-α)により媒介される疾患であることを特徴とする、請求項7又は8に記載の食品組成物。
- 前記小胞は、平均直径が10~200nmであることを特徴とする、請求項7~9のいずれか一項に記載の食品組成物。
- 前記小胞は、モルガネラ(Morganella)属細菌から自然的または人工的に分泌されることを特徴とする、請求項7~10のいずれか一項に記載の食品組成物。
- 前記モルガネラ(Morganella)属細菌由来小胞は、モルガネラ・モルガニイ(Morganella morganii)から分泌されることを特徴とする、請求項7~11のいずれか一項に記載の食品組成物。
- モルガネラ(Morganella)属細菌由来小胞の、胃癌、大腸癌、すい臓癌、胆管癌、乳癌、卵巣癌、膀胱癌、前立腺癌、リンパ腫、心筋梗塞、心筋症、心房細動、異型狭心症、脳卒中、糖尿病、パーキンソン病、および炎症性疾患よりなる群から選ばれる1つ以上の疾病の予防または治療用薬剤の製造のための使用。
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