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.
Highlights
The microbiota formed by microorganisms and residing in the gastrointestinal tract is referred to as “intestinal microbiota” or “gut microbiota” [1,2]
Mice were divided into six treatment groups (Table 1), and experimental animals received 200 μL per day of fecal slurry for fecal microbiota transplants (FMT) (FMT50: 50 mg/mL or FMT150: 150 mg/mL) via oral gavage during and two days after FOLFOX treatment (Figure 1A)
Though FMT (FMT50: 50 mg/mL or FMT150: 150 mg/mL) alone did not affect tumor growth (Figure 1C), in FOLFOX-challenged colon cancer-bearing mice, the tumor growth was significantly prevented by FOLFOX, as compared to that observed in controls
Summary
The microbiota formed by microorganisms and residing in the gastrointestinal tract is referred to as “intestinal microbiota” or “gut microbiota” [1,2]. The microbiota affects various aspects of human health, including providing nutrients and vitamins, protecting against pathogens, epithelial mucosa homeostasis, and immune system development [3]. Growing evidence implies that chemotherapeutics affect the intestinal microbial composition and that multidirectional interactions between the gut microbiota and the host immune system may influence development and progression of chemotherapy-induced intestinal inflammation [4,5,6]. Several pathogenic elements, including direct toxicity, change in the bowel microbial flora, oxidative stress, apoptosis, hypo-proliferation, and abnormal inflammation, are involved. No well-established or effective therapeutic strategies are currently available for the management of chemotherapy-induced intestinal mucositis [8]
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