Fecal Microbiota Transplantation Prevents Intestinal Injury, Upregulation of Toll-Like Receptors, and 5-Fluorouracil/Oxaliplatin-Induced Toxicity in Colorectal Cancer.

Abstract

FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin), a 5-fluorouracil (5-FU)-based chemotherapy regimen, is one of most common therapeutic regimens for colorectal cancer. However, intestinal mucositis is a common adverse effect for which no effective preventive strategies exist. Moreover, the efficacy and the safety of fecal microbiota transplants (FMT) in cancer patients treated with anti-neoplastic agents are still scant. We investigated the effect of FMT on FOLFOX-induced mucosal injury. BALB/c mice implanted with syngeneic CT26 colorectal adenocarcinoma cells were orally administered FMT daily during and two days after five-day injection of FOLFOX regimen for seven days. Administration of FOLFOX significantly induced marked levels of diarrhea and intestinal injury. FMT reduced the severity of diarrhea and intestinal mucositis. Additionally, the number of goblet cells and zonula occludens-1 decreased, while apoptotic and NF-κB-positive cells increased following FOLFOX treatment. The expression of toll-like receptors (TLRs), MyD88, and serum IL-6 were upregulated following FOLFOX treatment. These responses were attenuated following FMT. The disrupted fecal gut microbiota composition was also restored by FMT after FOLFOX treatment. Importantly, FMT did not cause bacteremia and safely alleviated FOLFOX-induced intestinal mucositis in colorectal cancer-bearing mice. The putative mechanism may involve the gut microbiota TLR-MyD88-NF-κB signaling pathway in mice with implanted colorectal carcinoma cells.

• Authors: Ching-Wei Chang, Hung-Chang Lee, Li-Hui Li, Jen-Shiu Chiang Chiau, Tsang-En Wang, Wei-Hung Chuang, Ming-Jen Chen, Horng-Yuan Wang, Shou-Chuan Shih, Chia-Yuan Liu, Tung-Hu Tsai, Yu-Jen Chen
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 2 (Jan 08 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 31936237 (Publication Type: Journal Article)

Chemical References

• Organoplatinum Compounds
• Toll-Like Receptors
• Oxaliplatin
• Leucovorin
• Fluorouracil

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Colorectal Neoplasms (complications, drug therapy, microbiology, pathology)
• Disease Models, Animal
• Fecal Microbiota Transplantation
• Fluorouracil (adverse effects, pharmacology)
• Gastrointestinal Microbiome (drug effects, genetics)
• Gene Expression Regulation, Neoplastic (drug effects)
• Heterografts
• Humans
• Intestinal Diseases (chemically induced, microbiology, pathology, prevention & control)
• Intestines (drug effects, injuries, microbiology)
• Leucovorin (adverse effects, pharmacology)
• Mice
• Organoplatinum Compounds (adverse effects, pharmacology)
• Oxaliplatin (adverse effects, pharmacology)
• Toll-Like Receptors (genetics)