Basic Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 21, 2020; 26(43): 6782-6794
Published online Nov 21, 2020. doi: 10.3748/wjg.v26.i43.6782
Lactobacillus bulgaricus inhibits colitis-associated cancer via a negative regulation of intestinal inflammation in azoxymethane/dextran sodium sulfate model
Denise Sayuri Calheiros Silveira, Luciana Chain Veronez, Luís Carlos Lopes-Júnior, Elen Anatriello, Mariângela Ottoboni Brunaldi, Gabriela Pereira-da-Silva
Denise Sayuri Calheiros Silveira, Luciana Chain Veronez, Department of Biochemistry and Immunology, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto 14049-900, SP, Brazil
Luís Carlos Lopes-Júnior, Health Sciences Center, Federal University of Espírito Santo - UFES, Vitória 29043-900, ES, Brazil
Elen Anatriello, Institute of Science and Technology, Federal University of São Paulo, UNIFESP, São José dos Campos 12231-280, SP, Brazil
Mariângela Ottoboni Brunaldi, Department of Pathology and Forensic Medicine, University of São Paulo, Ribeirão Preto 14040-902, SP, Brazil
Gabriela Pereira-da-Silva, Department of Maternal-Infant Nursing and Public Health, University of São Paulo at Ribeirão Preto College of Nursing, Ribeirão Preto 14040-902, SP, Brazil
Author contributions: Silveira DSC and Pereira-da-Silva G contributed substantially to the design of the study; Veronez LC and Silveira DSC were in charge of the experimental protocol, analysis and interpretation of the results; Lopes-Júnior LC and Anatriello E contributed to interpretation of the results, statistical analysis and discussion of the manuscript; Brunaldi MO performed the histopathological analyzed as well as interpreted the data; all authors interpreted the data and have contributed to writing, discussion and revised the manuscript critically; and all authors have given final approval of the version of the article to be published; Silveira DSC and Pereira-da-Silva G had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Supported by Brazilian National Council for Scientific and Technological Development (CNPq), No. 140152/2013-0.
Institutional review board statement: All authors declare that the Institutional Review Board approval was not applicable for this manuscript, once this study does not involve human beings.
Institutional animal care and use committee statement: All animal experiments conformed to the National Council for Animal Experiment Control accepted principles for the care and use of laboratory animals [ethics committee on the use of animals (CEUA), protocol No. 14.1.418.53.1].
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: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Gabriela Pereira-da-Silva, BSc, MSc, PhD, Professor, Research Scientist, Department of Maternal-Infant Nursing and Public Health, University of São Paulo at Ribeirão Preto College of Nursing, Av. Bandeirantes, 3900, Ribeirão Preto 14049-900, SP, Brazil. gbisson@eerp.usp.br
Received: May 7, 2020
Peer-review started: May 7, 2020
First decision: May 15, 2020
Revised: May 28, 2020
Accepted: October 1, 2020
Article in press: October 1, 2020
Published online: November 21, 2020
Abstract
BACKGROUND

Colitis-associated cancer (CAC) accounts for 2%-3% of colorectal cancer (CRC) cases preceded by inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis. Intestinal microbiota has been reported to play a central role in the pathogenesis of IBD and CAC. Recently, numerous prebiotics and probiotics have being investigated as antitumor agents due to their capacity to modulate inflammatory responses. Previous studies have indicated that lactic acid bacteria could be successfully used in managing sporadic CRC, however little is known about their role in CAC.

AIM

To investigate the effect of the probiotic Lactobacillus bulgaricus (L. bulgaricus) during the development of an experimental model of colitis associated colon cancer (CAC).

METHODS

C57BL/6 mice received an intraperitoneal injection of azoxymethane (10 mg/kg), followed by three cycles of sodium dextran sulphate diluted in water (5% w/v). Probiotic group received daily L. bulgaricus. Intestinal inflammation was determined by scoring clinical signs. Cytokines levels were determined from colon and/or tumor samples by ELISA BD OptEIATM kits. The level of significance was set at P < 0.05. Graphs were generated and statistical analysis performed using the software GraphPad Prism 6.0.

RESULTS

L. bulgaricus treatment inhibited of total tumor volume and mean size of tumors. In addition, the probiotic also attenuated the clinical signs of intestinal inflammation inducing a decrease in intestinal and tumor levels of IL-6, TNF-α, IL-17, IL-23 and IL-1β.

CONCLUSION

Our results suggest a potential chemopreventive effect of probiotic on CAC. L. bulgaricus regulates the inflammatory response and preventing CAC.

Keywords: Lactobacillus bulgaricus, Colitis-associated cancer, Colorectal cancer, Carcinogenesis, Probiotics, Inflammation

Core Tip: Recent studies suggested that consideration of the intestinal microbiota has an essential role in carcinogenesis. Probiotic supplementation is an alternative means of favourably modulating the intestinal microbiota. In this study, we investigate the effect of Lactobacillus bulgaricus (L. bulgaricus) during the development of an experimental model of colitis-associated colon cancer. Our results evidence an anti-inflammatory role and consequent antitumor effect of L. bulgaricus on colitis-associated cancer that may be used as a promising tool for the prevention and treatment of colitis-associated cancer.