Berberine May Rescue Fusobacterium Nucleatum-Induced Colorectal Tumorigenesis by Modulating the Tumor Microenvironment

Oncotarget. 2015 Oct 13;6(31):32013-26. doi: 10.18632/oncotarget.5166.

Abstract

Background: Accumulating evidence links colorectal cancer (CRC) with the intestinal microbiota. However, the disturbance of intestinal microbiota and the role of Fusobacterium nucleatum during the colorectal adenoma-carcinoma sequence have not yet been evaluated.

Methods: 454 FLX pyrosequencing was used to evaluate the disturbance of intestinal microbiota during the adenoma-carcinoma sequence pathway of CRC. Intestinal microbiota and mucosa tumor-immune cytokines were detected in mice after introducing 1,2-dimethylhydrazine (DMH), F. nucleatum or Berberine (BBR), using pyrosequencing and Bio-Plex Pro™ cytokine assays, respectively. Protein expressions were detected by western blotting.

Results: The levels of opportunistic pathogens, such as Fusobacterium, Streptococcus and Enterococcus spp. gradually increased during the colorectal adenoma-carcinoma sequence in human fecal and mucosal samples. F. nucleatum treatment significantly altered lumen microbial structures, with increased Tenericutes and Verrucomicrobia (opportunistic pathogens) (P < 0.05 = in wild-type C57BL/6 and mice with DMH treatment). BBR intervention reversed the F. nucleatum-mediated increase in opportunistic pathogens, and the secretion of IL-21/22/31, CD40L and the expression of p-STAT3, p-STAT5 and p-ERK1/2 in mice, compared with mice fed with F. nucleatum alone.

Conclusions: F. nucleatum colonization in the intestine may prompt colorectal tumorigenesis. BBR could rescue F. nucleatum-induced colorectal tumorigenesis by modulating the tumor microenvironment and blocking the activation of tumorigenesis-related pathways.

Keywords: Fusobacterium nucleatum; berberine; colorectal tumorigenesis; intestinal microbiota; tumor-immune cytokine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma / etiology
  • Adenoma / pathology
  • Adenoma / prevention & control*
  • Animals
  • Berberine / pharmacology*
  • Blotting, Western
  • Cell Transformation, Neoplastic / drug effects*
  • Cell Transformation, Neoplastic / pathology
  • Colorectal Neoplasms / etiology
  • Colorectal Neoplasms / pathology
  • Colorectal Neoplasms / prevention & control*
  • Cytokines / genetics
  • Cytokines / metabolism
  • Feces / microbiology
  • Fusobacterium Infections / complications*
  • Fusobacterium Infections / microbiology
  • Fusobacterium nucleatum / pathogenicity*
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured
  • Tumor Microenvironment / drug effects*

Substances

  • Cytokines
  • RNA, Messenger
  • Berberine