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Front Microbiol. 2018 May 15;9:983. doi: 10.3389/fmicb.2018.00983. eCollection 2018.

Lactobacillus casei Variety rhamnosus Probiotic Preventively Attenuates 5-Fluorouracil/Oxaliplatin-Induced Intestinal Injury in a Syngeneic Colorectal Cancer Model.

Chang CW1,2,3,4, Liu CY1,2,3,4, Lee HC3,4,5,6, Huang YH7, Li LH3, Chiau JC3, Wang TE2,4,5, Chu CH2,4,5, Shih SC2,4,5, Tsai TH1,8, Chen YJ1,3,4,9.

Author information

1
Institute of Traditional Medicine, National Yang-Ming University, Taipei, Taiwan.
2
Division of Gastroenterology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei, Taiwan.
3
Department of Medical Research, MacKay Memorial Hospital, New Taipei City, Taiwan.
4
Department of Medicine, MacKay Medical College, New Taipei City, Taiwan.
5
Mackay Junior College of Medicine, Nursing, and Management, New Taipei City, Taiwan.
6
MacKay Children's Hospital, Taipei, Taiwan.
7
Institute of Biomedical Informatics, Center for Systems and Synthetic Biology, National Yang-Ming University, Taipei, Taiwan.
8
Department of Chemical Engineering, National United University, Miaoli, Taiwan.
9
Department of Radiation Oncology, MacKay Memorial Hospital, Taipei, Taiwan.

Abstract

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.

KEYWORDS:

FOLFOX; Lactobacillus; apoptosis; gut microbiota; intestinal mucositis

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