Rationale
In 2012, over a million new cases of colorectal cancer (CRC) and more than half a million deaths due to CRC were estimated to occur globally [
1]. Of cancers that affect both men and women, CRC is the third most commonly diagnosed malignancy and the fourth most fatal in the world [
2]. The numbers of new cases of CRC and CRC deaths are expected to increase to 60% by 2030 [
2].
The etiology of CRC is widely recognized as being multifactorial [
3,
4], and previous research has suggested that modification of environmental and lifestyle factors can lead to important changes in cancer risk [
5,
6]. Still, according to comprehensive reviews of the available evidence conducted by expert panels from the American Institute for Cancer Research and the World Cancer Research Fund, the overall evidence for the causal nature of the association with CRC is considered convincing for only some of the previously suggested factors, namely, excess body fat, consuming processed meats and red meat, physical inactivity, cigarette smoking, and alcohol consumption [
7]. For the majority of the putative risk factors, the level of evidence is considered either fair or inadequate [
7‐
10]. Thus, identification of modifiable risk factors that could serve as targets for preventive interventions is a current public-health priority.
In the past few years, advances in high-throughput sequencing technologies have led to important discoveries on the role of gut microbial dysbiosis and specifically, of Fusobacterium nucleatum (F
. nucleatum) in colorectal carcinogenesis [
11‐
21]. F
. nucleatum is a Gram-negative, non-spore-forming anaerobic bacterium commonly found in saliva and oral biofilm [
18,
22,
23] . It is one of the dominant species of more than 500 organisms of the oral cavity and has five subspecies with different specific genome sequences [
24‐
31]. This invasive proinflammatory agent is involved in the pathogenesis of periodontal diseases [
22] as well as of other oral [
32] and extra-oral infections [
33,
34]. F
. nucleatum can independently invade host cells via surface adhesins and invasion molecules such as FadA [
21,
35]. Importantly, once disseminated outside the oral cavity, FadA activates proinflammatory and oncogenic signals and stimulates the growth of epithelial cells. Human studies have demonstrated that the FadA gene level in CRC tissue is higher than in normal tissue and is correlated with expression of inflammatory genes [
21]. Furthermore, a recent study found a strong correlation between F
. nucleatum and proinflammatory markers such as COX-2, IL-8, IL-6, IL1ß, and TNF-α in CRC [
15]. This evidence suggests that colonization resistance of the healthy gut can be disrupted by bacterial species that trigger a systematic inflammatory response, such as seen in periodontal disease. In a study by Dejea et al. [
36], the rate of CRC occurrence was more than five times as high in individuals with gut bacterial biofilms as in those without them [
36]. Interestingly, the gut bacterial biofilm composition and invasiveness were similar to those found in oral biofilm in periodontal disease, with
Fusobacteria being a dominant species [
36].
F
. nucleatum is now considered to be a pathogenic bacterium of the gut that can invade the colorectal submucosa and epithelium. Various studies have shown an overabundance of F
. nucleatum in tumors and fecal samples [
37] of CRC patients [
15,
17,
19‐
21,
38] . Additionally, some studies have demonstrated that levels of F.
nucleatum increased in parallel with the transition from healthy colorectal tissue to adenomas and finally to CRC [
39‐
41]. F.
nucleatum levels in cancerous colorectal tissue have also been shown to serve as a prognostic indicator in CRC [
11,
39,
42]. In vitro and in vivo studies showed that F
. nucleatum interrupts oncogene signaling and cell–cell adhesion and inhibits the anti-tumor activities of natural killer and cytotoxic T cells as well as anti-tumor immunity [
38,
43]. Increased levels of F
. nucleatum have been shown to be associated with microsatellite instability and molecular subsets of CRCs such as the CpG island methylator phenotype [
11,
44]. Decreased expression of MLH1, a primary cause of microsatellite instability, was found in samples abundant in F.
nucleatum [
13,
42]. Other markers of poor prognosis such as KRAS and BRAF are also overexpressed in samples rich in F.
nucleatum [
13,
45,
46]. Moreover, CRC patients have been found to have an increased level of serum anti-F
. nucleatum antibodies [
47].
The literature on the association between F. nucleatum and CRC is growing but has not yet been systematically reviewed to date. We aim to conduct a systematic review of observational studies on the association between F. nucleatum and CRC.