Tumour microbiomes and Fusobacterium genomics in Vietnamese colorectal cancer patients

Abstract

Perturbations in the gut microbiome have been associated with colorectal cancer (CRC), with the colonic overabundance of Fusobacterium nucleatum shown as the most consistent marker. Despite its significance in the promotion of CRC, genomic studies of Fusobacterium is limited. We enrolled 43 Vietnamese CRC patients and 25 participants with non-cancerous colorectal polyps to study the colonic microbiomes and genomic diversity of Fusobacterium in this population, using a combination of 16S rRNA gene profiling, anaerobic microbiology, and whole genome analysis. Oral bacteria, including F. nucleatum and Leptotrichia, were significantly more abundant in the tumour microbiomes. We obtained 53 Fusobacterium genomes, representing 26 strains, from the saliva, tumour and non-tumour tissues of six CRC patients. Isolates from the gut belonged to diverse F. nucleatum subspecies (nucleatum, animalis, vincentii, polymorphum) and a potential new subspecies of Fusobacterium periodonticum. The Fusobacterium population within each individual was distinct and in some cases diverse, with minimal intra-clonal variation. Phylogenetic analyses showed that within four individuals, tumour-associated Fusobacterium were clonal to those isolated from non-tumour tissues. Genes encoding major virulence factors (Fap2 and RadD) showed evidence of horizontal gene transfer. Our work provides a framework to understand the genomic diversity of Fusobacterium within the CRC patients, which can be exploited for the development of CRC diagnostic and therapeutic options targeting this oncobacterium.

The role of Fusobacteria in oral cancer and immune evasion

“…Another study reported similar results: Fusobacteria was higher in CRC than in tubular adenoma and sessile serrated adenoma/polyp [25]. Lastly, a recent study from Vietnam has shown that F. nucleatum were more abundant in tumor tissues compared to control in CRC patients [26 ]. Interestingly, Fusobacteria are conserved in CRC metastatic cancer cells.…”

Fusobacterium nucleatum subsp. polymorphum recovered from malignant and potentially malignant oral disease exhibit heterogeneity in adhesion phenotypes and adhesin gene copy number, shaped by inter-subspecies horizontal gene transfer and recombination-derived mosaicism

“…Previous work by Tran et al . has suggested that HGT may be responsible for fap2 and radD variation [66]. Here, we present analysis of TVa adhesin gene sequences that reveals highly mosaic gene structures shaped by recombination between different lineages of subspecies polymorphum and other F. nucleatum subspecies.…”

Crosstalk between microbial biofilms in the gastrointestinal tract and chronic mucosa diseases

“…FadA adhesin was found to bind to E-cadherin and further modulate E-cadherin/β-catenin signaling to induce adenomatous polyposis coli mutation ( Rubinstein et al, 2013 ). Moreover, in both periodontal disease and CRC, FadA forms functional amyloid-like assemblies that serve as a scaffold to facilitate biofilm formation and confer acid tolerance ( Meng et al, 2021 ; Tran et al, 2022 ). Studies of F. nucleatum as a sole initiator have shown that it promotes oncogenesis via a variety of pathways, including upregulating CRC cell glycolysis and activating TLR4 signaling to manipulate the expression of miRNA21, which results in the proliferation of CRC cells in the murine model ( Yang et al, 2017 , p. 21; Hong et al, 2021 ).…”