Basic Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Oct 15, 2021; 13(10): 1518-1531
Published online Oct 15, 2021. doi: 10.4251/wjgo.v13.i10.1518
Survival effect of probiotics in a rat model of colorectal cancer treated with capecitabine
Graciela Gigola, Pedro Carriere, María Belén Novoa Díaz, Gabriela Perdigon, Ariel Osvaldo Zwenger, Claudia Gentili
Graciela Gigola, Pedro Carriere, María Belén Novoa Díaz, Claudia Gentili, Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)- INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Buenos Aires Provincia, Argentina
Gabriela Perdigon, [CERELA] Centro de referencia para lactobacilos - [CCT CONICET NOA SUR], San Miguel de Tucumán 4000, Argentina
Ariel Osvaldo Zwenger, Centro de Estudios Clínicos SAGA, CEC SAGA, Santiago de Chile 8320000, Chile
Author contributions: Gigola G, Carriere P, Perdigón G and Zwenger AO explained the term; Gigola G, Perdigón G and Zwenger AO contributed to methodology, investigation and formal analysis; Gigola G, Carriere P, Novoa Diaz MB and Gentili C drafted the original manuscript; Gigola G and Gentili C reviewed and re-edited the manuscript; Gigola G and Zwenger AO received the financial support; all authors contributed to the conceptualization and visualization of this manuscript.
Supported by Universidad Nacional del Sur, Argentina, No. PGI 24/B138, No. PGI 24/ZB50, and No. PGI 24/ZB63.
Institutional review board statement: The study was evaluated and approved by a committee of experts on the subject conformed by members of the Department of Biology, Biochemistry and Pharmacy of the National University of the South.
Institutional animal care and use committee statement: All the animals employed in the experiments were under controlled conditions and the activities were supervised by a veterinarian in charge, in accordance with the principles of care and use of laboratory animals. The experimental design was evaluated and approved by experts on the subject and certified by the Department of Post-Graduate Studies the National University of the South.
Conflict-of-interest statement: The authors declare that they have no competing interests.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Graciela Gigola, PhD, Doctor, Professor, Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)- INBIOSUR (CONICET-UNS), San Juan 670, Bahía Blanca 8000, Buenos Aires Provincia, Argentina.
Received: April 27, 2021
Peer-review started: April 27, 2021
First decision: June 13, 2021
Revised: June 26, 2021
Accepted: August 27, 2021
Article in press: August 27, 2021
Published online: October 15, 2021

Probiotics are used to manage a number of gastrointestinal disorders due to their beneficial properties. Clinical reports showed that probiotics also improve the life quality of patients with colorectal cancer (CRC) subjected to oncologic treatment. In a CRC animal model, probiotics supplementation has the potential to decrease the formation of aberrant crypts and ameliorate tumor malignancy, enhancing the antitumor effect of 5-fluorouracil (5-FU) chemotherapy. Based on these data, we hypothesize that the administration of probiotics impact positively in the overall survival and life quality of rats with CRC under the treatment of capecitabine, which is the pro drug of 5-FU.


To evaluate the probiotics effects in a rat CRC model treated with capecitabine and followed until the end of life.


1,2-Dimethylhidrazine dihydrochloride (1,2-DMH) was employed as carcinogen inductor of CRC. Fifty male Wistar-Lewis rats were randomly assigned to one of five following groups: Control (n = 5), Control + probiotics (Control-P group, n = 5), 1,2-DMH alone (DMH group, n = 10), 1,2-DMH + capecitabine (DMH-C group, n = 10), 1,2-DMH + probiotics (DMH-P group, n = 10) and 1,2-DMH + capecitabine + probiotics (DMH-C-P group, n = 10). All parametric data were expressed as the mean ± SD. The statistical significance of differences was analyzed using one-way ANOVA. Data were analyzed with InfoStat software. The results were considered statistically significant at P < 0.05. Overall survival was evaluated with the Kaplan-Meier estimator with the log-rank test.


The data of mean overall survival for DMH, DMH-P, DMH-C, DMH-C-P, Control and Control-P groups were 250 d [95% confidence interval (CI): 242.5-253.1], 268 d (95%CI: 246.3-271.4), 380 d (95%CI: 337.8-421.9), 480 d (95%CI: 436.9-530.7), 588 d (95%CI: 565.8-609.3) and 590 d (95%CI: 564.3-612.9), respectively, with a significant difference between DMH-C and DMH-C-P groups (P = 0.001). Comparing all groups by Kaplan-Meier estimator, we found a significantly different in the overall survival of DMH and DMH-P groups respect to DMH-C (P = 0.001) and DMH-C-P (P = 0.001) groups; interestingly, there were no meaningful differences between Control, Control-P and DMH-C-P groups (P = 0.012). The tendency of change in body weight gain of the rats at 90 d of finishing DMH administration was similar in Control group compared with DMH-C and DMH-C-P groups; however, and of relevance, DMH-C-P group has experienced a higher body weight gain at the end of animal’s life than DMH-C group (P = 0.001). In DMH-C-P group we found a positive effect of probiotics in clinical manifestations since diarrhea, constipation and blood stool were absenting. Also, the tumor burden was lower in DMH-C-P than DMH-C, DMH-P or DMH groups (1.25 vs 1.81 vs 3.9 vs 4.8 cm2, respectively). DMH-C and DMH-C-P groups showed only mucinous carcinoma type while in other DMH groups the tumor types were variable. However, mucinous carcinoma from DMH-C-P group showed invasion until muscularis propria layer. Interestingly, metastatic lymph node was observed in DMH, DMH-C and DMH-P groups but not in DMH-C-P. All animals in Control group died from natural causes without objective injuries. All animals of DMH and DMH-P groups died from tumor complications (i.e., obstruction or intestinal perforation); however, this cause was seen only in 44.5% of DMH-C and DMH-C-P groups


Probiotics administration improves life quality of rats with CRC under capecitabine treatment and also has a positive effect in the overall survival of these animals treated with this drug.

Keywords: Colorectal cancer, Capecitabine, Probiotics, Survival, Life quality, Animal experimentation

Core Tip: Today it is still unclear which are the most effective forms of probiotics administration at long-term to reduce the incidence of human colorectal cancer (CRC) or which microorganisms are the most suitable; the amount, time and frequency that should be consumed in the diet. Also, which is their influence on side effect from chemotherapy in CRC? Herein we show, for the first time, that probiotics have a positive impact on the overall survival of rats with CRC under capecitabine treatment. These animals have also a benefit in weight gain, clinical manifestations, developing cancer, number, localization and tumor burden.