부산대학교 도서관

Fusobacterium nucleatum(Fn), a bacterium present in the human oral cavity and rarely found in the lower gastrointestinal tract of healthy individuals1, is enriched in human colorectal cancer (CRC) tumours2–5. High intratumoural Fnloads are associated with recurrence, metastases and poorer patient prognosis5–8. Here, to delineate Fngenetic factors facilitating tumour colonization, we generated closed genomes for 135 Fnstrains; 80 oral strains from individuals without cancer and 55 unique cancer strains cultured from tumours from 51 patients with CRC. Pangenomic analyses identified 483 CRC-enriched genetic factors. Tumour-isolated strains predominantly belong to Fnsubspecies animalis(Fna). However, genomic analyses reveal that Fna, considered a single subspecies, is instead composed of two distinct clades (FnaC1 and FnaC2). Of these, only FnaC2 dominates the CRC tumour niche. Inter-Fnaanalyses identified 195 FnaC2-associated genetic factors consistent with increased metabolic potential and colonization of the gastrointestinal tract. In support of this, FnaC2-treated mice had an increased number of intestinal adenomas and altered metabolites. Microbiome analysis of human tumour tissue from 116 patients with CRC demonstrated FnaC2 enrichment. Comparison of 62 paired specimens showed that only FnaC2 is tumour enriched compared to normal adjacent tissue. This was further supported by metagenomic analysis of stool samples from 627 patients with CRC and 619 healthy individuals. Collectively, our results identify the Fnaclade bifurcation, show that specifically FnaC2 drives the reported Fnenrichment in human CRC and reveal the genetic underpinnings of pathoadaptation of FnaC2 to the CRC niche.