RESUMEN
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.
Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Trasplante de Microbiota Fecal , Enfermedades Intestinales/prevención & control , Intestinos/microbiología , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Neoplasias Colorrectales/complicaciones , Neoplasias Colorrectales/microbiología , Neoplasias Colorrectales/patología , Modelos Animales de Enfermedad , Fluorouracilo/efectos adversos , Fluorouracilo/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Xenoinjertos , Humanos , Enfermedades Intestinales/inducido químicamente , Enfermedades Intestinales/microbiología , Enfermedades Intestinales/patología , Intestinos/efectos de los fármacos , Intestinos/lesiones , Leucovorina/efectos adversos , Leucovorina/farmacología , Ratones , Compuestos Organoplatinos/efectos adversos , Compuestos Organoplatinos/farmacología , Oxaliplatino/efectos adversos , Oxaliplatino/farmacología , Receptores Toll-Like/genéticaRESUMEN
Long term effects of subtotal gastrectomy on gut microbiota modifications with subsequent metabolic profiles are limited. We aimed to investigate and compare long-term effects of metabolic profiles and microbiota status in early gastric cancer patients post curative subtotal gastrectomy to the controls. In this cross-sectional study, we analyzed type II diabetes mellitus and metabolic syndrome occurrence in two groups: 111 patients after curative subtotal gastrectomy with Billroth II (BII) anastomosis and Roux-en-Y gastrojejuno (RYGJ) anastomosis and 344 age-sex matched controls. Fecal samples from those with BII, RYGJ, and controls were analyzed by next-generation sequencing method. Metabolic syndrome and type II diabetes mellitus occurrences were significantly lower in patients after subtotal gastrectomy with RYGJ than in controls over the long term (> 8 years) follow-up (P < 0.05). The richness and diversity of gut microbiota significantly increased after subtotal gastrectomy with RYGJ (P < 0.05). Compared with the control group, the principal component analysis revealed significant differences in bacterial genera abundance after subtotal gastrectomy with BII and RYGJ (P < 0.001). Genera of Oscillospira, Prevotella, Coprococcus, Veillonella, Clostridium, Desulfovibrio, Anaerosinus, Slackia, Oxalobacter, Victivallis, Butyrivibrio, Sporobacter, and Campylobacter shared more abundant roles both in the RYGJ group and BII groups. Early gastric cancer patients after subtotal gastrectomy with RYGJ had a lower occurrence of metabolic syndrome and type II diabetes mellitus than the controls during long term follow-up. In parallel with the metabolic improvements, gut microbial richness and diversity also significantly increased after subtotal gastrectomy with RYGJ.