Colon Cancer-Associated Fusobacterium nucleatum May Originate From the Oral Cavity and Reach Colon Tumors via the Circulatory System

Abstract

Fusobacterium nucleatum is a common oral bacterium that is enriched in colorectal adenomas and adenocarcinomas (CRC). In humans, high fusobacterial CRC abundance is associated with chemoresistance and poor prognosis. In animal models, fusobacteria accelerate CRC progression. Targeting F. nucleatum may reduce fusobacteria cancer progression and therefore determining the origin of CRC F. nucleatum and the route by which it reaches colon tumors is of biologic and therapeutic importance. Arbitrarily primed PCR performed previously on matched same-patients CRC and saliva F. nucleatum isolates, suggested that CRC F. nucleatum may originate from the oral cavity. However, the origin of CRC fusobacteria as well as the route of their arrival to the tumor have not been well-established. Herein, we performed and analyzed whole genome sequencing of paired, same-patient oral, and CRC F. nucleatum isolates and confirmed that CRC-fusobacteria originate from the oral microbial reservoir. Oral fusobacteria may translocate to CRC by descending via the digestive tract or using the hematogenous route during frequent transient bacteremia caused by chewing, daily hygiene activities, or dental procedures. Using the orthotropic CT26 mouse model we previously showed that IV injected F. nucleatum colonize CRC. Here, we compared CRC colonization by gavage vs. intravenous inoculated F. nucleatum in the MC38 and CT26 mouse orthotropic CRC models. Under the tested conditions, hematogenous fusobacteria were more successful in CRC colonization than gavaged ones. Our results therefore provide evidence that the hematogenous route may be the preferred way by which oral fusobacteria reach colon tumors.

The dysbiosis signature of Fusobacterium nucleatum in colorectal cancer-cause or consequences? A systematic review

“…Studies show that cancerous tissues contain significantly more Fusobacteria [ 73 ]. Previous research has indicated that infection with this bacterium increases the incidence of ulcerative colitis in which inflammation of the intestinal lining destroys the intestinal cells and consequently is a risk factor for colorectal cancer [ 27 ].…”

Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities

“…The notion that CRC-associated F. nucleatum originates from the oral cavity is supported by findings that identical strains of this organism are detected in the saliva and colorectal tumours of patients with CRC 115 . Oral F. nucleatum can haematogenously reach the colon 116 , where it exhibits tropism for CRC. This is because CRC cells overexpress a carbohydrate moiety (Gal-GalNAc) that is bound by the F. nucleatum lectin Fap2 (ref.…”

The Potential of Colonic Tumor Tissue Fusobacterium nucleatum to Predict Staging and Its Interplay with Oral Abundance in Colon Cancer Patients

“…However, it is not yet clear how Fn reaches the colon from the oral cavity. Recently some authors reported that Fn may migrate to the colon by descending via the digestive tract or using the circulation system during transient bacteriemia [ 60 , 61 ]. The digestive route would be possible in the case of patients taking drugs that reduce gastric acidity, in this way allowing bacteria to migrate to the colon.…”