Fusobacterium nucleatum - symbiont, opportunist and oncobacterium

Abstract

Fusobacterium nucleatum has long been found to cause opportunistic infections and has recently been implicated in colorectal cancer; however, it is a common member of the oral microbiota and can have a symbiotic relationship with its hosts. To address this dissonance, we explore the diversity and niches of fusobacteria and reconsider historic fusobacterial taxonomy in the context of current technology. We also undertake a critical reappraisal of fusobacteria with a focus on F. nucleatum as a mutualist, infectious agent and oncogenic microorganism. In this Review, we delve into recent insights and future directions for fusobacterial research, including the current genetic toolkit, our evolving understanding of its mechanistic role in promoting colorectal cancer and the challenges of developing diagnostics and therapeutics for F. nucleatum.

Fig. 1. The organizing role of Fusobacterium nucleatum in oral biofilms.

In oral biofilms (left panel, as visualized by combinatorial labelling and spectral imaging–fluorescence in situ hybridization (CLASI-FISH); right panel, schematic to demonstrate specific interactions), Fusobacterium nucleatum functions as a bridging organism that adheres first to early colonizers of the dental surface such as Streptococcus spp. One mechanism for this interaction is the binding of the RadD adhesin of F. nucleatum to the streptococcal adhesin SpaP. Two other fusobacterial adhesins, Aid1 and CmpA, have also been implicated in this interaction^,. Once adhered to the developing biofilm, F. nucleatum aggregates with the secondary colonizers such as P. gingivalis using the fusobacterial adhesins RadD, Fap2 and FomA^,–. RadD mediates additional interactions between F. nucleatum and Actinomyces naeslundii and between F. nucleatum and the fungus Candida albicans. Left panel reproduced with permission from ref., PNAS.

Fig. 2. oral and extraoral diseases associated with Fusobacterium nucleatum.

Fusobacterium nucleatum is one of the most commonly isolated oral bacteria in clinical infections, whether found alone or in polymicrobial infections (indicated by an asterisk). Unlike the related Fusobacterium necrophorum, for which a causative role in Lemierre syndrome is well established, whether F. nucleatum functionally contributes to each of these various diseases remains to be determined. We have scored the evidence linking F. nucleatum to the listed infections using a subjective assessment of both the breadth and depth of the existing literature with regard to isolation, association and experimental data in preclinical models. Beyond the oral cavity, there is the most mechanistic support for a role of F. nucleatum in adverse pregnancy outcomes and colorectal cancer. Further, the route of infection, oral or haematogenous, by which F. nucleatum may disseminate to these disparate sites remains to be clarified.

Fig. 3. Mechanisms by which Fusobacterium nucleatum may contribute to colorectal carcinogenesis.

Accumulating evidence suggests that Fusobacterium nucleatum influences many stages of colorectal cancer progression. First, F. nucleatum can increase cell proliferation in cancer cells through two distinct mechanisms: the binding of FadA to E-cadherin drives activation of the β-catenin and Wnt pathway, and activation of TLR4 and NF-κB results in increased expression of the oncogenic microRNA miR21 (ref.). These observations are supported by work in the Apc^Min/+ mouse model of intestinal tumorigenesis, in which F. nucleatum administration resulted in more aberrant crypt foci and high-grade dysplasia, both early stages of tumorigenesis. Once the tumour has developed, F. nucleatum can localize to the Gal-GalNAc-expressing tumour cells through binding of its Fap2 lectin, which results in enrichment of F. nucleatum. F. nucleatum functionally modifies the tumour microenvironment by influencing the accumulation of myeloid cells and blocking antitumoural immune responses of natural killer (NK) cells. F. nucleatum may also affect metastatic dissemination as it can be isolated from liver and lymph node metastases^,,. Once colorectal cancer is identified and treated, F. nucleatum is associated with increased risk of recurrence and the development of chemoresistance by suppressing specific miRNAs involved in autophagy. LPS, lipopolysaccharide.