JP2021522867A - ラクトバチルス・パラカゼイ株及びその使用 - Google Patents
ラクトバチルス・パラカゼイ株及びその使用 Download PDFInfo
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- JP2021522867A JP2021522867A JP2021513740A JP2021513740A JP2021522867A JP 2021522867 A JP2021522867 A JP 2021522867A JP 2021513740 A JP2021513740 A JP 2021513740A JP 2021513740 A JP2021513740 A JP 2021513740A JP 2021522867 A JP2021522867 A JP 2021522867A
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- lactobacillus paracasei
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Abstract
Description
i)炎症性サイトカインIL-6、TNF、IL-1b、IL-8、IL-2、IFN-γ、IL-4、IL-13、及びIL-17Aからなる群から選択される少なくとも1つの発現又は分泌の抑制;
ii)抗炎症性及び免疫調節性サイトカインIL-10の発現又は分泌の増加;並びに
iii)抗炎症性活性及び免疫調節に関与するTregの発現の増加。
(1)腸疾患、アレルギー性疾患、自己免疫疾患又は炎症性疾患の発生を阻害する、
(2)腸疾患、アレルギー性疾患、自己免疫疾患又は炎症性疾患の広がりを予防する、
(3)腸疾患、アレルギー性疾患、自己免疫疾患又は炎症性疾患を軽減する、
(4)腸疾患、アレルギー性疾患、自己免疫疾患又は炎症性疾患の再発を予防する、及び
(5)腸疾患、アレルギー性疾患、自己免疫疾患又は炎症性疾患の症状を緩和する。
免疫調節性機能を有するプロバイオティクス株を、白血球単球THP-1細胞系及び末梢血単核球(PBMC)を使用してスクリーニングした。ヒト腸又は膣に由来する株を、それぞれ、細胞系:株の比が1:100となるように上記の2つの細胞系に播種し、炎症反応を示す主なサイトカインであるIL-6に対する、炎症制御を示す主なサイトカインであるIL-10の比(IL-10/IL-6)、及び自己免疫反応を示す主なサイトカイン、IFN-γに対するIL-10の比(IL-10/IFN-γ)を測定した。合計23株を以下のようにスクリーニングに使用した:ラクトバチルス・ガセリ2株、ラクトバチルス・ロイテリ1株、ラクトバチルス・ラムノサス5株、ラクトバチルス・ファーメンタム(Lactobacillus fermentum)2株、ラクトバチルス・パラカゼイ4株、ラクトバチルス・サリバリウス(Lactobacillus salivarius)4株、ラクトバチルス・プランタルム1株、ラクトバチルス・アシドフィルス2株及びラクトコッカス・ラクティス2株。
前記ラクトバチルス・パラカゼイKBL382、KBL384及びKBL385株からの免疫調節性効果を検証するために、免疫調節に関与するサイトカインを生成する能力を、ラクトバチルス・パラカゼイKBL382、KBL384及びKBL385株で処理したTHP-1細胞系で確認し、一方、T細胞分化のマーカー遺伝子が発現されたかどうかを、ラクトバチルス・パラカゼイKBL382及びKBL385株で処理したPBMCで確認した。
B2M
フォワード: 5'-CCA GCA GAG AAT GGA AAG TC-3' (配列番号4)
リバース: 5'-GAT GCT TCT TAC ATG TCT CG-3' (配列番号5)
T-bet
フォワード: 5'-CCC CAA GGA ATT GAC AGT TG-3' (配列番号6)
リバース) 5'-GGG AAA CTA AAG CTC ACA AAC-3' (配列番号7)
GATA3
フォワード: 5'-CTG CAA TGC CTG TGG GCT C-3' (配列番号8)
リバース: 5'-GAC TGC AGG GAC TCT CGC T-3' (配列番号9)
RORγt
フォワード: 5'-AAG ACT CAT CGC CAA AGC AT-3' (配列番号10)
リバース: 5'-TCC ACA TGC TGG CTA CAC A-3' (配列番号11)
FOXP3
フォワード: 5'-TCA AGC ACT GCC AGG CG-3' (配列番号12)
リバース: 5'-CAG GAG CCC TTG TCG GAT-3' (配列番号13)
一方、ラクトバチルス・パラカゼイKBL382、KBL384及びKBL385株によるT細胞免疫調節性効果を検証するために、T細胞がPBMC細胞において活性化され、次いでその後前記パラカゼイKBL382、KBL384及びKBL385株で処理されたときの炎症性サイトカインの発現レベルを検証した。
本例は、ラクトバチルス・パラカゼイKBL382、KBL384及びKBL385株がインビボでも腸機能改善効果を示すかどうかを確認するためであった。この目的のために、C57BL/6マウスを各10匹の群に分け、次いで2% DSSをその中に溶解させた水道水を9日間与え、それにより腸炎を誘導した。同時に、対照群のマウスにPBS 200μLを毎日経口投与し、テスト群のマウスには、毎日投与量を4×109CFUに設定できるように2×1010CFU/mLまでPBSに希釈したラクトバチルス・パラカゼイKBL382、KBL384又はKBL385株の各々200μLを、経口投与により毎日提供した。次いで、DSSによって腸炎を誘導した9日の間、対照群及びテスト群のマウスの体重変化を毎日測定し、DSSを供給した9日後にマウスを剖検に供して結腸の長さを測定した。
腸管壁タイトジャンクションの強化に対するラクトバチルス・パラカゼイKBL382及びKBL385株の効果を検証するために、腸管壁タイトジャンクションに関与する遺伝子のmRNA発現レベルを、実施例4において単離したマウス結腸組織から単離した細胞で比較し、測定した。遺伝子発現量をチェックするために、RNAをまずeasy-spin(商標) (DNAフリー) Total RNA Extraction Kit (Intron社)を使用して組織から抽出し、次いでcDNAをHigh Capacity RNA-to-cDNAキット(ThermoFisher社)で合成した。Rotor-gene SYBR green PCRキット(Qiagen社)を使用して、腸管壁タイトジャンクションマーカータンパク質であるzonula occluden-1 (ZO-1)、クローディン3及びMUC-4のmRNA発現レベルをRotor-Gene (登録商標) Q (Qiagen社)によりインビボで測定した。ヒポキサンチン-グアニンホスホリボシルトランスフェラーゼ(HPRT)遺伝子の発現レベルを対照として測定して、各テスト群間の相対的な遺伝子発現レベルを正規化した。発現を確認するのに使用するプライマーを、各遺伝子に特異的に結合できるように以下のように調製する。
Zo-1
Fw: 5'-ACC CGA AAC TGA TGC TGT GGA TAG-3' (配列番号14)
Rw: 5'-AAA TGG CCG GGC AGA ACT TGT GTA-3' (配列番号15)
クローディン3
Fw: 5'-CAG ACG TCC GTC AGT TTT CG-3' (配列番号16)
Rw: 5'-CAT GGC TGC TGG ACT TGA AC-3' (配列番号17)
MUC-4
Fw: 5'-GTC TCC CAT CAC GGT TCA GT-3' (配列番号18)
Rw: 5'-TGT CAT TCC ACA CTC CCA GA-3' (配列番号19)
HPRT
Fw: 5'-TTA TGG ACA GGA CTG AAA GAC-3'' (配列番号20)
Rw: 5'-GCT TTA ATG TAA TCC AGC AGG T-3'' (配列番号21)
インフリキシマブ(製品名レミケード)は、関節リウマチ、強直性脊椎炎、潰瘍性大腸炎、成人のクローン病、小児のクローン病、乾癬、及び乾癬性関節炎等の自己免疫疾患に対する注射として使用される治療組換え抗体薬である。この試験の目的は、KBL 382株とインフリキシマブの間で腸疾患症状のインビボでの軽減に対する効果の違いを確認することであった。
KBL382株のアトピー軽減に対する効果を検証するために、アトピー皮膚疾患の動物モデル、NC/Ngaマウスモデルを使用した。
DFE誘導皮膚病変を評価するために、以下の方法により皮膚炎スコアを測定した。株を投与して以降、第3週から1週間隔で4週間撮影して皮膚状態をモニターした。皮膚の乾燥度、浮腫、紅斑/出血、及びびらん/表皮剥離の4つの指標をチェックした。合計スコアを、病変なし0点、軽度1点、中程度2点、及び重度3点で評価した。
DFEによって誘導されたアトピー性皮膚炎に罹患しているマウスモデルにおいてKBL382株の投与による掻痒の軽減に対する効果を検証するために、株投与の4週後に10分間、引っ掻き傷の数をマウスについて測定した。
DFEによって誘導されたアトピー性皮膚炎に罹患しているマウスモデルへのKBL382の投与後の皮膚の厚みを減少させる効果を検証するために、株を投与した4週後にマウスの耳の厚さ及び背部皮膚の厚さをノギスで測定し、アトピー性皮膚炎による浮腫症状の緩和を観察した。結果として、図7(C)に見られるように、KBL382を投与したテスト群では、対照群及びKBL365投与群と比較して、耳及び皮膚の厚みが有意に低減したことが観察された。
アトピー性皮膚炎を有する患者のIgEの濃度は、アトピー性皮膚炎の臨床的重症度が増加するにつれて主に増加していることが見出されている(Matsumoto M、J. Immunol. 1999)。故に、アトピー性皮膚炎が生じるにつれて現れる代表的な血液学的因子、IgEの濃度を、株を投与した3週間後に血液を回収し、そこから血清を分離し、Mouse IgE ELISA Set (カタログ番号555248、BD OptEIA(商標))を使用して測定した。結果として、図7(D)に示すように、血中IgEの濃度は、KBL382を経口投与したテスト群で有意に減少したことが見出された。これは、KBL382の摂取後のアトピー性皮膚炎の治療効果を示した。
受託番号: KCTC13509BP
受託日: 20180417
受託番号: KCTC13510BP
受託日: 20180417
受託番号: KCTC13511BP
受託日: 20180417
配列表の電子ファイルが添付される。
Claims (25)
- 受託番号KCTC13509BPを有するラクトバチルス・パラカゼイKBL382の株。
- 前記株が、配列番号1の16s rDNA配列を含むことを特徴とする、請求項1に記載の株。
- 受託番号KCTC13510BPを有するラクトバチルス・パラカゼイKBL384の株。
- 前記株が、配列番号2の16s rDNA配列を含むことを特徴とする、請求項3に記載の株。
- 受託番号KCTC13511BPを有するラクトバチルス・パラカゼイKBL385の株。
- 前記株が、配列番号3の16s rDNA配列を含むことを特徴とする、請求項5に記載の株。
- 有効量の、請求項1から6のいずれか一項に記載の株、前記株の培養物、前記株の溶解物、及び前記株の抽出物からなる群から選択される少なくとも1つを含む食品組成物。
- 有効量の、請求項1から6のいずれか一項に記載の株、前記株の培養物、前記株の溶解物、及び前記株の抽出物からなる群から選択される少なくとも1つを含む食品添加物組成物。
- 前記組成物が、腸の健康の改善のための健康機能性食品組成物であることを特徴とする、請求項7に記載の食品組成物。
- 有効量の、請求項1から6のいずれか一項に記載の株、前記株の培養物、前記株の溶解物、及び前記株の抽出物からなる群から選択される少なくとも1つを含む、腸疾患の治療又は予防のための医薬組成物。
- 前記腸疾患が、腹部膨満、腹部不快感、病原性微生物に起因する感染性下痢、胃腸炎、炎症性腸疾患、神経性腸炎症候群、過敏性腸症候群、小腸内微生物の異常増殖、及び経腸栄養下痢からなる群から選択されることを特徴とする、請求項10に記載の医薬組成物。
- 前記組成物が、アレルギー症状を改善するための健康機能性食品組成物であることを特徴とする、請求項7に記載の医薬組成物。
- 有効量の、請求項1から6のいずれか一項に記載の株、前記株の培養物、前記株の溶解物、及び前記株の抽出物からなる群から選択される少なくとも1つを含む、アレルギー性疾患の治療又は予防のための医薬組成物。
- 前記アレルギー性疾患が、アトピー性皮膚炎、蕁麻疹、アレルギー性鼻炎、アレルギー性結膜炎、喘息、食物アレルギー又はアナフィラキシーショックであることを特徴とする、請求項13に記載の医薬組成物。
- 前記組成物が、自己免疫疾患又は炎症性疾患を軽減するための健康機能性食品組成物であることを特徴とする、請求項7に記載の医薬組成物。
- 有効量の、請求項1から6のいずれか一項に記載の株、前記株の培養物、前記株の溶解物、及び前記株の抽出物からなる群から選択される少なくとも1つを含む、自己免疫疾患又は炎症性疾患の治療又は予防のための医薬組成物。
- 治療的有効量の、請求項1から6のいずれか一項に記載の株、前記株の培養物、前記株の溶解物、及び前記株の抽出物からなる群から選択される少なくとも1つを、それを必要とする対象に投与する工程を含む、腸疾患を治療するための方法。
- 治療的有効量の、請求項1から6のいずれか一項に記載の株、前記株の培養物、前記株の溶解物、及び前記株の抽出物からなる群から選択される少なくとも1つを、それを必要とする対象に投与する工程を含む、アレルギー性疾患を治療するための方法。
- 治療的有効量の、請求項1から6のいずれか一項に記載の株、前記株の培養物、前記株の溶解物、及び前記株の抽出物からなる群から選択される少なくとも1つを、それを必要とする対象に投与する工程を含む、自己免疫疾患又は炎症性疾患を治療するための方法。
- 請求項1から6のいずれか一項に記載の株、前記株の培養物、前記株の溶解物、及び前記株の抽出物からなる群から選択される少なくとも1つを含む、腸疾患の予防又は治療の使用のための組成物。
- 請求項1から6のいずれか一項に記載の株、前記株の培養物、前記株の溶解物、及び前記株の抽出物からなる群から選択される少なくとも1つを含む、アレルギー性疾患の予防又は治療の使用のための組成物。
- 請求項1から6のいずれか一項に記載の株、前記株の培養物、前記株の溶解物、及び前記株の抽出物からなる群から選択される少なくとも1つを含む、自己免疫疾患又は炎症性疾患の予防又は治療の使用のための組成物。
- 腸疾患の予防薬又は治療薬を調製するための、請求項1から6のいずれか一項に記載の株、前記株の培養物、前記株の溶解物、及び前記株の抽出物からなる群から選択される少なくとも1つを含む組成物の使用。
- アレルギー性疾患の予防薬又は治療薬を調製するための、請求項1から6のいずれか一項に記載の株、前記株の培養物、前記株の溶解物、及び前記株の抽出物からなる群から選択される少なくとも1つを含む組成物の使用。
- 自己免疫疾患又は炎症性疾患の予防薬又は治療薬を調製するための、請求項1から6のいずれか一項に記載の株、前記株の培養物、前記株の溶解物、及び前記株の抽出物からなる群から選択される少なくとも1つを含む組成物の使用。
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EP (1) | EP3792342A4 (ja) |
JP (1) | JP7121233B2 (ja) |
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BR (1) | BR112020022749A2 (ja) |
CA (1) | CA3099668C (ja) |
MX (1) | MX2020011916A (ja) |
MY (1) | MY186993A (ja) |
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Cited By (1)
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KR102582127B1 (ko) * | 2022-11-24 | 2023-09-25 | 힐링파머스 주식회사 | 탄소중립 실현을 위한 메탄가스 절감 및 축우 생산성 향상, 등급율 개선을 위한 기능성 단미사료 조성물 및 이의 제조방법 |
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JP7195714B2 (ja) * | 2020-10-19 | 2022-12-26 | 曽根ファーム株式会社 | 炎症性腸疾患用組成物 |
KR102330009B1 (ko) * | 2020-02-26 | 2021-11-23 | 경일대학교산학협력단 | 제주 토속 발효식품으로부터 분리한 락토바실러스 파라카제이 jskiu 12-9 (kctc18805p) 및 이를 포함하는 항노화, 항암, 항충치 효능이 있는 조성물 |
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KR20230015688A (ko) * | 2021-07-23 | 2023-01-31 | (주) 에이투젠 | 신규한 락토바실러스 파라카제이 atg-e1 균주 또는 이를 포함하는 호흡기 질환의 예방 또는 치료용 조성물 |
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CN115517367B (zh) * | 2022-11-28 | 2023-05-05 | 广东益可维生物技术有限公司 | 副干酪乳杆菌smn-lbk在制备促进肠道健康产品中的应用 |
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KR102582127B1 (ko) * | 2022-11-24 | 2023-09-25 | 힐링파머스 주식회사 | 탄소중립 실현을 위한 메탄가스 절감 및 축우 생산성 향상, 등급율 개선을 위한 기능성 단미사료 조성물 및 이의 제조방법 |
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CA3099668A1 (en) | 2019-11-14 |
US11291698B2 (en) | 2022-04-05 |
CA3099668C (en) | 2023-10-03 |
AU2019265196B2 (en) | 2022-06-16 |
PH12020551878A1 (en) | 2021-05-31 |
KR20220024383A (ko) | 2022-03-03 |
KR102188020B1 (ko) | 2020-12-07 |
US20220175857A1 (en) | 2022-06-09 |
CN112534043A (zh) | 2021-03-19 |
EP3792342A4 (en) | 2022-01-12 |
SG11202010944RA (en) | 2020-12-30 |
MY186993A (en) | 2021-08-26 |
US20210077550A1 (en) | 2021-03-18 |
KR102365414B1 (ko) | 2022-02-21 |
KR20200140225A (ko) | 2020-12-15 |
KR20200140224A (ko) | 2020-12-15 |
MX2020011916A (es) | 2021-04-13 |
SG10202112104UA (en) | 2021-12-30 |
KR102448946B1 (ko) | 2022-09-30 |
JP7121233B2 (ja) | 2022-08-18 |
WO2019216662A1 (ko) | 2019-11-14 |
AU2019265196A1 (en) | 2020-11-26 |
BR112020022749A2 (pt) | 2021-03-02 |
KR102285958B1 (ko) | 2021-08-05 |
KR20190129014A (ko) | 2019-11-19 |
EP3792342A1 (en) | 2021-03-17 |
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