Cancer-protective effect of a synbiotic combination between Lactobacillus gasseri 505 and a Cudrania tricuspidata leaf extract on colitis-associated colorectal cancer

Gut Microbes. 2020 Nov 9;12(1):1785803. doi: 10.1080/19490976.2020.1785803. Epub 2020 Jul 14.

Abstract

Previously, a synbiotic combination of probiotic Lactobacillus gasseri 505 (LG) and a new prebiotic, Cudrania tricuspidata leaf extract (CT) in fermented milk, designated FCT, showed an in vitro immunomodulatory effect and antioxidant activity. Although synbiotic combination might have cancer-protective effects, these activities have not been fully validated in vivo. Ten-week treatment of LG, CT, or FCT to azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colitis-associated colorectal cancer (CAC) mouse model reduced both the incidence of colonic tumors and damage to the colonic mucosa effectively, suggesting a cancer-protective effect. To understand these, biomarkers associated with inflammation, colon barrier, apoptosis, and cancer cell proliferation were monitored in AOM/DSS group versus LG/CT/FCT groups. A synbiotic combination (FCT) down-regulated pro-inflammatory cytokines (TNF-α, IFN-γ, IL-1β, and IL-6) and inflammation-associated enzymes (iNOS and COX-2), and up-regulated anti-inflammatory cytokines (IL-4 and IL-10). In addition, colon barrier experiment revealed that biomarkers of mucus layer (MUC-2 and TFF3) and tight junction (occludin and ZO-1) were up-regulated. Subsequent apoptosis experiment showed that pro-apoptotic factors (p53, p21, and Bax) were up-regulated and anti-apoptotic factors (Bcl-2 and Bcl-xL) were down-regulated. Furthermore, comparative metagenome analysis of gut microbiota revealed that Staphylococcus decreased but Lactobacillus, Bifidobacterium, and Akkermansia increased, supporting their protective effects, accompanied by increased short-chain fatty acids (SCFAs). Taken together, the FCT administration showed cancer-protective effects by reducing the risk of colitis-associated colon cancer via regulation of inflammation, carcinogenesis, and compositional change of gut microbiota. Consequently, the synbiotic combination (FCT) could be a novel potential health-protective natural agent against CAC.

Keywords: apoptosis; colorectal cancer; immune modulation; microbiome; synbiotics; tight junction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / metabolism
  • Apoptosis / drug effects
  • Cell Proliferation / drug effects
  • Colitis-Associated Neoplasms / drug therapy*
  • Colitis-Associated Neoplasms / immunology
  • Colitis-Associated Neoplasms / microbiology
  • Colitis-Associated Neoplasms / pathology
  • Colon / drug effects
  • Colon / metabolism
  • Colon / microbiology
  • Colon / pathology
  • Cultured Milk Products / analysis
  • Cultured Milk Products / microbiology
  • Cytokines / metabolism
  • Disease Models, Animal
  • Fatty Acids, Volatile / analysis
  • Feces / chemistry
  • Feces / microbiology
  • Gastrointestinal Microbiome / drug effects
  • Immunomodulation
  • Inflammation
  • Lactobacillus gasseri / physiology*
  • Maclura / chemistry*
  • Mice
  • Plant Extracts / therapeutic use*
  • Plant Leaves / chemistry
  • Synbiotics* / administration & dosage
  • Synbiotics* / analysis

Substances

  • Antioxidants
  • Cytokines
  • Fatty Acids, Volatile
  • Plant Extracts

Grants and funding

This work was supported by the grant of High Value-Added Food Technology Development Program of the Korea Institute of Planning and Evaluation for Technology in Food, Agriculture, Forestry, and Fisheries (iPET) and the Ministry for Food, Agriculture, Forestry, and Fisheries of the Republic of Korea (313036-03-2-SB010).