Fusobacterium’s link to colorectal neoplasia sequenced: A systematic review and future insights

Abstract

AIMTo critically evaluate previous scientific evidence on Fusobacterium’s role in colorectal neoplasia development.METHODSTwo 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.RESULTSStudies 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.CONCLUSIONEvidence 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.

Specific Bacteria and Metabolites Associated With Response to Fecal Microbiota Transplantation in Patients With Ulcerative Colitis

“…31 The latter has also been proposed as an etiological agent in colorectal cancer. [34][35][36][37][38] F nucleatum and Fusobacterium necrophorum have been implicated in acute appendicitis, 39 with an inverse relationship between previous appendectomy and the incidence of UC reported. 40 Prevotella species dominance (specifically P copri) was a prominent feature in many patients during and after FMT therapy, often associated with decreased Bacteroides in the enteric microbiota.…”

Colorectal Cancer: Genetic Abnormalities, Tumor Progression, Tumor Heterogeneity, Clonal Evolution and Tumor-Initiating Cells

“…Some bacterial species seem particularly prone to favoring colorectal cancer development. In this context, several studies have suggested a positive association between Fusobacterium and, particularly, Fusobacterium nucleatum and colorectal cancer development [ 507 ]. Even stronger associations were observed in colorectal cancers proximal to the splenic flexure and CIMP-high colorectal cancers [ 507 ].…”

“…In this context, several studies have suggested a positive association between Fusobacterium and, particularly, Fusobacterium nucleatum and colorectal cancer development [ 507 ]. Even stronger associations were observed in colorectal cancers proximal to the splenic flexure and CIMP-high colorectal cancers [ 507 ]. Additional data also suggested shorter overall survival in patients with increased Fusobacterium nucleatum DNA in the tumoral tissue [ 507 ].…”

“…Even stronger associations were observed in colorectal cancers proximal to the splenic flexure and CIMP-high colorectal cancers [ 507 ]. Additional data also suggested shorter overall survival in patients with increased Fusobacterium nucleatum DNA in the tumoral tissue [ 507 ]. The mechanisms responsible for the enrichment of Fusobacterium nucleatum in colon cancer tissues are unclear but could be related to changes in the colon microenvironment [ 507 ].…”

Antibody Responses to Fusobacterium nucleatum Proteins in Prediagnostic Blood Samples are not Associated with Risk of Developing Colorectal Cancer

“…Several studies reported an overabundance of Fusobacterium nucleatum (F. nucleatum) in stool and tumor tissue of patients with colorectal cancer (1,2). Although mechanistic studies suggest an etiologic role of the bacterium in colorectal carcinogenesis, it remains possible that it is simply an opportunistic passenger within developing tumors (1).…”