Systematic Reviews
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 28, 2017; 23(48): 8626-8650
Published online Dec 28, 2017. doi: 10.3748/wjg.v23.i48.8626
Fusobacterium’s link to colorectal neoplasia sequenced: A systematic review and future insights
Hisham Hussan, Steven K Clinton, Kristen Roberts, Michael T Bailey
Hisham Hussan, Kristen Roberts, Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, United States
Hisham Hussan, Steven K Clinton, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, United States
Steven K Clinton, Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, United States
Michael T Bailey, Department of Pediatrics, OSU College of Medicine And Center for Microbial Pathogenesis, The Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, United States
Author contributions: Hussan H was involved in conception, design, systematic review of data, and drafting and critical revision of the manuscript; The above author had full access to all of the data in the study and takes responsibility for the integrity of the data; Roberts K performed an independent systematic review of the literature and contributed to critical review of the data and manuscript; Clinton SK and Bailey MT contributed to the design, interpretation of data, writing of the manuscript, and final review of the manuscript; all gave final approval of the submitted manuscript and take responsibility for the integrity of the work.
Conflict-of-interest statement: The authors do not have any relevant conflicts of interest (including relevant financial interests, activities, relationships, and/or affiliations).
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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/
Correspondence to: Hisham Hussan, MD, Assistant Professor, Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The Ohio State University Wexner Medical Center, 395 W 12th Ave, Suite 240, Columbus, OH 43210, United States. hisham.hussan@osumc.edu
Telephone: +1-614-2931576 Fax: +1-614-2938518
Received: July 30, 2017
Peer-review started: July 30, 2017
First decision: August 30, 2017
Revised: October 9, 2017
Accepted: November 8, 2017
Article in press: November 8, 2017
Published online: December 28, 2017
Processing time: 151 Days and 17.1 Hours
Abstract
AIM

To critically evaluate previous scientific evidence on Fusobacterium’s role in colorectal neoplasia development.

METHODS

Two independent investigators systematically reviewed all original scientific articles published between January, 2000, and July, 2017, using PubMed, EMBASE, and MEDLINE. A total of 355 articles were screened at the abstract level. Of these, only original scientific human, animal, and in vitro studies investigating Fusobacterium and its relationship with colorectal cancer (CRC) were included in the analysis. Abstracts, review articles, studies investigating other colonic diseases, and studies written in other languages than English were excluded from our analysis. Ninety articles were included after removing duplicates, resolving disagreements between the two reviewers, and applying the above criteria.

RESULTS

Studies have consistently identified positive associations between Fusobacterium, especially Fusobacterium nucleatum (F. nucleatum), and CRC. Stronger associations were seen in CRCs proximal to the splenic flexure and CpG island methylator phenotype (CIMP)-high CRCs. There was evidence of temporality and a biological gradient, with increased F. nucleatum DNA detection and quantity along the traditional adenoma-carcinoma sequence and in CIMP-high CRC precursors. Diet may have a differential impact on colonic F. nucleatum enrichment; evidence suggests that high fiber diet may reduce the risk of a subset of CRCs that are F. nucleatum DNA-positive. Data also suggest shorter CRC and disease-specific survival with increased amount of F. nucleatum DNA in CRC tissue. The pathophysiology of enrichment of F. nucleatum and other Fusobacterium species in colonic tissue is unclear; however, the virulence factors and changes to the local colonic environment with disruption of the protective mucus layer may contribute. The presence of a host lectin (Gal-GalNAc) in the colonic epithelium may also mediate F. nucleatum attachment to CRC and precursors through interaction with an F. nucleatum protein, fibroblast activation protein 2 (FAP2). The clinical significance of detection or enrichment of Fusobacterium in colorectal neoplasia is ambiguous, but data suggest a procarcinogenic effect of F. nucleatum, likely due to activation of oncogenic and inflammatory pathways and modulation of the tumor immune environment. This is hypothesized to be mediated by certain F. nucleatum strains carrying invasive properties and virulence factors such as FadA and FAP.

CONCLUSION

Evidence suggests a potential active role of Fusobacterium, specifically F. nucleatum, in CRC. Future prospective and experimental human studies would fill an important gap in this literature.

Keywords: Colon microbiota; Fusobacterium; Systematic; review; Fusobacterium nucleatum; Colorectal cancer; Colorectal polyps; Carcinogenesis

Core tip: This is, to our knowledge, the first review to systematically examine the heterogeneous literature linking Fusobacterium to colorectal neoplasia. Accumulating evidence suggests that Fusobacterium, specifically Fusobacterium nucleatum (F. nucleatum), is more frequently detected in colorectal neoplasia, especially the pathway involving microsatellite instability. Multiple observational and animal experimental studies also suggest a procarcinogenic effect of F. nucleatum, likely due to activation of oncogenic and inflammatory pathways and modulation of the tumor immune environment. Virulence factors of F. nucleatum may contribute to its procarcinogenic effect. This information may be used to create novel strategies targeting colorectal cancer detection and chemoprevention.