Published online Dec 28, 2017. doi: 10.3748/wjg.v23.i48.8626
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
The presence of Fusobacterium, specifically Fusobacterium nucleatum (F. nucleatum), in the colon is increasingly linked to colorectal cancer (CRC). However, significant heterogeneity in study methods and findings poses challenges to interpretation. An evaluation of this rapidly expanding literature will help direct future studies to answer unresolved questions and to avoid previous design pitfalls in order to further our knowledge in this exciting field.
A critical evaluation of the scientific literature regarding the link between Fusobacterium/F. nucleatum and CRC may contribute to the development of more comprehensive and novel studies to better define this relationship and its potential applications in CRC treatment and prevention.
This systematic review evaluated the clinical and experimental evidence linking Fusobacterium and CRC. The authors reviewed studies investigating the relationship between Fusobacterium and the following variables: CRC, CRC patients’ characteristics and dietary patterns, CRC anatomic location, CRC molecular features, and CRC stage and prognosis. The authors also reviewed studies looking at presence of Fusobacterium in pre-neoplastic lesions, as well as experimental evidence testing the procarcinogenic potential of Fusobacterium. Finally, the authors looked at the implications of Fusobacterium for CRC detection and treatment. Elucidating these heterogeneous studies may impact our understanding of the relationship between Fusobacterium and CRC, as well as improve detection and chemoprevention tactics for CRC.
This is, to our knowledge, the first systematic review of the scientific evidence surrounding the link between Fusobacterium and CRC. Using PubMed, Embase, and Medline, the authors systematically reviewed all original studies investigating Fusobacterium/F. nucleatum and CRC published between January 1st, 2000, and July 1st, 2017. All abstracts were screened to identify original human, animal, and in vitro research. Out of the 355 articles that were screened, 90 articles were included in this review. Articles were excluded if diseases other than CRC were included and if they were written in languages other than English. All review articles and citations including only an abstract were excluded from analysis.
An accumulating body of evidence supports the hypothesis that Fusobacterium, especially F. nucleatum is more frequently detected in colorectal neoplasia, especially the microsatellite instability neoplastic pathway and proximal CRC. Studies investigating F. nucleatum in colorectal precancerous tissue suggest temporality and a biological gradient; however, ambiguity still exists on whether this increased detection of Fusobacterium is a cause or consequence of colorectal neoplasia. Diet may have a differential impact on colonic F. nucleatum enrichment, high fiber diet potentially reducing the risk of a subset of CRCs that are F. nucleatum-positive. Evidence also suggests a shorter CRC disease-specific survival in the presence of F. nucleatum, albeit with no relations between F. nucleatum and CRC staging. The homing of Fusobacteria and F. nucleatum to the colonic epithelium maybe partly due to increased Gal-GalNAc expression on colonic cells, virulence factors of F. nucleatum and other Fusobacteria, and changes to the local colonic environment with disruption of the protective mucus layer. Experimental evidence suggests that Fusobacterium nucleatum has a procarcinogenic potential that is likely mediated by activation of oncogenic and inflammatory pathways, as well as modulation of the tumor immune environment. The lack of prospective human studies is a large limitation of current literature. Furthermore, it will be essential to further delineate mechanisms and timing of Fusobacterium homing to the colonic mucosa, as well as its relation to cancer progression. This review may be used to develop hypotheses for novel strategies targeting colorectal cancer detection and prevention. Future robust analysis would also benefit from adjusting for confounders, such as Fusobacterial strain virulence factors, colonic preparation, antibiotic use, and diet.
Accumulating evidence supports the hypothesis that F. nucleatum may enhance colorectal carcinogenesis, especially the neoplastic pathway involving defects in microsatellite instability. Virulence factors of F. nucleatum may contribute to its procarcinogenic effect. The lack of prospective human studies is a large limitation of current literature regarding the link between Fusobacterium and CRC. This review may be used to guide novel strategies targeting colorectal cancer detection and prevention.
This review gathers an ample evidence implicating Fusobacterium in CRC etiology and highlights the promising global efforts aimed at testing the role of Fusobacterium in CRC detection, chemoprevention and outcomes. There are multiple gaps in knowledge and the current evidence lacks prospective human studies. To advance our knowledge, future prospective studies need to clarify the timing and mechanisms of Fusobacterium transmission to the colon in relation to colorectal carcinogenesis and histopathology of these findings. In order to potentially design future CRC therapies, additional investigations are also warranted to delineate the relationships between virulent Fusobacterium strains, specifically F. nucleatum, and induction of inflammatory, pro carcinogenic and immune mechanisms involved in early colorectal carcinogenesis. Furthermore, future efforts need to prospectively test the impact of diet, probiotics and other chemopreventative agents on colonic Fusobacterium and whether modulation of colonic presence/concentrations of Fusobacterium will alter the risk or outcomes of CRC. Finally the role of Fusobacterium in CRC screening is intriguing and studies combing Fusobacterium testing with other CRC screening methods such as stool DNA testing or even colonoscopy may potentially improve CRC detection and preventative efforts. This study outlines the significant heterogeneity in the methods used and the need for more consistent design. In order to attain more robust results, the authors suggest future studies to: (1) use a blinded prospective randomized controlled design and/or large sample size when possible; (2) perform better sampling by collecting unprepared colonic tissue stored as fresh frozen samples; (3) have more detailed microbiome sequencing using whole-genome shotgun metagenomic sequencing, FISH and other methods in order to assess Fusobacterium sub-species concentrations, the presence of virulence factors and location of Fusobacterium in relation to the colonic epithelium; and (4) adjust for potential dietary, geographic and racial variables that may have an impact on Fusobacterium/F. nucleatum presence or concentration within specimens.