title: Berberine may rescue Fusobacterium nucleatum-induced colorectal tumorigenesis by modulating the tumor microenvironment.
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.
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.|Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China.
authors.forename: Ya-Nan
authors.initials: YN
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Ta-Chung
authors.initials: TC
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Hui-Jun
authors.initials: HJ
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Tian-Tian
authors.initials: TT
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Hao-Yan
authors.initials: HY
authors.lastname: Chen
authors.affiliation: Shanghai Majorbio Bio-pharm Biotechnology Co. Ltd., Shanghai, China.
authors.forename: Hui-Fang
authors.initials: HF
authors.lastname: An
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Yu-Rong
authors.initials: YR
authors.lastname: Weng
authors.affiliation: Department of Medicine & Therapeutics, State Key Laboratory of Digestive Disease, Institute of Digestive Disease and LKS Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Clinical Laboratory, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
authors.forename: Wen-Xin
authors.initials: WX
authors.lastname: Qin
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Xiong
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Hong
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Jing-Yuan
authors.initials: JY
authors.lastname: Fang
mesh_terms: D000236:Adenoma / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D001599:Berberine / Q000494:pharmacology*; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005243:Feces / Q000382:microbiology; D005674:Fusobacterium Infections / Q000150:complications* / Q000382:microbiology; D016967:Fusobacterium nucleatum / Q000472:pathogenicity*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects*
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; D001599:Berberine
keywords: Fusobacterium nucleatum; berberine; colorectal tumorigenesis; intestinal microbiota; tumor-immune cytokine