Lactobacillus casei Variety rhamnosus Probiotic Preventively Attenuates 5-Fluorouracil/Oxaliplatin-Induced Intestinal Injury in a Syngeneic Colorectal Cancer Model.
Lactobacillus casei Variety rhamnosus Probiotic Preventively Attenuates 5-Fluorouracil/Oxaliplatin-Induced Intestinal Injury in a Syngeneic Colorectal Cancer Model.
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DOI：
10.3389/fmicb.2018.00983
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发表时间：
2018
影响因子：
5.2
通讯作者：
Chen YJ
中科院分区：
文献类型：
--
作者：
Chang CW;Liu CY;Lee HC;Huang YH;Li LH;Chiau JC;Wang TE;Chu CH;Shih SC;Tsai TH;Chen YJ
建议对结直肠癌进行基于5-氟尿嘧啶（5-FU）的辅助化疗，包括FOLFOX（5-FU、甲酰四氢叶酸和奥沙利铂）。然而，肠粘膜炎仍然是一种常见的不良反应，没有有效的预防策略。为了开发一种方便和新颖的方法来减轻粘膜炎，我们研究了干酪乳杆菌鼠李糖变种（Lcr 35）对FOLFOX诱导的粘膜损伤的影响。皮下注射同基因CT 26结直肠腺癌细胞的BALB/c小鼠在FOLFOX方案注射5天之前、期间和之后每天口服施用Lcr 35，持续14天。使用以下方法：毒性腹泻评分、细胞因子产生的ELISA、肠损伤的组织病理学、细胞凋亡/增殖和调节蛋白的免疫组织化学、细胞因子mRNA表达的RT-PCR和粪便肠道微生物群的DNA测序。对结直肠癌荷瘤小鼠给予FOLFOX显著抑制肿瘤生长以及伴随的显著腹泻和肠损伤，其组织学特征为绒毛缩短和肠隐窝破坏。Lcr 35的预防性给药剂量依赖性地降低了腹泻和肠粘膜炎的严重程度，而不影响FOLFOX的抗肿瘤作用。FOLFOX后凋亡、NF-κB-和BAX激活细胞的数量增加，Lcr 35可减轻这些反应。Lcr 35减弱了FOLFOX治疗引起的TNF-α和IL-6上调。被FOLFOX干扰的厚壁菌门和拟杆菌门的粪便肠道微生物群组成被Lcr 35显著逆转为优先分布。总之，口服益生菌Lcr 35可预防结直肠癌荷瘤小鼠中FOLFOX诱导的肠粘膜炎。推测的机制可能涉及调节肠道微生物群和促炎反应，抑制肠损伤中的内源性凋亡。
Adjuvant 5-fluorouracil (5-FU)-based chemotherapy, including FOLFOX (5-FU, leucovorin, and oxaliplatin), is recommended for colorectal cancer. However, intestinal mucositis remains a common adverse effect for which no effective preventive strategies are available. To develop a convenient and novel way to alleviate mucositis, we investigated the effect of Lactobacillus casei variety rhamnosus (Lcr35) on FOLFOX-induced mucosal injury. BALB/c mice subcutaneously injected with syngeneic CT26 colorectal adenocarcinoma cells were orally administered Lcr35 daily before, during, and after 5-day injection of FOLFOX regimen, for 14 days. The following methods were used: diarrhea score for toxicity, ELISA for cytokine production, histopathology for intestinal injury, immunohistochemistry for apoptosis/proliferation and regulatory proteins, RT-PCR for cytokine mRNA expression, and DNA sequencing for fecal gut microbiota. FOLFOX administration to colorectal cancer-bearing mice significantly inhibited tumor growth and the accompanying marked diarrhea and intestinal injury histologically characterized by the shortening of villi and destruction of intestinal crypts. Preventive administration of Lcr35 dose-dependently reduced the severity of diarrhea and intestinal mucositis without affecting the anti-tumor effect of FOLFOX. The numbers of apoptotic, NF-κB-, and BAX-activated cells increased after FOLFOX, and these responses were mitigated by Lcr35. TNF-α and IL-6 upregulation by FOLFOX treatment was attenuated by Lcr35. The fecal gut microbiota composition of Firmicutes and Bacteroidetes disturbed by FOLFOX was significantly reversed by Lcr35 toward a preferential profile. In conclusion, the oral probiotic Lcr35 prevented FOLFOX-induced intestinal mucositis in colorectal cancer-bearing mice. The putative mechanism might involve modulation of gut microbiota and proinflammatory responses with suppression of intrinsic apoptosis in intestinal injury.
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影响因子：
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作者：
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通讯作者：
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