[0013] 抑制乳桿菌屬乳酸菌減少用之組成物 本發明之組成物係一種於經施予抗菌藥物之對象中，抑制腸道內乳桿菌屬乳酸菌減少用之組成物，其係包含源自丙酸桿菌之乳清發酵物而成。將源自丙酸桿菌之乳清發酵物作為有效成分使用，不僅可抑制腸道內比菲德氏菌的減少，於施予抗菌藥物前、施予中，亦或施予後的對象中，皆可顯著地抑制腸道內乳桿菌屬乳酸菌之減少，係為意料外的事實。 [0014] 所謂「經施予抗菌藥物之對象」，係指預計施予抗菌藥物(施予前)的對象、正施予(施予中的)對象或已施予(施予後的)對象，較佳係指，預計因抗菌藥物而使腸道內之乳桿菌屬乳酸菌減少、正減少中或已減少之對象。對象雖係較佳為人，然而人以外(例如，馬、牛等的家畜、齧齒類、犬、貓等的寵物、於動物園等中被飼養之鑑賞動物)亦佳，本發明中相關態樣亦包含於其中。 [0015] 本發明之抗菌藥物，若為乳桿菌屬乳酸菌對其顯示有感受性之抗菌藥物則無特別限制，然而較佳係乳桿菌屬乳酸菌對其顯示有感受性之抗生素。作為更具體的例子，可舉例為例如青黴素類抗菌藥物(例如，安莫西林(AMPC)、安比西林(ABPC))、頭孢烯類抗菌藥物(例如，頭孢匹羅(CPR))、頭孢菌素類抗菌藥物(例如，頭孢他啶(CAZ))、碳氫黴烯類抗菌藥物(例如，美羅培南(MEPM))、β-內醯胺脢抑制劑、噁唑烷酮類抗菌藥物(例如，利奈唑胺(LZD))、新喹諾酮類抗菌藥物(例如，左氧氟沙星(LVFX) 、帕珠沙星(PZFX))及大環內酯類抗菌藥物(例如，阿奇黴素(AZM))之外，可列舉為林可黴素類抗菌藥物、氨基配醣體類抗生素抗菌藥物、四環素類抗菌藥物、氯黴素類抗菌藥物、肽類抗菌藥物、磺胺類藥物、抗結核藥物、喹諾酮類類抗菌藥物、抗病毒藥物、抗真菌藥物。抗菌藥物較佳為，青黴素類抗菌藥物(例如，安莫西林(AMPC)、安比西林(ABPC))、頭孢烯類抗菌藥物(例如，頭孢匹羅(CPR))、頭孢菌素類抗菌藥物(例如，頭孢他啶(CAZ))、碳氫黴烯類抗菌藥物(例如，美羅培南(MEPM))、β-內醯胺脢抑制劑、噁唑烷酮類抗菌藥物(例如，利奈唑胺(LZD))、新喹諾酮類抗菌藥物(例如，左氧氟沙星(LVFX)、帕珠沙星(PZFX))，以及大環內酯類抗菌藥物(例如，阿奇黴素(AZM))。 [0016] 抗菌藥物之施予方法，若腸道內乳桿菌屬乳酸菌顯示感受性則無特別限定，例如，可由經口攝取(或經口施予)、經腸施予、胃造口術、皮下施予、經靜脈施予等，根據施予抗菌藥物之對象及用途(例如，治療目的或預防目的)，適當選擇。抗菌藥物之使用方法，若為本發明技術領域中具有通常知識者可依照對象所具有的疾病、狀態、用途適當選擇，例如，若為本發明技術領域中具有通常知識者可依據JAID/JAS感染症治療方針2014(JAID/JAS感染症治療方針・指導方針制定委員會編輯)所記載之手法適當選擇。 [0017] 乳桿菌屬乳酸菌為革蘭氏陽性之桿菌，已知作為一種益菌。作為較佳之乳桿菌屬乳酸菌之具體例，由人類臨床試驗之結果，可舉例為保加利亞乳桿菌(Lactobacillus bulgaricus)、約氏乳桿菌(L. johnsonii)、酪蛋白乳桿菌(L. casei)、副乾酪乳桿菌(L. paracasei)、加氏乳桿菌(L. gasseri)、瑞士乳桿菌(L. helveticus)、鼠李糖乳桿菌(L. rhamnosus)、嗜酸乳桿菌(L. acidophilus)、唾液乳桿菌(L. salivarius)、戊糖乳桿菌(L. pentosus)、胚芽乳桿菌(L. plantarum)、短乳桿菌(L. brevis)、洛德因乳桿菌(L. reuteri)、芽孢乳桿菌(L. sporogenes)等。乳桿菌屬乳酸菌，已知具有例如，整腸作用(例如，對於腹瀉、便祕、過敏性腸症候群之整腸作用)、免疫活化作用、幽門螺桿菌之除菌作用、異位性皮膚炎、花粉症、氣喘等的過敏抑制作用、過敏性腸症候群(IBS)之改善作用、脂質代謝或內臟脂肪蓄積之改善作用、呼吸系統疾病等的感染症風險抑制作用、發炎性大腸疾病之改善作用、子宮內膜異位症之改善作用、癌抑制作用、壓力及QOL的改善作用、糖尿病改善作用、氧化壓力改善作用等的生理活性。乳桿菌屬乳酸菌，由於具有上述生理活性之特點故期望其菌數於腸道內以一定數量存在。 [0018] 腸道內乳桿菌屬乳酸菌，以腸內細菌叢含有之乳桿菌屬乳酸菌為佳，較佳為，具有使腸內環境保持良好平衡機能之乳酸菌。腸道內乳桿菌屬乳酸菌數，係每1g人類糞便中存在有Log104
個以上為佳，更佳為Log105
個以上，再更佳為Log106
個以上，再更佳為Log107
個以上。 [0019] 本發明中所使用之源自丙酸桿菌之乳清發酵物，係藉由將丙酸桿菌，於使用含有乳清之培養基培養而得。 [0020] 所謂丙酸桿菌，是屬於丙酸桿菌屬(Propionibacterium)之革蘭氏陽性之厭氧菌，為將醣類無氧地生成丙酸之微生物，自古以來被利用作為埃文達起司等的菌元，其安全性已被確認。本發明中使用之丙酸桿菌，例如，可列舉為費氏丙酸桿菌(Propionibacterium freudenreichii)、特恩丙酸桿菌(P. thoenii)、丙酸丙酸桿菌(P. acidipropionici)、詹森丙酸桿菌 (P. jensenii)、貪婪丙酸桿菌 (P. avidum)、痤瘡丙酸桿菌(P. acnes)、嗜淋巴丙酸桿菌(P. lymphophilum)、顆粒丙酸桿菌(P. granulosam)，較佳為費氏丙酸桿菌。可使用上述之1種，亦可將2種以上組合使用。 丙酸桿菌，較佳為，屬於費氏丙酸桿菌之比菲德氏菌增殖促進物質(BGS)產生菌，例如，可舉例為費氏丙酸桿菌ET-3(寄存號碼：FERM-BP-8115)、費氏丙酸桿菌 ATCC 6207、費氏丙酸桿菌 ATCC 8262、費氏丙酸桿菌 IFO 12424、費氏丙酸桿菌 IFO 12426、費氏丙酸桿菌 IFO 12391，更佳為費氏丙酸桿菌 ET-3(寄存號碼：FERM-BP-8115)。 [0021] 所謂乳清，亦被稱為乳漿(whey)，係指由牛乳中去除脂肪份、酪蛋白、脂溶性維生素等去除後，剩餘的透明黃綠色之水溶性成分。作為本發明使用之乳清可列舉為，例如，乳漿的原液(甜乳漿、酸乳漿等)、其濃縮物、其乾燥物 (乳漿粉)、其冷凍物等，及此些之還原溶液，以及，去鹽乳漿、乳漿蛋白濃縮物(WPC)、乳漿蛋白分離物(WPI)、α-乳白蛋白(α-La)、β-乳球蛋白(β-Lg)、免疫球蛋白、乳鐵蛋白等，及上述之還原溶液、上述之乳漿蛋白質分解物。乳清係較佳為選自乳漿之原液、乳漿粉、WPC、WPI其此些之還原溶液，以及此些之蛋白水解酶分解物。可僅使用上述之1種，亦可組合2種以上使用。 [0022] 乳清係相對於培養基，作為蛋白質的量，較佳以1～5質量%，更佳為1.5～4.0質量%含有。又，糖質係相對於培養基，以1～4質量%，較佳為以1.5～3.0質量%含有。為了成為這樣的培養基組成，可使用調節乳清之添加量(摻混量)之物。糖質，較佳為葡萄糖或將乳糖經乳糖酶處理之單糖。培養基若為可培養革蘭氏陽性之厭氧菌之培養基，亦可含有乳清以外之成分。於此，蛋白質的量，可藉由凱氏定氮法或勞立法測定算出。於凱氏定氮法的情況，係測定各種蛋白質中所含有之氮，而可將該數值乘以氮-蛋白質換算係數(通常為6.25)算出。 [0023] 本發明可使用之培養基，較佳係由10質量%乳漿粉還原液之蛋白水解酶分解物而成之pH5～8(較佳為5.5～7.5)之培養基。蛋白水解酶若可將乳漿蛋白質適度分解，則無特別限定。作為培養基，例如，可使用經蛋白水解酶 AMANO A(天野製藥股份公司)將10質量%之乳漿粉還原液於50℃、pH7.0下分解者。 [0024] 丙酸桿菌的培養，除了使用含有乳清的培養基以外，可依據常用方法，好氧地或厭氧地 (例如N2
氣體加壓下 (0.5kg/cm2
))培養。通常，係將培養基之溫度調製為20～40℃、pH6～8的程度，為了使生菌數成為107
～108
cfu/mL，攝取作為菌元的丙酸桿菌，液体培養3～4天即可。以這樣的方式得到的培養物中所含有的丙酸桿菌之濃度達到菌元的約5倍。 [0025] 本發明之源自丙酸桿菌之乳清發酵物，係可使用藉由丙酸桿菌之培養所得到的培養物、經分離之細菌本體、培養液 (培養上清液)、或上述之混合物之至少一種，源自丙酸桿菌之乳清發酵物可為此些之萃取物、冷凍乾燥物或稀釋物。此外，源自丙酸桿菌之乳清發酵物可為經施加殺菌處理者。作為殺菌步驟，可舉例為例如低溫長時間殺菌、高溫長時間殺菌、高溫短時間殺菌、超高溫瞬間殺菌。 [0026] 根據本發明之一較佳態樣，作為本發明之源自丙酸桿菌之乳清發酵物，可使用將費氏丙酸桿菌ET-3(Propionibacterium freudenreichii ET-3)(寄存號碼：FERM BP-8115)以10質量%乳漿粉還原液培養而獲得之源自丙酸桿菌之乳清發酵物，更佳為，可使用將費氏丙酸桿菌ET-3，由以10質量%乳漿粉還原液之蛋白水解酶AMANO A(天野製藥股份公司)，於50℃、pH7.0下分解之分解物所成之培養基，於35℃、pH6.0下培養75小時所得到之源自丙酸桿菌之乳清發酵物。這樣得源自丙酸桿菌之乳清發酵物，可合成，亦可使用市售品。作為市售品、例如，作為原料，舉例為Profec (「Profec」(商標)、明治 股份公司製)，此為，對於主要腸內細菌，特別是比菲德氏菌具有增殖促進作用，被認可作為特定保健用食品的相關成分。 [0027] 根據本發明之一態樣，本發明之源自丙酸桿菌之乳清發酵物亦可包含比菲德氏菌增殖促進物質(BGS)。作為比菲德氏菌增殖促進物質，例如，舉例為1,4-二羥基-2-萘甲酸(1,4-dihydroxy-2-naphthoic acid、DHNA)、2-胺基-3-羧基-1,4-萘醌(2-amino-3-carboxy-1,4-naphthoquinone、ACNQ)及上述之類似物，該類似物中係包含1,4-萘醌、2-甲基-1,4-萘醌、4-胺基-2-甲基-1-萘酚及2-胺基-3-氯-1,4-萘醌。依據本發明之較佳實施態樣，本發明之源自丙酸桿菌之乳清發酵物中，包含1,4-二羥基-2-萘甲酸。 [0028] 本發明使用之源自丙酸桿菌之乳清發酵物，可就這樣當作為抑制乳桿菌屬乳酸菌減少用之組成物。 [0029] 本發明之抑制乳桿菌屬乳酸菌減少用之組成物，除了源自丙酸桿菌之乳清發酵物以外，亦可含有口服上可容許的其他成分。作為其他成分，在不妨礙本發明之效果的範圍內無特別限定，舉例可為賦形劑、穩定劑、防腐劑、潤濕劑、乳化劑、潤滑劑、甜味劑、著色劑、香料、緩衝劑、抗氧化劑、pH調整劑等的添加劑等。 依據本發明之較佳態樣，本發明之抑制乳桿菌屬乳酸菌減少用之組成物，係包含成為乳桿菌屬乳酸菌之「飼料」之機能性糖質(例如，寡糖或食物纖維)而成。藉包含有成為乳桿菌屬乳酸菌之「飼料」之機能性糖質，成為腸道內剩下之乳桿菌屬乳酸菌「飼料」，可促進增殖。 [0030] 又，本發明之抑制乳桿菌屬乳酸菌減少用之組成物之態樣並未特別限定，固形狀(粉末狀、錠劑狀等)、液狀(引用劑狀等)、半液狀之任一者皆可，然而較佳為粉末狀、錠劑狀或液狀。作為此種型態的市售品，舉例為粉末狀的明治B.G.S. POWDER(明治股份公司製)、錠劑狀之腸胃活力錠劑 (明治股份公司製)、液狀之YH Flore(明治股份公司製)等。 [0031] 依據本發明之較佳態樣，本發明之抑制乳桿菌屬乳酸菌減少用之組成物中，含有1,4-二羥基-2-萘甲酸、蛋白質、碳水化物(例如，糖質、食物纖維)，依據情況的不同，含有維生素及/或礦物質(例如，鈉、鈣、磷、鎂、鉀)。依據較佳態樣，本發明之抑制乳桿菌屬乳酸菌減少用之組成物1.5g中，含有1,4-二羥基-2-萘甲酸0.01～1000μg，更佳係0.1～100μg，再更佳為含有0.5～50μg。 [0032] 攝取本發明之抑制乳桿菌屬乳酸菌減少用之組成物，可有效的抑制經施予抗菌藥物之對象中，腸道內之乳桿菌屬乳酸菌的減少。 腸道內乳桿菌屬乳酸菌之減少抑制效果係如同實施例之例1中所記載，可藉由經施予抗菌藥物之對象中，定量腸道內之乳桿菌屬菌數，以已攝取及未攝取本發明之組成物之群中之菌數作為指標進行比較試驗而進行評價。進行之比較試驗中，相較於未攝取本發明之組成物之群，經攝取本發明之組成物之群中，乳桿菌屬菌數顯著地變高，且，相較於施予抗菌藥物前之乳桿菌屬菌數增加之情況下，本發明之組成物，被認為具有高度抑制乳桿菌屬乳酸菌減少之活性。 [0033] 又，本發明之抑制乳桿菌屬乳酸菌減少用之組成物，係由於含有源自丙酸桿菌之乳清發酵物，故與各種食材相合性高，可安全且簡易的攝取。 [0034] 根據本發明之一態樣，本發明之抑制乳桿菌屬乳酸菌減少用之組成物，係較佳與乳桿菌屬之生菌同時或依次施予。若本發明之抑制乳桿菌屬乳酸菌減少用之組成物與作為益生菌之乳桿菌屬之生菌同時或依次攝取，可使於經施予抗菌藥物之對象中，腸道內乳桿菌屬乳酸菌之菌數增加，亦可使腸內細菌叢之平衡變得更良好。 [0035] 根據本發明之一態樣，本發明之抑制乳桿菌屬乳酸菌減少用之組成物，為了使源自丙酸桿菌之乳清發酵物，成為抑制經施予抗菌藥物之對象中腸道內乳桿菌屬乳酸菌之減少有效量，較佳係由1日攝取量單位之形態所構成。本發明之抑制乳桿菌屬乳酸菌減少用之組成物中上述單位為，每日攝取量(施予量)為，以源自丙酸桿菌之乳清發酵物之乾燥質量換算，期望成為攝取0.15～200mg/kg體重，較佳為0.65～120mg/kg體重，更佳為1.15～70mg/kg體重，再更佳為成為攝取1.5～20mg/kg體重。於此，以對象之代表性體重為60kg進行估算。 [0036] 此外，本發明之抑制乳桿菌屬乳酸菌減少用之組成物係較佳以1次的攝取量為單位包裝的形態提供。作為相當於1次之攝取量單位包裝形態，舉例可為藉由包裝袋、容器等規定一定量的形態，亦可於該些之表面上註明1次之攝取量之成分，以及，註明抑制腸道內乳桿菌屬乳酸菌減少等之用途。作為所述單位包裝形態之適宜的例子，舉例可為營養輔助食品、醫藥製劑等。 [0037] 使對象攝取本發明之抑制乳桿菌屬乳酸菌減少用之組成物之方法(或施予方法)，在不妨礙本發明之效果的範圍內並無特別限定，根據該對象及用途可由經口攝取(或經口施予)、經管施予、經腸施予、胃造口術等適當選擇。 [0038] 本發明之抑制乳桿菌屬乳酸菌減少用之組成物，可於施予抗菌藥物前使對象攝取，亦可讓施予抗菌藥物中的對象攝取，使對象於施予抗菌藥物後攝取亦可。較佳為，讓施予抗菌藥物前之對象攝取本發明之組成物。於施予抗菌藥物前之期間，若攝取本發明之組成物之攝取期間越長越佳，由源自丙酸桿菌之乳清發酵物改善之腸內細菌叢角度考慮，較佳為施予之前1天，更佳為前3天，再更佳為施予之前5天。又，使正施予抗菌藥物之對象攝取本發明之組成物之情況下，可使對象同時亦攝取抗菌藥物，然較佳為72小時以內，更佳為24小時以內依次攝取。 [0039] 又，本發明之抑制乳桿菌屬乳酸菌減少用之組成物之攝取計畫，並未有特別限制，本發明技術領域中具有通常知識者可因應對象之年齡、性別、症狀及狀態適宜設定。例如，針對對象，1次的經口攝取量單位可每日1～10次施予，然而較佳為每日1～3次，更佳為攝取1次。又，本發明之抑制乳桿菌屬乳酸菌減少用之組成物，可與食物一同攝取。 [0040] 根據本發明之一實施態樣，本發明之抑制乳桿菌屬乳酸菌減少用之組成物，可就這樣單獨使用，然而，於經施予抗菌藥物之對象中，使抑制腸道內乳桿菌屬乳酸菌減少機能可發揮之前提下，對於食品或醫藥品等各種的經口攝取用(經口施予用)之組成物，亦可使其含有原料(素材)或添加劑等，可得到於經施予抗菌藥物之對象中，具有抑制腸道內乳桿菌屬乳酸菌減少效果之組成物(例如，醫藥組成物或食品組成物)。本發明之抑制乳桿菌屬乳酸菌減少用之組成物，由於於飲食中添加亦不損其味道，故可於平時的飲食中、飲料中添加，可簡易的攝取。 [0041] 依據本發明之較佳態樣，係提供一種包含源自丙酸桿菌之乳清發酵物而成，於經施予抗菌藥物之對象中，抑制腸道內乳桿菌屬乳酸菌減少用食品。 「食品」(食品組成物)之形態並未有特別限制，溶液、懸濁液、乳濁液、粉末、固體成形物等，可經口攝取型態即可。具體可舉例為，速食麵、蒸煮袋食品、罐頭、電子微波食品、即席湯、味增湯類，冷凍乾燥食品等的即席食品類；清涼飲料、果汁飲料、蔬菜飲料、豆乳飲料、咖啡飲料、茶飲料、粉末飲料、濃縮飲料、酒精飲料等的飲料類；麵包、義大利麵、麵條、蛋糕混合料、麵包粉等的小麥粉製品；糖果、牛奶糖、口香糖、巧克力、餅乾、軟餅、蛋糕、派、點心、鹹餅乾、和果子、甜品糖果等的點心類；醬汁、番茄加工調味料、風味調味料、調理混合料、調味料類、沙拉醬類、醬油露類、咖哩・燉菜之原料類等的調味料；加工油脂、奶油、人造黃油、美乃滋等的油脂類；乳飲料、發酵乳(優格等)、乳酸菌飲料、天然起司、加工乾酪類、冰淇淋類、奶油類等的乳製品；農產罐頭、果醬・柑橘醬類、穀物等的農產加工品；冷凍食品、流質食品等。 [0042] 又，食品中，亦包含以健康食品、機能性食品、營養補助食品、特定保健用食品、病患用食品、嬰幼兒用的調整奶粉、孕婦產婦用或哺乳婦人用之奶粉，或如同附有以於經施予抗菌藥物之對象中，抑制腸道內乳桿菌屬乳酸菌減少而使用之物為主旨之表示之食品的分類者。 [0043] 根據本發明之其他態樣，係提供一種包含源自丙酸桿菌之乳清發酵物而成，於經施予抗菌藥物之對象中，抑制腸道內乳桿菌屬乳酸菌減少用之醫藥品。所謂「醫藥品」(醫藥組成物)，係併用為了製劑化而可容許的添加物，依照常用方法，係作為經口製劑或非經口製劑而調製者。醫藥品為經口製劑之情況可選擇錠劑、藥粉、細顆粒劑、顆粒劑、膠囊、丸劑、緩釋劑等的固形製劑、溶液、懸濁液、乳濁液等的液狀製劑之型態。又，醫藥品為非經口製劑之情況下，可選擇注射劑或栓劑之型態。此外，由針對使患者攝取(施予)之簡易性的觀點而言，醫藥品係較佳為經口製劑。於此，為了製劑化而可容許之添加劑中，可舉例為例如，賦形劑、穩定劑、防腐劑、潤濕劑、乳化劑、潤滑劑、甜味劑、著色劑、香料、緩衝劑、抗氧化劑、pH調整劑等。本發明之醫藥品，係可用於有必要於經施予抗菌藥物之對象中，抑制腸道內乳桿菌屬乳酸菌之減少之疾病，具體而言，係可用於源自施予抗菌藥物所造成之便秘、腹瀉、噁心、頭痛等的副作用之症狀的治療或預防。 [0044] 本發明之抑制乳桿菌屬乳酸菌減少用之組成物，係將源自丙酸桿菌之乳清發酵物，與所期望之經口方面容許之其他成分混合而可簡易製造。因此，依據本發明之其他態樣，係提供一種於經施予抗菌藥物之對象中，抑制腸道內乳桿菌屬乳酸菌減少用之組成物之製造方法，其特徵在於該組成物中含有源自丙酸桿菌之乳清發酵物之有效量。 [0045] 又，根據本發明之其他態樣，係提供一種於經施予抗菌藥物之對象中，抑制腸道內乳桿菌屬乳酸菌減少之方法，其特徵在於，其係包含使上述對象攝取源自丙酸桿菌之乳清發酵物之有效量而成。於此，依據本發明之其他較佳態樣，抑制腸道內乳桿菌屬乳酸菌之減少之方法，係排除對人類之醫療行為者。於此，所謂「對於人類之醫療行為」係以醫師等之處方為必要，對於人類係使之攝取(施予)醫藥品之行為等的意思。又，於上述之實施態樣，其對象較佳為健康之常人。 [0046] 又，本發明之抑制腸道內乳桿菌屬乳酸菌之減少之方法，亦可用於改善與經施予抗菌藥物之對象中，腸道內乳桿菌屬乳酸菌之減少相關聯之疾病或狀態。因此，本發明之抑制腸道內乳桿菌屬乳酸菌之減少之方法，係與施予抗菌藥物而產生之腸道內乳桿菌屬乳酸菌之減少相關聯之疾病或狀態之改善方法，更佳係為便祕、腹瀉、噁心以及其所伴隨之頭痛之改善方法。於此，所謂的「改善」，不僅為治療已確立之疾病或狀態，亦包含將來有被確立之可能性之疾病或狀態之預防。 [0047] 於抑制方法中，源自丙酸桿菌之乳清發酵物之有效量，可使其與上述組成物之1次之攝取量單位相同。 [0048] 依據本發明之一實施態樣，其係用於抑制於經施予抗菌藥物之對象中，腸道內乳桿菌屬乳酸菌之減少。提供一種源自丙酸桿菌之乳清發酵物之使用方式。依據本發明之一較佳實施態樣，本發明之使用方式，係以非治療性地使用。 [0049] 依據本發明之一實施態樣，係提供源自丙酸桿菌之乳清發酵物之用途，該用途係於經施予抗菌藥物之對象中抑制腸道內乳桿菌屬乳酸菌減少用之組成物之製造。依據本發明之一較佳實施態樣，該用途係為乳桿菌屬乳酸菌減少抑制用食品或醫藥品之製造之目的。 [0050] 依據本發明之一實施態樣，係提供一種源自丙酸桿菌之乳清發酵物，係用於抑制經施予抗菌藥物之對象中，腸道內乳桿菌屬乳酸菌之減少之目的。 [實施例] [0051] 本發明係藉由以下的例子詳細說明，然而本發明並不限於此等。 [0052] 例1：組成物之調製(藉由丙酸調製乳清發酵物) 為了使生菌數成為107
～108
cfu/mL，將費氏丙酸桿菌 ET-3(Propionibacterium freudenreichii ET-3)(寄存號碼：FERM BP-8115)作為菌元，攝取由10質量%乳漿粉還原液以蛋白水解酶 AMANOA(天野製藥股份公司)於50℃、pH7.0下分解而得之分解物所成之培養基，於35℃、pH6.0下培養75小時。將所得到之培養上清液殺菌，冷凍乾燥。相對於0.2g冷凍乾燥物，添加葡萄糖、含有食物纖維之糊精，成為總量1.5g之調製物。該組成物中，含有之蛋白質為0.03g、脂質為0g、作為碳水化物之糖質為0.6g、食物纖維為0.8g、鈉為2.6mg、鈣為1.0mg、磷為1.3mg、鎂為0.2mg、鉀為15.8mg。 [0053] 將所得到的調製物作為本發明之組成物使用。以1.5g單位的鋁個別包裝作為調製物。 [0054] 例2：臨床試驗 (1)試驗對象 臨床試驗係以對照群與施予組成物之群等2群分開實施。兩群之試驗之受驗者，皆為送入大阪府三島救命中心之重症患者 (腦出血、外傷、腦栓塞之患者)。受驗者係原則上於入院時以管灌餵食進行管理，由鼻腔將軟管***留置於胃中。又，原則上，抗菌藥物係於試驗開始後一周以內開始施予。此外，抗菌藥物係依據患者所具有之疾病、狀態，依據JAID/JAS感染症治療方針2014(JAID/JAS感染症治療方針・指導方針制定委員會編輯)所記載之技巧，由下述表1所列舉之抗菌藥物選擇後施予。 [0055][0056] 對照群與施予組成物之群 於對照群中，係施予2星期之流質食物。作為流質食物，係使用至少1種選自由MEIBALANCE HP(メイバランスHP)或MEIN(明治股份公司)等2種類所組成之群組。此些中，不含有對於腸道內細菌叢產生影響之成分，特別是不含使乳桿菌屬乳酸菌減少之成分。另一方面，施予組成物之群中，將於由例1所得之組成物(2包/日(3g/日))添加至流質食物中，施予2週之期間。對照群為46人，施予組成物之群為14人。此外，對照群中之1人，由於於2週之試驗期間中係非施予抗菌藥物，故將此1人除外再進行分析。因此，分析人數之對照群為45人，施予組成物之群為14人。 [0057] 經分析之對照群與施予組成物之群的患者背景與施予抗菌藥物之天數之結果由下述表2所示。 [0058][0059] 如表2所示，對照群之11.5±3.2天與施予組成物之群之11.8±2.9天之兩群間，抗菌藥物施予天數幾乎沒有差異。又，男女比與APACHE II亦幾乎沒有看見差異。 [0060] (2)糞便中之菌叢之分析 採取糞便 對照群及施予組成物之群中，各自於試驗開始(流質食物施予)前(第0天)、試驗開始後第3天、試驗開始後第7天(1星期)、試驗開始後第14天 (2星期)實施糞便之採取。 [0061] 糞便中之菌叢之分析 所採取之糞便，於採取後立即保存於-20℃以下。由患者之糞便中將糞便中之菌叢DNA，使用Multi-Beads Shocker(安井機械股份公司)，按照QIAamp DNA stool Mini Kit (QIAGEN公司)之方法抽出。又，Real-time PCR之反應，係使用QuantiTect SYBR Green RT-PCR(QIAGEN社)，並使用下述表3記載之引子，以95℃、15秒鐘→(94℃、15秒鐘→各引子之黏合溫度、30秒鐘→72℃、30秒鐘)×30～55循環，乳桿菌屬乳酸菌數、比菲德氏菌數及總菌數以ABI 7300 Real Time PCR System(Applied Biosystems 公司)定量。菌數係以每1g糞便之菌數之對數值表示。 [0062][0063] 各群內之前後比較係以對應之t檢定進行分析。又，對照群與施予組成物之群之2群間的分析，係以對照群與施予組成物之群之試驗結果相比較來進行評價，以Students’ t test(等分散)或Welch test(不等分散)分析。 [0064] 結果如圖1～4所示。 圖1為，顯示對照群之糞便中的總菌數與乳桿菌屬菌數之變化之圖表。圖1之對照群中，試驗開始後之第3天以後，總菌數與乳桿菌屬之菌數皆相較於試驗開始時顯著地減少。 圖2為，顯示施予組成物之群之糞便中的總菌數與乳桿菌屬菌數之變化之圖表。圖2之施予組成物之群中，與試驗開始前相比較，並未發現試驗期間中乳桿菌屬菌數有意義的減少情況。另一方面，相較於試驗開始前，於試驗開始後之第7天總菌數雖顯著地減少，然而第3天與第14天並未有顯著的差別。 圖3，係比較對照群及施予組成物之群之糞便中的總菌數與乳桿菌屬菌數。觀察圖3之乳桿菌屬菌數，對照群及施予組成物，於試驗開始時幾乎無差別，然而試驗開始後第3天以後，與施予組成物之群相比較，對照群之一方正顯著地減少。另一方面，試驗期間中兩群間之總菌數並未看出有顯著的變化(圖3)。如此，雖然施予抗菌藥物使腸道內之乳桿菌屬菌數減少，然於抗菌藥物施予前或施予中，施予本發明之組成物，則確認可抑制腸道內之乳桿菌屬菌數之減少。 圖4為，顯示對象群及施予組成物之群之糞便中的比菲德氏菌數比較之圖表。圖4之比菲德氏菌數，對照群與施予組成物之群一同，於試驗開始後第3天以後，與試驗開始時相比顯著地減少。又，對照群與施予組成物之群之比菲德氏菌數相比較之結果，兩群間未看見顯著的變化。[0013] Composition for inhibiting reduction of Lactobacillus lactic acid bacteria The composition of the present invention is a composition for inhibiting the reduction of Lactobacillus lactic acid bacteria in the intestine in a subject administered with an antibacterial drug, and the composition comprises Fermented from whey fermentation of acid bacteria. Using the whey fermented product derived from Propionibacterium as an active ingredient can not only reduce the reduction of Biederella in the intestine, but also before, during, or after the administration of antibacterial drugs. It is an unexpected fact that the reduction of Lactobacillus lactic acid bacteria in the intestinal tract can be significantly suppressed. [0014] The term "subject administered with an antibacterial agent" means an object expected to be administered with an antibacterial agent (before administration), an object being administered (under administration), or an object that has been administered (after administration), Preferably, it refers to a subject whose Lactobacillus lactic acid bacteria in the intestinal tract is expected to be reduced, is being reduced, or has been reduced due to antibacterial drugs. Although the object is preferably a human, other than humans (for example, domestic animals such as horses and cattle, pets such as rodents, dogs, and cats, and appreciation animals that are kept in zoos and the like) are also preferable. Related aspects in the present invention Also included. [0015] The antibacterial drug of the present invention is not particularly limited if it is an antibacterial drug exhibited by Lactobacillus lactic acid bacteria, but it is preferably an antibiotic exhibited by Lactobacillus lactic acid bacteria. More specific examples include, for example, penicillin-based antibacterials (for example, amoxicillin (AMPC), ampicillin (ABPC)), cephalosporin-based antibacterials (for example, cefpirome (CPR)), and cephalosporins. Class antibacterials (e.g., ceftazidime (CAZ)), carbapenem antibacterials (e.g., meropenem (MEPM)), beta-lactamidine inhibitors, oxazolidone antibacterials (e.g., linezol) In addition to amines (LZD), neoquinolone antibacterials (e.g., levofloxacin (LVFX), pazufloxacin (PZFX)), and macrolides (e.g., azithromycin (AZM)), forests can be listed. Colenomycin antibacterials, aminoglycoside antibacterials, tetracycline antibacterials, chloramphenicol antibacterials, peptide antibacterials, sulfonamides, antituberculosis drugs, quinolone antibacterials, antiviral drugs Antifungal drugs. The antibacterial agent is preferably a penicillin-based antibacterial agent (for example, amoxicillin (AMPC), ampicillin (ABPC)), a cephalosporin-based antibacterial agent (for example, cefpirome (CPR)), and a cephalosporin-based antibacterial agent ( For example, ceftazidime (CAZ)), carbapenem antibacterials (e.g., Meropenem (MEPM)), beta-lactamidine inhibitors, oxazolidone antibacterials (e.g., linezolid (LZD) ), Neoquinolone antibacterials (eg, levofloxacin (LVFX), pazufloxacin (PZFX)), and macrolides (eg, azithromycin (AZM)). [0016] The method of administering the antibacterial drug is not particularly limited as long as the Lactobacillus lactobacillus in the intestine exhibits susceptibility. For example, it can be taken orally (orally), enterally, gastrostomy, subcutaneously. The administration, intravenous administration, and the like are appropriately selected depending on the target and application (for example, treatment purpose or prevention purpose) of the antibacterial drug administration. The method of using the antibacterial drug can be appropriately selected by those with ordinary knowledge in the technical field of the present invention according to the disease, state, and application of the subject. For example, if the person with ordinary knowledge in the technical field of the present invention can be infected according to JAID / JAS The guidelines described in the Guidelines for the Treatment of Infectious Diseases 2014 (edited by the JAID / JAS Infectious Diseases Treatment Guidelines and Guidelines Development Committee) are appropriately selected. [0017] Lactobacillus is a gram-positive bacterium and known as a beneficial bacteria. As a specific example of a preferred Lactobacillus lactic acid bacteria, the results of human clinical trials can be exemplified by Lactobacillus bulgaricus, L. johnsonii, L. casei, and L. paracasei, L. gasseri, L. helveticus, L. rhamnosus, L. acidophilus, saliva L. salivarius, L. pentosus, L. plantarum, L. brevis, L. reuteri, Lactobacillus (L. sporogenes), etc. Lactobacillus lactobacillus is known to have, for example, intestinal rectifying effects (e.g., intestinal rectifying effects on diarrhea, constipation, allergic bowel syndrome), immune activation, bactericidal effects of H. pylori, atopic dermatitis, pollen Allergic suppression of asthma and asthma, improvement of allergic bowel syndrome (IBS), improvement of lipid metabolism or visceral fat accumulation, suppression of risk of infectious diseases such as respiratory diseases, improvement of inflammatory bowel disease, uterus Physiological activities such as improvement of endometriosis, cancer suppression, improvement of stress and QOL, improvement of diabetes, improvement of oxidative stress. Lactobacillus genus Lactobacillus is expected to exist in a certain number in the intestinal tract due to its physiological activity. [0018] The Lactobacillus genus Lactobacillus in the intestinal tract is preferably the Lactobacillus Lactobacillus contained in the intestinal bacterial plexus, and more preferably, a Lactobacillus that has a good balance function in the intestinal environment. The number of Lactobacillus lactic acid bacteria in the intestine is more than 4 Log10 per 1g of human feces, more preferably 5 or more Log10, more preferably 6 or more Log10, and 7 or more Log10. [0019] The propionic acid-derived whey fermentation product used in the present invention is obtained by culturing a propionic acid bacterium in a culture medium containing whey. [0020] The so-called propionibacterium is a Gram-positive anaerobic bacteria belonging to the Propionibacterium genus. It is a microorganism that produces propionic acid by anaerobic sugars, and has been used as an Evandar cheese since ancient times. And other bacterial cells, its safety has been confirmed. Examples of the Propionibacterium used in the present invention include Propionibacterium freudenreichii, P. thoenii, P. acidipropionici, and J. propioni P. jensenii, P. avidum, P. acnes, P. lymphophilum, P. granulosam, preferably For Propionibacterium fischeri. One of them may be used, or two or more of them may be used in combination. Propionibacterium is preferably a Bifidobacterium proliferation-promoting substance (BGS) -producing bacteria belonging to Propionibacterium freudenreichii, and, for example, P. fischeri ET-3 (registered number: FERM-BP- 8115), Propionibacterium freudenii ATCC 6207, Propionibacterium freudenii ATCC 8262, Propionibacterium freudenii IFO 12424, Propionibacterium freudenii IFO 12426, Propionibacterium freudenii IFO 12391, and more preferably P. fibriformis Bacillus ET-3 (registration number: FERM-BP-8115). [0021] The so-called whey, also referred to as whey, refers to the remaining transparent yellow-green water-soluble components after removing fat, casein, and fat-soluble vitamins from cow milk. Examples of the whey used in the present invention include, for example, a stock solution of a milk slurry (sweet milk slurry, sour milk slurry, etc.), a concentrate thereof, a dried product thereof (milk powder), a frozen product thereof, and the like Reducing solution, and desalted milk, milk protein concentrate (WPC), milk protein isolate (WPI), α-lactalbumin (α-La), β-lactoglobulin (β-Lg), immunity Globulin, lactoferrin, etc., as well as the above-mentioned reducing solution and the above-mentioned milk protein degradation product. The whey system is preferably a reducing solution selected from the group consisting of a milk stock solution, a milk powder, WPC, and WPI, and proteolytic enzyme degradation products thereof. Only one kind may be used, or two or more kinds may be used in combination. [0022] The amount of protein in the whey system relative to the culture medium is preferably 1 to 5 mass%, more preferably 1.5 to 4.0 mass%. Glycans are contained in an amount of 1 to 4% by mass, preferably 1.5 to 3.0% by mass, with respect to the culture medium. In order to make such a culture medium composition, a thing which adjusts the addition amount (blending amount) of whey can be used. The sugar is preferably glucose or a monosaccharide in which lactose is treated with lactase. If the medium is a medium capable of culturing Gram-positive anaerobic bacteria, it may also contain components other than whey. Here, the amount of protein can be calculated by the Kjeldahl method or labor legislation. In the case of the Kjeldahl method, the nitrogen contained in various proteins is measured, and this value can be calculated by multiplying this value by a nitrogen-protein conversion coefficient (usually 6.25). [0023] The culture medium usable in the present invention is preferably a culture medium having a pH of 5 to 8 (preferably 5.5 to 7.5) formed from a proteolytic enzyme decomposed product of a 10% by mass milk powder reducing solution. The proteolytic enzyme is not particularly limited as long as it can degrade the milk protein moderately. As the culture medium, for example, a proteolytic enzyme AMANO A (Amano Pharmaceutical Co., Ltd.) can be used to decompose a 10% by mass reduction solution of the milk powder at 50 ° C and pH 7.0. [0024] The culture of Propionibacterium can be performed aerobically or anaerobically (for example, under N 2 gas pressure (0.5 kg / cm 2 )) in addition to the culture medium containing whey. Generally, the temperature of the culture medium is adjusted to a temperature of 20 to 40 ° C and a pH of 6 to 8. In order to achieve a bacterial count of 10 7 to 10 8 cfu / mL, a propionibacterium that is a bacterial cell is ingested, and the liquid culture is performed for 3 to 4 days. Just fine. The concentration of propionibacteria contained in the culture obtained in this way reached about 5 times the bacterial cell. [0025] The whey fermentation product derived from Propionibacterium according to the present invention may be a culture obtained by culturing Propionibacterium, an isolated bacterial body, a culture solution (culture supernatant), or the above. At least one of the mixtures, the whey fermentation product derived from Propionibacterium can be an extract, freeze-dried or diluent of these. In addition, the whey fermentation product derived from Propionibacterium may be a sterilization treatment. Examples of the sterilization step include low-temperature long-term sterilization, high-temperature long-term sterilization, high-temperature short-time sterilization, and ultra-high-temperature instant sterilization. [0026] According to a preferred aspect of the present invention, as the whey fermentation product derived from Propionibacterium of the present invention, Propionibacterium freudenreichii ET-3 (registered number: FERM BP-8115) Propionibacterium-derived whey fermentation product obtained by culturing in a 10% by mass milk powder reducing solution. More preferably, P. fibribacterium ET-3 can be used at a concentration of 10% by mass. Proteolytic enzyme AMANO A (Amano Pharmaceutical Co., Ltd.), which is a proteolytic enzyme in the reducing solution of the milk powder, is a medium obtained from the decomposed product decomposed at 50 ° C and pH 7.0, and is a source obtained by culturing at 35 ° C and pH 6.0 for 75 hours Whey Fermentation from Propionibacterium. In this way, a whey fermentation product derived from Propionibacterium can be synthesized, and a commercially available product can also be used. As a commercially available product, for example, as a raw material, Profec ("Profec" (trademark), manufactured by Meiji Corporation) is exemplified. This is recognized as having a proliferation-promoting effect on major intestinal bacteria, particularly Bifidobacterium, and is recognized. As a related ingredient of specific health foods. [0027] According to one aspect of the present invention, the whey fermentation product derived from Propionibacterium of the present invention may further include a Bifidobacterium proliferation promoting substance (BGS). Examples of Bifidobacterium proliferation-promoting substances include, for example, 1,4-dihydroxy-2-naphthoic acid (DHNA), and 2-amino-3-carboxyl-1 2,4-naphthoquinone (2-amino-3-carboxy-1,4-naphthoquinone, ACNQ) and the above-mentioned analogs, which include 1,4-naphthoquinone, 2-methyl-1,4- Naphthoquinone, 4-amino-2-methyl-1-naphthol and 2-amino-3-chloro-1,4-naphthoquinone. According to a preferred embodiment of the present invention, the propionic acid-derived whey fermentation product of the present invention comprises 1,4-dihydroxy-2-naphthoic acid. [0028] The whey fermentation product derived from Propionibacterium used in the present invention can be used as a composition for inhibiting the reduction of Lactobacillus lactic acid bacteria. [0029] The composition for inhibiting the reduction of lactic acid bacteria of the genus Lactobacillus of the present invention may contain other ingredients that are orally acceptable in addition to the whey fermentation product derived from propionibacterium. The other ingredients are not particularly limited as long as they do not interfere with the effects of the present invention. Examples include excipients, stabilizers, preservatives, wetting agents, emulsifiers, lubricants, sweeteners, colorants, flavors, Additives such as buffers, antioxidants, and pH adjusters. According to a preferred aspect of the present invention, the composition for inhibiting the reduction of Lactobacillus lactic acid bacteria according to the present invention is composed of functional saccharides (for example, oligosaccharides or dietary fiber) serving as a "feed" for Lactobacillus lactic acid bacteria. . By containing functional saccharides that become the "feed" of Lactobacillus lactic acid bacteria, it can become the "feed" of Lactobacillus lactic acid bacteria remaining in the intestinal tract and promote proliferation. [0030] The form of the composition for inhibiting the reduction of lactic acid bacteria of the genus Lactobacillus according to the present invention is not particularly limited, and it is in a solid form (powder form, tablet form, etc.), a liquid form (injected form, etc.), and a semi-liquid form. Either one may be used, but it is preferably in a powder form, a tablet form, or a liquid form. Examples of commercially available products of this type include powdered Meiji BGS POWDER (manufactured by Meiji Co., Ltd.), lozenge gastrointestinal active tablets (manufactured by Meiji Co., Ltd.), and liquid YH Flore (manufactured by Meiji Co., Ltd.) )Wait. [0031] According to a preferred aspect of the present invention, the composition for inhibiting lactic acid bacteria reduction of the genus Lactobacillus according to the present invention contains 1,4-dihydroxy-2-naphthoic acid, protein, and carbohydrate (for example, sugar, Dietary fiber), depending on the situation, contains vitamins and / or minerals (for example, sodium, calcium, phosphorus, magnesium, potassium). According to a preferred aspect, 1.5 g of the composition for inhibiting the reduction of lactic acid bacteria of the genus Lactobacillus according to the present invention contains 1,4-dihydroxy-2-naphthoic acid 0.01 to 1000 μg, more preferably 0.1 to 100 μg, and even more preferably Contains 0.5 to 50 μg. [0032] Ingestion of the composition for inhibiting the reduction of Lactobacillus lactic acid bacteria of the present invention can effectively inhibit the reduction of Lactobacillus lactic acid bacteria in the intestinal tract in a subject administered an antibacterial drug. The inhibitory effect of Lactobacillus lactobacillus in the intestinal tract is as described in Example 1 of the Example. The number of Lactobacillus bacteria in the intestinal tract can be quantified in the intestinal tract by subjecting the antibacterial agent to administration. The number of bacteria in the group ingesting the composition of the present invention was used as an index to perform a comparative test and evaluated. In the comparative test performed, the number of Lactobacillus bacteria was significantly higher in the group ingested with the composition of the present invention than in the group not ingested with the composition of the present invention, and compared with that before administration of the antibacterial drug When the number of Lactobacillus bacteria is increased, the composition of the present invention is considered to have a high activity of inhibiting the reduction of Lactobacillus lactic acid bacteria. [0033] In addition, the composition for inhibiting the reduction of lactic acid bacteria of the genus Lactobacillus according to the present invention contains a whey fermentation product derived from propionic acid bacteria, and therefore has high compatibility with various food materials, and can be safely and easily ingested. [0034] According to one aspect of the present invention, the composition for inhibiting the reduction of lactic acid bacteria of the genus Lactobacillus according to the present invention is preferably administered simultaneously or sequentially with the bacterium of the genus Lactobacillus. If the composition for inhibiting the reduction of Lactobacillus lactic acid bacteria of the present invention is taken simultaneously or sequentially with the probiotic bacteria of Lactobacillus genus, the intestinal lactobacillus bacteria Increasing the number of bacteria can also make the balance of intestinal bacteria clusters better. [0035] According to one aspect of the present invention, the composition for inhibiting the reduction of lactic acid bacteria of the genus Lactobacillus according to the present invention, in order to make the whey fermentation product derived from propionibacterium become the target of suppressing the intestinal tract administered with antibacterial drugs The effective amount for reducing Lactobacillus lactobacillus is preferably in the form of a daily intake unit. The above-mentioned unit in the composition for inhibiting lactic acid bacteria reduction of the genus Lactobacillus according to the present invention is that the daily intake (administration amount) is based on the dry mass of the whey fermented product derived from Propionibacterium, and it is expected to be 0.15 to ～ 200 mg / kg body weight, preferably 0.65 to 120 mg / kg body weight, more preferably 1.15 to 70 mg / kg body weight, and still more preferably 1.5 to 20 mg / kg body weight. Here, it is estimated that the subject's representative weight is 60 kg. [0036] In addition, the composition for inhibiting the reduction of lactic acid bacteria of the genus Lactobacillus of the present invention is preferably provided in the form of a package for each ingestion amount. Examples of the unit packaging form equivalent to a single ingestion amount may be a form in which a certain amount is specified by a packaging bag, a container, or the like. The components of the single ingestion amount may also be indicated on the surface, and the intestinal suppression may be indicated. Uses of Lactobacillus genus Lactobacillus reduction in the tract. As suitable examples of the unit packaging form, examples include nutritional supplementary foods, pharmaceutical preparations, and the like. [0037] The method (or method of administration) for ingesting the composition for inhibiting the reduction of Lactobacillus lactic acid bacteria according to the present invention is not particularly limited as long as the effect of the present invention is not hindered. The oral ingestion (or oral administration), intravenous administration, enteral administration, gastrostomy, etc. are appropriately selected. [0038] The composition for inhibiting the reduction of Lactobacillus lactic acid bacteria of the present invention can be ingested by the subject before the administration of the antibacterial medicine, or can be ingested by the subject administered the antibacterial medicine, and the subject can also be ingested after the administration of the antibacterial medicine. can. Preferably, the subject of the present invention ingests the composition before the antibacterial drug is administered. In the period before administration of the antibacterial drug, if the ingestion period of the composition of the present invention is taken as long as possible, it is preferable from the standpoint of the intestinal bacterial clump improved by the whey fermentation product derived from propionibacterium, preferably before administration 1 day, more preferably 3 days before, and even more preferably 5 days before administration. When the subject to be administered an antibacterial drug ingests the composition of the present invention, the subject can also ingest the antibacterial drug at the same time, but it is preferably taken within 72 hours and more preferably within 24 hours. [0039] In addition, the intake plan of the composition for inhibiting the reduction of Lactobacillus lactic acid bacteria according to the present invention is not particularly limited, and those with ordinary knowledge in the technical field of the present invention can adapt to the age, sex, symptoms, and status of the subject. set up. For example, a unit of oral intake can be administered to a subject 1 to 10 times per day, but it is preferably 1 to 3 times per day, and more preferably 1 time. The composition for inhibiting the reduction of Lactobacillus lactic acid bacteria of the present invention can be ingested with food. [0040] According to one embodiment of the present invention, the composition for inhibiting Lactobacillus lactobacillus reduction according to the present invention can be used alone as it is. However, in a subject administered with an antibacterial drug, the intestinal milk is inhibited. The lactic acid bacteria reduction function of Bacillus genus can be mentioned before. It can also be used for various oral ingestion (oral administration) compositions such as foods and pharmaceuticals, and it can also contain raw materials (materials) or additives. Among the subjects to which the antibacterial agent is administered, a composition (for example, a pharmaceutical composition or a food composition) having an effect of inhibiting the reduction of Lactobacillus lactic acid bacteria in the intestinal tract. The composition for inhibiting the reduction of lactic acid bacteria of the genus Lactobacillus according to the present invention does not impair its taste even when added to the diet, so it can be added to a normal diet or a drink and can be easily ingested. [0041] According to a preferred aspect of the present invention, a food containing whey fermentation product derived from propionibacterium is provided, and the food for inhibiting Lactobacillus lactobacillus in the intestinal tract is reduced in a subject administered with an antibacterial drug. . The form of the "food" (food composition) is not particularly limited, and a solution, a suspension, an emulsion, a powder, a solid formed article, or the like can be ingested orally. Specific examples include instant foods such as instant noodles, retort pouches, canned foods, electronic microwave foods, instant soups, miso soups, freeze-dried foods, etc .; refreshing beverages, fruit juice drinks, vegetable drinks, soy milk drinks, coffee drinks, tea Beverages such as beverages, powdered drinks, concentrated drinks, alcoholic beverages; bread, pasta, noodles, cake mixes, bread flour and other wheat flour products; confectionery, milk sugar, chewing gum, chocolate, biscuits, soft cakes, cakes , Pie, dim sum, salty biscuits, confectionery such as fruit, dessert, etc .; sauce, tomato processing seasoning, flavor seasoning, conditioning mixture, seasoning, salad dressing, soy sauce, curry, stew Seasonings such as raw materials; processed oils, butter, margarine, mayonnaise and other oils; milk drinks, fermented milk (yugao), lactic acid bacteria drinks, natural cheeses, processed cheeses, ice creams, creams Dairy products such as canned foods; processed agricultural products such as canned agricultural products, jams and citrus jams, cereals; frozen foods, liquid foods, etc. [0042] The food also includes health food, functional food, nutritional supplement food, food for specific health care, food for patients, adjusted milk powder for infants and young children, milk powder for pregnant women or breastfeeding women, or As with the classification of foods with the main purpose of inhibiting the reduction of Lactobacillus lactic acid bacteria in the intestinal tract among subjects administered antibacterial drugs. [0043] According to another aspect of the present invention, there is provided a medicine comprising a whey fermentation product derived from propionibacterium, which is used for inhibiting the reduction of Lactobacillus lactic acid bacteria in the intestine in a subject administered with an antibacterial drug. Product. The "medicine" (pharmaceutical composition) is a combination of additives that are allowed for formulation, and is prepared as an oral or parenteral preparation according to a common method. When the pharmaceutical product is an oral preparation, a solid preparation such as a tablet, a powder, a fine granule, a granule, a capsule, a pill, a sustained release, a liquid preparation such as a solution, a suspension, and an emulsion can be selected. state. When the pharmaceutical is a parenteral preparation, an injection or a suppository can be selected. In addition, from the viewpoint of ease of ingestion (administration) by a patient, the pharmaceutical product is preferably an oral preparation. Here, examples of the allowable additives for formulation include, for example, excipients, stabilizers, preservatives, wetting agents, emulsifiers, lubricants, sweeteners, colorants, flavors, buffers, Antioxidants, pH adjusters, etc. The medicinal product of the present invention can be used for diseases in which it is necessary to inhibit the reduction of Lactobacillus lactic acid bacteria in the intestine in a subject administered with an antibacterial drug, and specifically, it can be used for the drug derived from the administration of an antibacterial drug Treatment or prevention of side effects such as constipation, diarrhea, nausea, and headache. [0044] The composition for inhibiting the reduction of lactic acid bacteria of the genus Lactobacillus according to the present invention can be simply manufactured by mixing a whey fermentation product derived from propionibacterium with other ingredients that are acceptable in the oral cavity. Therefore, according to another aspect of the present invention, a method for producing a composition for inhibiting the reduction of Lactobacillus lactobacillus in the intestine in a subject administered with an antibacterial drug is provided, which is characterized in that the composition contains Effective amount of Propionibacterium whey fermentation. [0045] According to another aspect of the present invention, there is provided a method for inhibiting the reduction of Lactobacillus lactobacillus in the intestinal tract in a subject administered with an antibacterial drug, characterized in that it comprises a source for ingesting the subject. Made from an effective amount of a whey fermentation product of Propionibacterium. Here, according to another preferred aspect of the present invention, the method for inhibiting the reduction of Lactobacillus lactic acid bacteria in the intestinal tract is to exclude medical behaviors for humans. Here, the "medical behavior for humans" means that a doctor or the like is necessary, and for humans, it means the act of ingesting (administering) a pharmaceutical product. Moreover, in the above-mentioned embodiment, the target is preferably a healthy ordinary person. [0046] In addition, the method for inhibiting the reduction of Lactobacillus lactobacillus in the intestine of the present invention can also be used to improve the disease or state associated with the reduction of Lactobacillus lactobacillus in the intestine in a subject administered with an antibacterial drug. . Therefore, the method for inhibiting the reduction of Lactobacillus lactobacillus in the intestine of the present invention is a method for improving the disease or state associated with the reduction of Lactobacillus lactobacillus in the intestinal tract caused by the administration of an antibacterial drug, and more preferably Methods to improve constipation, diarrhea, nausea and the headaches that accompany it. Here, the so-called "improvement" is not only the treatment of established diseases or conditions, but also the prevention of diseases or conditions that may be established in the future. [0047] In the suppression method, the effective amount of the whey fermented product derived from Propionibacterium can be made the same as the unit of the amount of one intake of the above composition. [0048] According to one embodiment of the present invention, it is used for inhibiting the reduction of Lactobacillus lactic acid bacteria in the intestinal tract in a subject administered with an antibacterial drug. A method for using a whey fermentation product derived from Propionibacterium is provided. According to a preferred embodiment of the present invention, the application mode of the present invention is used non-therapeuticly. [0049] According to one embodiment of the present invention, the use is to provide a whey fermentation product derived from Propionibacterium, which is used for inhibiting the reduction of Lactobacillus lactic acid bacteria in the intestinal tract in a subject administered with an antibacterial drug. Manufacture of composition. According to a preferred embodiment of the present invention, the use is for the purpose of producing a food or a medicine for the reduction of Lactobacillus lactic acid bacteria. [0050] According to one embodiment of the present invention, a whey fermentation product derived from propionibacterium is provided for the purpose of inhibiting the reduction of Lactobacillus lactic acid bacteria in the intestinal tract in a subject administered with an antibacterial drug. . [Examples] The present invention is explained in detail by the following examples, but the present invention is not limited to these. [0052] Example 1: Preparation of Composition (Preparation of Whey Fermentation by Propionic Acid) In order to make the number of bacteria 10 7 to 10 8 cfu / mL, Propionibacterium freudenreichii ET- 3) (Registration number: FERM BP-8115) As a bacterial cell, ingest a decomposed product obtained by decomposing a proteolytic enzyme AMINOA (Amano Pharmaceutical Co., Ltd.) from a 10% by mass milk powder reducing solution at 50 ° C and pH 7.0. The resulting medium was cultured at 35 ° C and pH 6.0 for 75 hours. The obtained culture supernatant was sterilized and freeze-dried. To 0.2 g of freeze-dried product, dextrin containing glucose and dietary fiber was added to make a total preparation of 1.5 g. The composition contains 0.03 g of protein, 0 g of lipid, 0.6 g of carbohydrate as carbohydrate, 0.8 g of dietary fiber, 2.6 mg of sodium, 1.0 mg of calcium, 1.3 mg of phosphorus, and 0.2 of magnesium. mg and potassium were 15.8 mg. [0053] The obtained preparation is used as a composition of the present invention. Individual packaging of 1.5 g of aluminum was used as a preparation. [0054] Example 2: Clinical trial (1) Test subject The clinical trial was performed separately in two groups, such as a control group and a group to which the composition was administered. The subjects of the two groups of trials were all severe patients (cerebral hemorrhage, trauma, cerebral embolism) who were sent to the Mishima Lifesaving Center in Osaka Prefecture. Subjects were managed by tube feeding during admission in principle, and the tube was inserted into the stomach and left in the stomach. In addition, in principle, the administration of the antibacterial drug is started within one week after the start of the test. In addition, antibacterial drugs are based on the diseases and conditions of patients, and are based on the techniques described in JAID / JAS Infectious Diseases Treatment Guidelines 2014 (edited by JAID / JAS Infectious Diseases Treatment Guidelines and Guidelines Development Committee), as listed in Table 1 Antibiotics are selected after administration. [0055] [0056] The control group and the group to which the composition is administered In the control group, liquid food was administered for 2 weeks. As the liquid food, at least one type selected from the group consisting of MEIBALANCE HP (MEIBALANCE HP) and MEIN (Meiji Co., Ltd.) is used. Among these, it does not contain a component which affects the bacterial flora in the intestinal tract, and especially does not contain a component which reduces Lactobacillus lactic acid bacteria. On the other hand, in the group to which the composition was administered, the composition (2 packs / day (3g / day)) obtained in Example 1 was added to the liquid food for a period of 2 weeks. The control group was 46 people, and the composition administration group was 14 people. In addition, one person in the control group did not administer antibacterial drugs during the two-week test period, so this person was excluded for analysis. Therefore, the control group for analysis number was 45, and the composition administration group was 14 persons. [0057] The results of the patient background of the control group and the group to which the composition was administered and the number of days to which the antibacterial agent was administered are shown in Table 2 below. [0058] [0059] As shown in Table 2, there was almost no difference in the number of days of antibacterial drug administration between the two groups of 11.5 ± 3.2 days of the control group and 11.8 ± 2.9 days of the group to which the composition was administered. In addition, the male-to-female ratio was almost the same as that of APACHE II. [0060] (2) Analysis of bacterial flora in feces The fecal control group and the composition-administered group were taken before the start of the test (liquid food administration) (day 0), on the third day after the start of the test, Feces were collected on the 7th day (1 week) after the start of the test and on the 14th day (2 weeks) after the start of the test. [0061] Analysis of the bacterial flora in the feces The feces collected were immediately stored below -20 ° C after being taken. From the stool of the patient, the bacterial flora DNA in the stool was extracted using Multi-Beads Shocker (Anjing Machinery Co., Ltd.) according to the method of QIAamp DNA stool Mini Kit (QIAGEN). For the real-time PCR reaction, QuantiTect SYBR Green RT-PCR (QIAGEN) was used, and primers described in Table 3 below were used at 95 ° C, 15 seconds → (94 ° C, 15 seconds → each primer). Adhesion temperature, 30 seconds → 72 ℃, 30 seconds) × 30 ～ 55 cycles. The number of Lactobacillus lactic acid bacteria, Bifidobacterium, and total bacteria were quantified by ABI 7300 Real Time PCR System (Applied Biosystems). . The number of bacteria was expressed as the logarithm of the number of bacteria per 1 g of feces. [0062] [0063] The comparison between the groups before and after is analyzed by the corresponding t test. In addition, the analysis between the control group and the group to which the composition is applied is evaluated by comparing the test results between the control group and the group to which the composition is applied, and the students' t test (equal dispersion) or Welch test is used for evaluation. (Unequal dispersion) analysis. [0064] The results are shown in FIGS. 1 to 4. FIG. 1 is a graph showing the change in the total bacterial count and the Lactobacillus bacterial count in the feces of the control group. In the control group of FIG. 1, after the third day after the start of the test, the total bacterial count and the bacterial count of the genus Lactobacillus were significantly reduced compared with that at the start of the test. FIG. 2 is a graph showing a change in the total bacterial count and the Lactobacillus bacterial count in the feces of the group to which the composition is applied. In the group of the applied composition in FIG. 2, compared with the test before the start, no significant decrease in the number of Lactobacillus bacteria in the test period was found. On the other hand, although the total bacterial count decreased significantly on the 7th day after the start of the test compared to before the start of the test, there was no significant difference between the 3rd day and the 14th day. FIG. 3 compares the total bacterial count in the feces of the control group and the group to which the composition is applied with the bacterial count of Lactobacillus. Observing the number of Lactobacillus bacteria in Figure 3, the control group and the applied composition showed little difference at the beginning of the test. However, after 3 days after the start of the test, compared with the group administered with the composition, one of the control groups was founder. Significantly reduced. On the other hand, no significant change was seen in the total bacterial count between the two groups during the test period (Figure 3). In this way, although the administration of an antibacterial drug reduced the number of Lactobacillus bacteria in the intestine, it was confirmed that the administration of the Lactobacillus in the intestinal tract can be suppressed before or during the administration of the antibacterial drug. Decrease in the number of bacteria. FIG. 4 is a graph showing a comparison of the number of Bifidobacterium in the feces of the subject group and the group to which the composition is applied. The number of Bifidobacterium in FIG. 4, the control group and the group to which the composition was administered, were significantly reduced after 3 days after the start of the test compared to the start of the test. In addition, as a result of comparison of the Bifidobacterium number of the control group and the group to which the composition was administered, no significant change was seen between the two groups.