Lactobaciilus casei rhamnosus 在腸胃道疾病中之功能性角色

Abstract

宿主的健康狀態與其腸道菌相有極為密切的關係，以益生菌來預防及治療腸胃道感染性或免疫性疾病已行之有年且已被許多研究證實其效果。不同商品化的益生菌對感染性疾病的預防有不同程度的效益，但以益生菌增補來達到預防腸胃道疾病的目標是可以確定的。益生菌是如何達到幫助宿主減少罹患腸胃道感染性或免疫性疾病之機制至今仍不清楚。可能是經由刺激宿主特異性與非特異性的免疫能力；或是益生菌自己合成一些抗菌物質，與病原菌競爭營養源，甚或抑制病原菌附著及侵入宿主之黏膜上皮組織等方式來達成。本實驗之目的在於探討不同Lactobacillus strains在宿主腸胃道疾病預防或治療上所扮演之功能性角色。首先，藉由比較長期增補三種不同市售益生菌產品對宿主感染性疾病影響之研究顯示：長期增補L. rhamnosus T cell-1對於預防病毒性感染有顯著成效；以混合多種/株乳酸菌之益生菌製品，則對小兒腸胃道疾病有極佳之預防效果。L. casei rhamnosus不論對小兒病毒性、細菌性、腸胃道感染或呼吸道感染性疾病的預防效果都最為顯著。我們以臨床成效最佳之L. casei rhamnosus 為主要研究菌種，探討以之對抗宿主病原細菌之可能機制。將L. casei rhamnosus分別與E. Coli ATCC25922、Bacteroides fragilis及C. difficile等不同腸道致病菌死菌共培養，結果發現在不同腸道致病菌存在下，L. casei rhamnosus抗菌能力並不受腸道致病菌誘導而發生改變，顯示L. casei rhamnosus在不需病原菌共同存在下即可分泌抗菌物質達成抗菌之效益。最後，我們亦證明L. casei rhamnosus預防或治療腸胃道發炎性疾病之可能性。L. casei rhamnosus可分泌具熱穩定性之促細胞凋亡因子 (LcrS5-30)，分子量介於5-30 kDa。此胞外因子LcrS5-30可特異性誘導淋巴球或單核球以粒線體凋亡途徑進行凋亡，卻不會誘導腸黏膜上皮細胞發生凋亡。以脂多醣刺激淋巴球或單核球，在LcrS5-30存在下可有效抑制發炎細胞激素的產生，有趣的是LcrS5-30亦可同時誘導抗發炎細胞激素β1轉化生長因子之分泌，而此β1轉化生長因子之分泌並非誘導免疫細胞凋亡的主因，顯示細胞凋亡的效應乃由LcrS5-30所促成。

Some strains of Lactobacilli have been widely used as probiotics expecting to improve certain immune functions in humans and animals. Probiotics are microorganisms which have benefits on the health of the host beyond inherent general nutrition. The effects of probiotics can be direct or indirect through modulation of the endogenous flora or of the immune system. Therefore, the purposes of this study are to understand how Lactobacillus strains alter enteric bacterial flor aand the immunomodulating capacity, and improve gastrointestinal infectious or immune diseases. First, the investigation showed that long-term consumption of L. rhamnosus T cell-1 decreased the incidence of bacterial infection; a multi-species probiotic reduced gastrointestinal disease significantly; and L. casei rhamnosus can widespread control including bacterial, viral and respiratory infections. Therefore, L. casei rhamnosus has been intensively studied and thought to be a useful species in clinical and nutritional fields. To determine the antimicrobial activity of Lactobacillus strains when coclutured with various ratio of three kind of pathogens. The results indicated that Lcr promoted the greatest antimicrobial activities and there were no significant differences on the size of the inhibition halos in Lcr cocultured with different pathogens or Lcr cultured alone. Thus, pathogens cannot stimulate the antimicrobial capacities of the Lcr strains. The antimicrobial capacities of Lcr are non pathogenesis-inducible. Finally, probiotic L. casei rhamnosus produced heat-stable molecules (MW range 5-30 kDa) that promoted immune cell apoptosis without affecting intestinal epithelial cells. LcrS5-30 triggered apoptosis by a mitochondrial pathway, but not via TGF-β signaling pathway. LcrS5-30 also inhibited LPS-induced inflammatory cytokines by immune cells. Thus, LcrS5-30 promotes apoptosis of immune cells, and suggests probiotics-based regimens for prevention of inflammatory bowel disease.