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標題: | 益生菌Lactobacillus casei Shirota 對VHL基因缺失小鼠腎損傷及免疫調節的影響 Renal protective effect of Lactobacillus casei Shirota on renal injury and immunomodulation in Vhlh gene-knockout mice |
作者: | Yu-Ting Chen 陳郁婷 |
指導教授: | 林璧鳳(Bi-Fong Lin) |
關鍵字: | Lactobacillus casei Shirota,馬兜鈴酸,腎病變,腸道免疫,抗發炎, Lactobacillus casei Shirota,aristolochic acid,nephropathy,gut-immune system,anti-inflammation, |
出版年 : | 2020 |
學位: | 碩士 |
摘要: | 台灣末期腎臟病盛行率多年來於全球排名中高居首位,近期的研究發現腎臟病與腸道共生菌的失衡有關。給予末期腎臟病人補充乳桿菌屬代田菌後,可降低病人血清的尿素含量。目前對於益生菌的補充是否可改善腎損傷尚未有定論,故本研究欲探討代田菌 (Lactobacillus casei Shirota, 簡稱LcS) 的給予對腎臟損傷及其免疫調控的影響。 實驗一為每天給予VHL基因缺失而自發性腎癌之Vhlhfl/fl小鼠1×10^9 CFU的LcS,結果得知生命期顯著延長。實驗二接著利用馬兜鈴酸 (aristolochic acid , 簡稱AA) 誘發Vhlhfl/+小鼠腎病變,探討代田菌的影響機轉。先給予8到12週齡小鼠1×10^9 CFU/d LcS 4週後,加AA (4 mg/kg BW/d)餵2週後犧牲分析指標。共四組小鼠:Con組、LcS組、AA組、與LcS-AA組。結果顯示LcS可顯著降低AA誘發之腎損傷程度、尿蛋白肌酸酐比值、尿液KIM-1及血清尿素氮濃度等腎功能指標,全身性發炎指標血清IL-6濃度及纖維化相關基因Lgals3與Fn1的mRNA表現量也有減少趨勢;腎臟的免疫分析觀察到,AA誘發M2巨噬細胞、Th細胞及Treg細胞浸潤至腎臟,同時,MCP-1及IL-10濃度上升且IL-1b、TNF-a及IL-4濃度下降。補充LcS顯著降低M1巨噬細胞的浸潤比例及M1/M2比例,M2巨噬細胞及Treg浸潤程度也有下降的趨勢,此外,TGF-b和 IL-4的濃度增加。腸道和脾臟細胞免疫指標顯示,AA促進IL-6、MLN和脾臟細胞TNF-a、PP細胞IL-10、MLN細胞TGF-b的分泌。補充LcS增加腸道固有層的樹突細胞比例,抑制PP免疫細胞分泌IL-17A,促進PP和脾臟免疫細胞分泌IL-10,MLN和脾臟免疫細胞分泌IFN-g,抑制脾臟免疫細胞分泌IL-6。綜合以上結果,補充LcS可能藉由影響調節型和發炎性的細胞激素平衡,能顯著促進PP進而脾臟細胞的IL-10分泌和MLN細胞與腎的IL-4分泌,能抑制PP細胞IL-17A及脾臟細胞IL-6的分泌進而降低血清IL-6濃度,影響腸道免疫進而調控全身性及腎臟的免疫反應,顯著降低AA造成的尿蛋白和KIM-1濃度、BUN和IL-6濃度增加,且延長自發性腎炎致腎癌小鼠的生命期,具有抑制發炎以達護腎之潛力。 It has been noted that the prevalence and incidence rate of end-stage renal disease in Taiwan are the highest in the world. It is interesting to find out if probiotic could delay the progression of renal disease by ameliorating inflammatory response and reducing pathobionts which generate uremic toxin. Lactobacillus casei Shirota (LcS) has been demonstrated that to reduce serum urea level in III-IV stage chronic kidney disease patients. In this study, we investigated whether Lactobacillus casei Shirota could improve renal injury and exert the immunomodulation effect. The results demonstrated that supplementary of LcS (1×10^9 CFU/day) prolonged the lifespan of Vhlhfl/fl mice. Further, 8-12-week-old Vhlhfl/+ mice were fed AIN-93 diet with or without LcS for 4 weeks and then fed aristolochic acid added diets (AA; 4 mg/kg BW) for induction of renal injury for 2 weeks to investigate the effects. There are the Con, LcS, AA, LcS-AA groups. The results showed urinary protein and KIM-1, serum urea, M1 macrophages infiltration in kidney were decreased by LcS supplement. AA promoted renal MCP-1 and IL-10 level, decreased IL-1b, IL-6, TNF-a, and IL-4 level. LcS supplement increased IL-4 and TGF-b secretion under AA induction. LcS supplement increased dendritic cells infiltration in lamina propria, downregulated IL-17A and upregulated IL-10 secretion by Peyer’s patch. Levels of IFN-g and TGF-b were elevated in mesenteric lymph node. Splenocyte decreased IL-6 and promoted IL-2, IFN-g and IL-10 secretion. In conclusion, LcS supplement might have the nephroprotective effects by regulating the immune response and possibly maintaining the balance of gut microbiota. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/8157 |
DOI: | 10.6342/NTU202003787 |
全文授權: | 同意授權(全球公開) |
電子全文公開日期: | 2025-08-20 |
顯示於系所單位: | 生化科技學系 |
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