Synbiotics suppress colitis-induced tumorigenesis in a colon-specific cancer mouse model

PLoS One. 2019 Jun 26;14(6):e0216393. doi: 10.1371/journal.pone.0216393. eCollection 2019.

Abstract

Although synbiotics may be effective in maintaining remission of inflammatory bowel disease, their anticarcinogenic effects are still debated. To address this issue, we evaluated the effects of synbiotics, probiotics, and prebiotics on tumorigenesis using a CDX2P-Cre; Apc+/flox mouse model harboring a colon-specific Apc knock out, which develops adenoma and adenocarcinoma of the colon. Dextran sodium sulfate (DSS)-administration promoted colonic tumor development in CDX2P-Cre; Apc+/flox mice, and these tumors were associated with loss of Apc heterozygosity, as confirmed by observation of well-differentiated adenocarcinomas with β-catenin accumulation in tumor cell cytoplasm. Synbiotics-treatment suppressed dextran sodium sulfate-induced colitis in CDX2P-Cre; Apc+/flox mice, thereby reducing mortality, and inhibited tumorigenesis accelerated by DSS-administration. Conversely, neither probiotics nor prebiotics had any effect on inflammation and tumorigenesis. Lactobacillus casei and Bifidobacterium breve were detected in the fecal microbiota of probiotics-treated mice. Synbiotics-treatment suppressed DSS-induced expression of IL-6, STAT-3, COX-2, and TNF-α gene transcripts in normal colonic epithelium, indicating the possibility of suppressing tumor development. Importantly, these genes may be potential therapeutic targets in inflammation-associated colon cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / drug effects*
  • Colitis / complications*
  • Colonic Neoplasms / etiology*
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / microbiology
  • Colonic Neoplasms / pathology*
  • Cytoplasm / drug effects
  • Cytoplasm / metabolism
  • Disease Models, Animal
  • Feces / microbiology
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Heterozygote
  • Interleukin-6 / genetics
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology
  • Mice
  • Microbiota / drug effects
  • Prebiotics
  • Probiotics / pharmacology
  • STAT3 Transcription Factor / genetics
  • Synbiotics*
  • Tumor Necrosis Factor-alpha / genetics
  • beta Catenin / metabolism

Substances

  • Interleukin-6
  • Prebiotics
  • STAT3 Transcription Factor
  • Tumor Necrosis Factor-alpha
  • beta Catenin

Grants and funding

This work was supported by JSPS KAKENHI Grant Numbers JP22390257 (2010-2012), JP25293284 (2013-2016), JP18K08694 (2018-) and by The Japanese Society of Gastroenterology Grant-in-Aid 2010. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.